Diuretics Merged

Diuretic drugs
Diuretics exert their effect directly on the

kidneys. Most of them lead to electrolyte
excretion and
Hydrochlorothiazide Amiloride
consequently to Chlorthalidone Triamterene
Indapamide Spironolactone
osmotic excretion
of water, which
increases the
24-hr
urine volume. Mannitol
Acetazolamide
Furosemide
Furosemide
Torsemide
Torsemide
Diuretics
• Carbonic anhydrase inhibitors

• Loop diuretics
• Thiazides
• Potassium-sparing diuretics
• Osmotic diuretics
• ADH antagonists
1. Carbonic anhydrase inhibitors
Acetazolamide inhibits carbonic

anhydrase (CA) mainly in proximal tubules.
CA
H2O + CO2 H2CO3 H2CO3– + H+
Proximal tubule
Lumen
Acetazolamide
Acetazolamide has weak diuretic action.
It significantly enhances urine K+ excretion.
The loss of HCO3– anions decreases blood
alkaline reserve (for 48-72 h) and causes
metabolic acidosis. In this state the drug
becomes ineffective.
Acetazolamide blocks not only renal CA, but

also CA in the ciliary body in the eye
(reducing production of eye liquid) and in the
brain (facilitates GABA synthesis).
Acetazolamide
• Inhibitor of the carbonic acid anhydrase
• Causes the inhibition of the bicarbonate reabsorption in the proximal tubule
 bicarbonate loss via urine – ↑ pH urine within 0,5-2h and persists 12h
– Result: hyperchloremic metabolic acidosis
• Diuretic (natriuretic) effect is limited
– compensated within the distal parts of the nephron
– decrease of the effect within few days of the treatment
• Indication
– Glaucoma treatment (shorter treatment, before surgery)
carbonic acid anhydrase is also in the cilliary body to control secretion of the
bicarbonate and Na into the aqueous humour
acetolazamide decreases the intraocular humour production  decreases intraocular
pressure
– Local glaucoma treatment – dorzalamide
– Alkalization of the urine – e.g., in cysteinuria (excretion facilitation)
– Metabolic alkalosis in patients suffering from HF and oedema when standard
treatment employing volume correction is not applicable
Acetazolamide – adverse reactions
• Hyperchloremic metabolic acidosis
– Predictable loses of the HCO3- stores – limitation for both
long term safety and efficacy of the treatment
• Phosphaturia and hypercalciuria, nephrolithiasis
– higher concentration of the salts and their lower solubility in the alkaline
environment
• Potassium wasting resulting into the hypokalaemia

• Contraindications – hepatic encephalopathy
– alkalization of the urine
 lower NH4 excretion which may further contribute to the
hyperammoneamia and hepatic encephalopathy in patients with cirrhosis
2. Loop Diuretics
Torasemide
Loop of Henle
Lumen
Furosemide
Loop diuretics
1. Renal effects (within 10 min after i.v. administration, but quite short-
term effect: furosemide 2-3 h)
a) Inhibition of Na+/K+/2Cl- re-uptake
b) Decrease the lumen-positive potential that comes from K+
recycling
 decreased reabsorption divalent cationts, resulting into the
hypocalcaemia and hypomagnesaemia
a) Increased prostaglandine synthesis – improved renal perfusion
2. Extrarenal effects
– Vasodilation (venous system) – important in i.v. treatment of
acute pulmonary oedema, where it can overtake the urinary
effects – incompletely understand mechanisms
– Decreased preload and filling pressures in RV and later also in
LV – important in HF
– Decreased pulmonary congestion/oedema
Loop diuretics
Pharmacokinetics
• Oral administration (quite good absorption, torasemide is
absorbed faster than furosemide)
• I.V. in urgent cases
• High plasma protein binding
• Renal elimination – GF (limited) + tubular secretion
• Effect duration – quite short (2-3 h furosemide),
torasemide is longer (4-6h) and it has an active metabolite
• Tubular secretion can be decreased by the
competition due to the competition with other drugs
(e.g., NSAID)
Loop diuretics – indications
• Acute pulmonary oedema – i.v. treatment
Active tubular secretion makes it useful even in shock-like
• CHF (esp. with signs of blood congestion)
– Decreased Na+ retention, intravascular volume and preload and reduction of oedema, improve
symptoms.
• Other diseases with fluid/sodium retention and oedema
E.g. In the liver disease associated with ascites etc.
• Acute renal failure – useful even when Clcr is below 30 ml/min. (in high DD, together with
mannitol)
– For prevention of Na/fluid retention with oligouria/anuria
For flush-out of intratubular casts arising from haemolysis or rhabdomyolysis
• Eclampsia
• Forced diuresis in acute intoxications
• Acute hypercalcemia (accompanying small cell lung cancer)
• Hyperkalaemia
• Hypertension – only when associated with renal/heart failure
Loop diuretics – adverse reactions
• Hypokalemia – hypokalemic metabolic alkalosis
– ↓ Na reabsorption in the Loop  ↑ Na concentrations in collecting tub.  ↑
reabsorption, but in exchange for K+  K+ wasting (H+)
– Increased risk of potentially fatal ventricular arrhythmias
– Prevention – low NaCl diet, K+ compensation (KCl) or combination with K+
sparring diuretics
• Hypomagnesemia – predictable, esp. in patients with dietary deficit
• Hypocalcemia
• Hypovolemia (diuresis up to 4 L/24 h), dehydratation, hypotension
• Ototoxicity Ototoxic risk is increased in co-medicaton with aminoglycosides,
cephalosporines, polymyxins, sulfonamides or quinolones.
• Hyperuricemia and gout precipitation – also attributable to hypovolemia
• Hyperglycemia
• Allergic reactions – sulfonamide moiety
- skin rashes, eosinophilia, exceptionally interstitial nephritis
Loop diuretics
contraindications
• Electrolyte imbalance
– hyponatraemia, hypokalaemia, hypochloremic alkalosis,
hypotension
• Liver failure with impaired consciousness

– the risk of profound hypokalaemia
• Hypersensitivity to furosemide
– cross-hypersensitivity with sulfonamides
Furosemide enhances the action of antihypertensive drugs and non-

depolarazing neuromuscular blockers
3. Salidiuretics
(thiazides and their analogues)
They increase equivalently Na+ and Cl-
excretion (1:1) in distal renal tubules and
this increases diuresis. They lead to
excretion of 5 to 10% from filtrated Na+ ions
and have moderate diuretic action. They
can be classified as sulfonamides with free
–NH2 group, without antimicrobial activity.
Salidiuretics (saluretics)
Thiazides Thiazide analogues

•Hydrochlorothiazide •Clopamide
•Cyclopenthiazide •Chlorthalidone
Vasodilators with antihypertensive effect

•Indapamide (stimulates synthesis of renal PGs
with vasodilating action)
Distal tubule
Distal tubule
Lumen
Thiazides
Indapamide SR
(does not have Hydrochlorothiazide
metabolic effects) Chlorthalidone
•cardioprotector
•nephroprotector
Indapamide
5-10%
Thiazide diuretics
structure and pharmacokinetics
• Thiazides – sulfonamide structure
- indapamide and metipamide have different structure
• All of them can be given orally
– daily treatment, long treatment
• Different T1/2,
– hydrochlorothiazide (12h), others (>24h)
• All of them are secreted actively by tubular secretion
• Indapamide and metipamide are mainly excreted by the
liver, but sufficient amount can get into the kidney
Thiazides
pharmacodynamics
1. Renal effects
– Inhibition of Na+ reabsorption in the distal tubule –
decreased Na retention and intravascular volume
– natriuretic and diuretic effects are less pronounced
than those of loop diuretics.
– increased Ca2+ reabsorption
2. Extrarenal effects
– Decreased preload and consequently also afterload
– Indapamide and metipamide have also direct
vasodilating effects
Thiazides have a weak antihypertensive
effect because they reduce arterial wall
sensitivity to NA (noradrenaline) and AT
(Angiotensin).
They potentiate significantly the effect
of other antihypertensive drugs.
Thiazides increase plasma renin levels.
“Paradoxal” antidiuretic effect in diabetes
insipidus: Thiazides decrease GF (glomerular
filtration). Kidney does not respond to ADH.
Thiazide diuretics
Indications
• Arterial hypertension
• Chronic heart failure (rather milder
forms)
• Recurrent nephrolithiasis arising from
idiopathic hypercalciuria
• Might be useful in patient with
osteoporosis
• Nephrogenic diabetes insipidus
Thiazide diuretics
adverse effects
• Hypokalaemia and metabolic hypochloremic alkalosis
– the mechanism of development is the same as loop
diuretics:
– ↓ Na reabsorption  ↑ Na concentrations in collecting tub.  ↑ reabsorption, but in
exchange for K+  K+ wasting (H+)
– Increased risk of potentially fatal ventricular arrhythmias
– Prevention – low NaCl diet, K+ compensation (KCl) or combination with K+ sparring
diuretics
• Impaired glucose tolerance

– Link to hypokalemia which may decrease insulin secretion. Dose and correction.
• Dyslipidemia – increased total cholesterol and LDL,

potentially triglycerides
• Muscle weakness and fatigue, impotence
Thiazide diuretics
adverse effects
• Hyperuricemia – competition for secretion transporters
with uric acid (prevention/correction with allopurinol)
• Hyponatraemia, hypovolaemia
• GI disorders, photosensibilization
• Allergic reaction
– sulfonamide structure, skin rashes, very rarely haemolytic
anaemia
• They reduce plasma volume in pregnant women and

decrease fetal oxygenation (PRC: D)
Low doses used in hypertension (e.g., 6.25/12.5-25mg/day)
– still good therapeutic response along with much less complications
4. Potassium- Amiloride
Triamterene
sparing diuretics Spironolactone
3%
Often they are used

They have weak
in combination with
diuretic action
diuretics, causing
and save K+.
hypokalaemia.
Potassium-sparing diuretics
Competitive Blockers of the

aldosterone amiloride-sensitive
antagonists: Na+ channels:
•Spironolactone •Amiloride
•Triamterene
Potassium-sparring diuretics
Collecting tubule
Lumen
Amiloride
Triamterene
Spironolactone
• PD effects:
– Decreased Na+ reabsorption in the collecting tubule with
slightly increased natriuresis
– Decreased K+ secretion (excretion) into the lumen of the
collecting tubule
• Overall diuretic effect – relatively small
• PK
– Amiloride – p.o., slower onset of action (peak at 6h, duration
24h)
– Spironolactone – short T1/2, but its active metabolite canrenone
(T1/2 = 16h) is responsible for most of the drug´s effects
– Eplerenon – once daily, p.o., no active metabolites
indications
• In combination with other diuretics
– To effectively prevent K+ wasting (hypokalaemia) in patients
on low NaCl diet
– As alternative to long term KCl supplementation (it is not as
practical, poor compliance)
• Spironolactone and eplerenone

– Primary and secondary hyperaldosteronism (e.g., induced by liver
cirrhosis)
– to prevent excessive Na+ and extravascular fluid retention
– Chronic heart failure – moderate to severe forms
• in addition to other drugs
• Improve symptoms and prognosis
• Prevent and regress pathological remodelling of the heart and vessels
adverse effects
• Hyperkalemia
– dose dependent
– It is very likely to develop in combination with other
drugs with antialdosterone effects – ACE-inhibitors,
beta-blockers or K+ supplementation
• Hyperchloremic metabolic acidosis
• Spironolactone
– gynaecomastia, menstrual disorders etc (much less in
eplerenon)
Spironolactone is a steroid compound,
which is a competitive aldosterone antagonist.
It increases Na+ excretion and decreases K+
and urea excretion. Its diuretic action is
weak and is achieved slowly.
Spironolactone is effective in oedemas,
caused by increased production of
aldosterone ascites in liver cirrhosis and
oedemas in congestive heart failure.
Spironolactone in low doses (25 mg/24 h)
potentiates the effect of ACE inhibitors. It
saves K+ and Mg2+ ions and has antiarrhyth-
mic effect. It also prevents the development of
myocardial fibrosis, caused by aldosterone
and in this way contributes to enhancing
myocardial contractility.
Diuretidin®
(triamterene/hydrochlorothiazide)
is indicated in oedemas cardiac, renal,
liver or other origin and for the
treatment of hypertension with
other antihypertensive drugs.
Moduretic®
(amiloride/hydrochlorothiazide)
has the same indications too.
5. Osmotic diuretics
60-80%
After oral administration Mannitol is not
absorbed and has laxative effect.
After i.v. administration it is not
metabolized, it filtrates in the glomerulus
and not reabsorbed in renal tubules,
causing increased osmotic pressure and
excretion of isoosmotic equivalent of
water.
It increases blood flow in 30%.
Мannitol does not influence renin
synthesis.
Osmotic diuretics
Mannitol 10-20% solution
• Osmotically active agent without any specific pharmacological action
• Non-reabsorbable osmotically active agent
– administered i.v.
– significantly increase diuresis via water excretion along with minor Na+ excretion
• They act mostly in proximal tubule and thin descendent limb of the loop – where
the nephron is penetrable for water
Indications
– Enhance water excretion without loss of Na+ (lack of natriuretic action). The treatment
of initial stages of acute renal failure, chronic renal failure, intoxications with drugs,
excreted in the urine
– Different clinical use than in other diuretics (and rather limited)
• To decrease intracranial or intraocular pressures (brain oedema, glaucoma)
– they enter neither eye nor brain, they just increase plasma osmolality and this result in
the extraction of water from these compartments
• to prevent anuria in acute renal failure (due to the pigment load – hemolysis,
rhabdomyolysis, infections or hemorrhage)
Osmotic diuretics
adverse reactions
• water extraction from the intracellular compartment
• expansion of the intravascular and interstitial fluid
volume
• Hyponatremia
– dilution by water extracted from the tissues (in impaired kidney
functions)
• Complications
– Acute pulmonary edema
– HF
– Common: headache, nausea, vomiting
– Overdose: dehydratation, hypernatremia
6. ADH Agonists
and
Antagonists
ADH Agonists
• Vasopressin and desmopressin are
used in the treatment of central diabetes
insipidus.
• The renal action appears to be mediated
primarily via V2 receptors
• They are ineffective in nephrogenic
diabetes insipidus
– Treatment involves salt restriction, water
restriction, thiazides and loop diuretics
ADH Antagonists
• Syndrome of Inappropriate Antiduiretic
Hormone (SIADH) secretion, causes
water retention.
• Conivaptan is an antagonist against both
V1a and V2 ADH receptors.
• Tolvaptan is an antagonist with more
selectivity for V2 ADH receptors than V1a.
Clinical Indications
• In SIADH when water restriction has failed.
Toxicity
Nephrogenic Diabetes Insipidus
7. Phytodiuretics
Rhizoma Graminis
(Couch-grass) Fructus Petroselini
Stipites Cerasorum (Parsley)
(Cherry) Stigmata Maydis
Fructus Faseoli sine semine (Maize, corn)
(Haricot)
Rubia tinctorum L. (madder). Radix Rubiae
contains 2–3% di- or trioxyanthraquinones
glycosides, flavonoids and other bioactive
substances with diuretic, urolitholytic and
spasmolytic effects.
Infusions (1:10) made from madder facilitate dilution

of calculi, containing calcium and magnesium sulfate
in the renal pelvis and bladder.
It is an important ingredient of many phytoproducts

(Cystenal©, Rowatinex©), indicated in urolithiasis.
Antihypertensive Drugs
HYPERTENSION is the strongest modi-
fiable risk factor for coronary heart disease.
It is also responsible for considerable
(potentially preventable) disability from
stroke, heart and renal failure.
Despite this, usually, hypertension continues
to be underdiagnosed and undertreated.
Many clinical investigations show the
relationship between mean blood pressure
(BP) and the risk of coronary heart disease
(CHD) and stroke (insultus cerebri).
HYPERTENSION
Types of
Hypertension
Essential Secondary
A disorder of unknown origin affecting the

Secondary to other disease processes
Blood Pressure regulating mechanisms
Environmental
Factors
Stress Na+ Intake Obesity Smoking

Most patients with persistent arterial disease
have ESSENTIAL HYPERTENSION.
But hypertension is occasionally secondary
to some distinct disease:
•Coarctation of aorta
•Renal artery stenosis
•Parenchymal or obstructive renal disease
•Cushing’s syndrome
•Pheochromocytoma, etc.
Essential
hypertension
5% 5%
90%
There is changes in perceived norms
recently target values for blood pressure.
Norm now taken 135/85 mm Hg.
For patients over 60 years old today
accepted by cardiologists targeted
values for blood pressure are
140/90 mm Hg, and in people
over 80 years old they
are 150/90 mm Hg.
Hypertension
> 140 mmHg > 90 mmHg

****************************************************
Systolic Blood Diastolic Blood

Pressure (SBP) Pressure (DBP)
Cushing’s syndrome
is a side effect of
glucocorticosteroids
(hydrocortisone,
betamethasone, etc.)
The main symptom is
arterial hypertension.
ARTERIAL BLOOD PRESSURE
is determined by cardiac output and
peripheral vascular resistance. The
kidney plays a key role in its control.
•Excretion of salt and water controls
intravascular volume, which influences
the forces of contraction of the heart.
•Excretion of renin influences vascular
tone and electrolyte balance.
Arterial blood
pressure >>>
120/80 mm Hg
at rest
•Increased: peripheral vessel resistance,

cardiac output, tone of sympathetic nervous
system, synthesis of AII, aldosterone.
•Inhibited synthesis of NO, kinins, PGE, PGI2.
Treatment
• Symptomatic treatment is Mandatory:
– Damage to the vascular epithelium,
paving the path for atherosclerosis (IHD,
CVA) or nephropathy due to high intra-
glomerular pressure
– Increased load on heart due to high BP
can cause CHF
– Hypertension, even asymptomatic needs
treatment
Normal Blood Pressure Regulation
• Hydraulic equation:
Blood Pressure = Cardiac output (CO) X
Resistance to passage of blood through
precapillary arterioles (PVR)
• Physiologically CO and PVR is maintained
minute to minute by – arterioles (1)
postcapillary venules (2) and Heart (3)
• Kidney is the fourth site – volume of
intravascular fluid
• Baroreflex, humoral mechanism and renin-
angiotensin-aldosterone system regulates
the above 4 sites
• Local agents like Nitric oxide
• In hypertensives – Baroreflex and renal
blood-volume control system – set at
higher level
• All antihypertensives act via interfering
with normal mechanisms
Baroreceptor reflex arc
Postural baroreflex:
The Renal response
• Long-term blood pressure control – by controlling blood
volume
• Reduction in renal pressure – intrarenal redistribution of
pressure and increased absorption of salt and water
• Decreased pressure in renal arterioles and sympathetic
activity – renin production – angiotensin II production
• Angiotensin II:
– Causes direct constriction of renal arterioles
– Stimulation of aldosterone synthesis – sodium absorption
and increase in intravascular blood volume
• Diuretics:
– Thiazides: Hydrochlorothiazide, chlorthalidone
– High ceiling: Furosemide
– K+ sparing: Spironolactone, triamterene and amiloride
MOA: Acts on Kidneys to increase excretion of Na and H2O – decrease
in blood volume – decreased BP
• Angiotensin-converting Enzyme (ACE) inhibitors:
– Captopril, lisinopril, enalapril, ramipril and fosinopril
MOA: Inhibit synthesis of Angiotensin II – decrease in peripheral
resistance and blood volume
• Angiotensin (AT1) blockers:
– Losartan, candesartan, valsartan and telmisartan
MOA: Blocks binding of Angiotensin II to its receptors
• Centrally acting:
– Clonidine, methyldopa
MOA: Act on central α2A receptors to decrease sympathetic outflow
• ß-adrenergic blockers:
– Non selective: Propranolol (others: nadolol, pindolol, labetolol)
– Cardioselective: Metoprolol (others: atenolol, betaxolol)
MOA: Bind to beta adrenergic receptors and blocks the activity
• ß and α – adrenergic blockers:
– Labetolol and carvedilol
• α – adrenergic blockers:
– Prazosin, doxazosin, phenoxybenzamine and phentolamine
MOA: Blocking of alpha adrenergic receptors in smooth muscles -
vasodilatation
• Calcium Channel Blockers (CCB):
– Verapamil, diltiazem, nifedipine, felodipine, amlodipine,
nimodipine etc.
MOA: Blocks influx of Ca++ in smooth muscle cells – relaxation of
SMCs – decrease BP
• K+ Channel activators:
– Diazoxide, minoxidil, pinacidil and nicorandil
MOA: Leaking of K+ due to opening – hyper polarization of SMCs –
relaxation of SMCs
• Vasodilators:
– Arteriolar – Hydralazine (also CCBs and K+ channel activators)
– Arterio-venular: Sodium Nitroprusside
RAS – Introduction
• Renin is a proteolytic enzyme and also called angiotensinogenase
• It is produced by juxtaglomerular cells of kidney
• It is secreted in response to:
– Decrease in arterial blood pressure
– Decrease Na+ in macula densa
– Increased sympathetic nervous activity
• Renin acts on a plasma protein – Angiotensinogen (a glycoprotein synthesized and
secreted into the bloodstream by the liver) and cleaves to produce a decapeptide
Angiotensin-I
• Angiotensin-I is rapidly converted to Angiotensin-II (octapeptide) by ACE (present in
luminal surface of vascular endothelium)
• Furthermore degradation of Angiotensin-II by peptidases produce Angiotensin-III
• Both Angiotensin-II and Angiotensin-III stimulates Aldosterone secretion from
Adrenal Cortex (equipotent)
• AT-II has very short half life – 1 min
RAS – Physiology
Increased
Blood Vol.
Rise in BP
Vasoconstriction
Na+ & water

retention
Kidney
(Adrenal cortex)
Types – circulating RAS and tissue RAS
Circulating RAS: Renin is the rate limiting factor of Ang-II release
• Plasma t1/2 of Renin is 15 minutes
• Ang-I is less potent (1/100th) than of Ang-II
• Ang-I is rapidly converted to Ang-II by ACE (in vascular endothelium- mainly
lungs)
• Ang-II half life is 1 minute only
• Degradation product is Ang-III (heptapeptide) - 2-10 times less potent than
Ang-II
• Both Ang-II and An-III stimulates Aldosterone secretion fromAdrenal Cortex
(equipotent)
• Ang-IV – different from all – mainly CNS action via AT4 receptor
Tissue RAS:
• Blood vessels capture Renin and Angiotensinogen from circulation – produce
Ang-II (Extrinsic local RAS) – on cell surface – local response
• Many tissues also – Heart, brain, kidneys, adrenals capture Renin and
Angiotensinogen to produce intracellularly Ang-II (Intrinsic local RAS) -
Important in these organs – regulates organ function, cell growth/death
RAS – actions of Angiotensin-II
1. Powerful vasoconstrictor particularly arteriolar – direct action and release
of Adr/NA release
– Promotes movement of fluid from vascular to extravascular
– More potent vasopressor agent than NA – promotes Na+ and water
reabsorption
– It increases myocardial force of contraction (CA++ influx promotion) and
increases heart rate by sympathetic activity, but reflex bradycardia occurs
– Cardiac output is reduced and cardiac work increases
2. Aldosterone secretion stimulation – retention of Na++ in body
3. Vasoconstriction of renal arterioles – rise in IGP – glomerular damage
4. Decreases NO release
5. Decreases Fibrinolysis in blood
6. Induces drinking behaviour and ADH release by acting in CNS – increase
thirst
7. Mitogenic effect – cell proliferation
Angiotensin-II
• What are the ill effects on chronic ?
– Volume overload and increased total peripheral resistance
– Cardiac hypertrophy and remodeling
• Coronary vascular damage and remodeling
– Hypertension – long standing will cause ventricular
hypertrophy
– Myocardial infarction – hypertrophy of non-infarcted area of
ventricles
– Renal damage
– Risk of increased CVS related morbidity and mortality
• ACE inhibitors reverse cardiac and vascular hypertrophy and
remodeling
Hypertrophy – image
Angiotensin-II – Pathophysiological Roles
1. Mineralocorticoid secretion
2. Electrolyte, blood volume and pressure homeostasis: Renin is released
when there is changes in blood volume or pressure or decreased Na+ content
– Intrarenal baroreceptor pathway – reduce tension in the afferent glomerular
arterioles by local production of Prostaglandin – intrarenal regulator of blood flow
and reabsorption
– Low Na+ conc. in tubular fluid – macula densa pathway – COX-2 and nNOS are
induced – release of PGE2 and PGI2 – more renin release
– Baroreceptor stimulation increases sympathetic impulse – via beta-1 pathway –
renin release
• Renin release – increased Angiotensin II production – vasoconstriction and
increased Na+ and water reabsorption
• Long term stabilization of BP is achieved – long-loop negative feedback and
short-loop negative feedback mechanism
3. Hypertension
4. Secondary hyperaldosteronism
•Competitive inhibition of ACE reduces
generation of AT II and release of aldo-
sterone. Inhibition of tissue ACE in the vas-
scular wall is more important for the hypo-
tensive effect of these drugs than its action
on the circulating renin-angiotensin system.
•Reduced tissue concentrations of AT
lead to arterial and venous dilation.
Angiotensinogen Kininogen
Renin
Kallikrein
ACE (kininase II)

Angiotensin I
Bradykinin
Angiotensin II
Aldosterone Degradation
release products
•Captopril
•Cilazapril
•Enalapril
•Fosinopril
•Lisinopril
•Perindopril
•Ramipril
•Trandolapril
CAPTOPRIL
(prodrug)
(prodrug)
ACE inhibitors – used in:
AH, CHD, atherosclerosis, DM
Unwanted effects:
•Cough: unproductive;
may be due to accumulation of kinins in the
lung; occurs up to 10-20 % of patients
(more common in women!).
•Postural hypotension (some-
times after the first dose)
•Disturbances of taste, K+
•Rashes, angioneurotic edema
•Teratogenicity (PRC: D)
Captopril
• Sulfhydryl containing dipeptide and abolishes
pressor action of Angiotensin-I and not
Angiotensin-II and does not block AT receptors
• Pharmacokinetics:
– Available only orally, 70-75% is absorbed
– Partly absorbed and partly excreted unchanged in
urine
– Food interferes with its absorption
– Half life: 2 Hrs, but action stays for 6-12 Hrs
Captopril – Pharmacological actions
1. In Normal:
– Depends on Na+ status – lowers BP marginally on single dose
– When Na+ depletion – marked lowering of BP
2. In hypertensive:
– Lowers PVR and thereby mean, systolic and diastolic BP
– RAS is overactive in 80% of hypertensive cases and contributes to
the maintenance of vascular tone – inhibition causes lowering of BP
– Initially correlates with renin-angiotensin status but chronic
administration is independent of renin activity
– Captopril decreases t.p.r on long term – arterioles dilate – fall in
systolic and diastolic BP
– No effect on Cardiac output
– Postural hypotension is not a problem – reflex sympathetic
stimulation does not occur
– Renal blood flow is maintained – greater dilatation of vessels
Captopril – Adverse effects
• Cough – persistent brassy cough in 20% cases – inhibition of
bradykinin and substanceP breakdown in lungs
• Hyperkalemia in renal failure patients with K+ sparing diuretics, NSAID
and beta blockers (routine check of K+ level)
• Hypotension – sharp fall may occur – 1st dose
• Acute renal failure: CHF and bilateral renal artery stenosis
• Angioedema: swelling of lips, mouth, nose etc.
• Rashes, urticaria etc
• Dysgeusia: loss or alteration of taste
• Foetopathic: hypoplasia of organs, growth retardation etc
• Neutripenia
Contraindications: Pregnancy, bilateral renal artery stenosis,
hypersensitivity and hyperkalaemia
Enalapril
• It’s a prodrug – converted to enalaprilate

• Advantages over captopril:
– Longer half life – OD (5-20 mg OD)
– Absorption not affected by food
– Rash and loss of taste are less frequent
– Longer onset of action
– Less side effects
Ramipril
• It’s a popular ACEI now – long acting and extensive tissue
distribution
• It is also a prodrug with long half life
• Tissue specific – Protective of heart and kidney
Uses: Diabetes with hypertension, CHF, MI and cardio protective in
angina pectoris
Dose: Start with low dose; 2.5 to 10 mg daily
• Reports:
1) improves mortality rate in early MI cases
2) reduces the chance of development of AMI
3) reduces the chances of development of nephropathy etc.
Lisinopril
• It’s a lysine derivative
• Not a prodrug
• Slow oral absorption – less chance of 1st dose
phenomenon
• Absorption not affected by food and not
metabolized – excrete unchanged in urine
• Long duration of action – single daily dose
Doses: available as 1.25, 2.5, 5, 10 and 20 mg tab
– start with low dose
ACE inhibitors and hypertension
• 1st line of Drug:
– No postural hypotension or electrolyte imbalance (no fatigue
or weakness)
– Safe in asthmatics and diabetics
– Prevention of secondary hyperaldosteronism and K+ loss
– Renal perfusion well maintained
– Reverse the ventricular hypertrophy and increase in lumen
size of vessel
– No hyperuraecemia or deleterious effect on plasma lipid
profile
– No rebound hypertension
– Minimal worsening of quality of life – general wellbeing, sleep
and work performance etc.
ACE inhibitors – uses
effective in younger patients (below 55 yrs)
Congestive Heart Failure:
• Reduction in preload and afterload
• Some benefits – Reduction in pulmonary artery pressure, right atrial
pressure, systemic vascular resistance
• Improved Renal perfusion (Na+ and water excretion)
• CO and stroke volume increases – with reduced heart rate (less
cardiac work)
• 1st line of drug with beta-blocker and diuretics in all cases (digitalis ?)
Myocardial Infarction: 0-6 weeks
• Reduces mortality
• Also reduces recurrent MI
• Extension of therapy – in CHF patients
ACE inhibitors – uses
effective in younger patients (below 55 yrs)
Prophylaxis of high CVS risk subjects: Ramipril – post MI,
diabetes etc.
Diabetic Nephropathy and non-diabetic nephropathy –
reduce albuminuria (both type 1 and 2) – higher creatinine
clearance
• Better haemodynamic and prevention of mesangial growth
• Schleroderma crisis: Rise in BP and deteriorating renal
function (Ang-II)
Particular advantages:
– Renal blood flow improvement
– Retard diabetic nephropathy
– Regression of LV and vascular hypertrophy – cardioprotective
b) AT1-blockers
Losartan Irbesartan Valsartan
Oral: in a once daily dosing regimen.

Expensive, but with small ARs.
Angiotensin Receptor Blockers
Angiotensin Receptors:
• Specific angiotensin receptors have been discovered, grouped
and abbreviated as – AT1 and AT2
• They are present on the surface of the target cells
• Most of the physiological actions of angiotensin are mediated via
AT1 receptor
• Transducer mechanisms of AT1 inhibitors: In different tissues
show different mechanisms. For example -
– PhospholipaseC-IP3/DAG-intracellular Ca++ release
mechanism – vascular and visceral smooth muscle
contraction
– In myocardium and vascular smooth muscles AT1 receptor
mediates long term effects by MAP kinase and others
• Losartan is the specific AT1 blocker
AT1-antagonists differ from ACE inhibitors in the
following ways:
• They do not interfere with degradation of kinins

(so no rise in level or potentiation of bradykinin).
• They block completely AT1-receptors and therefore
alternative pathways of AT generation do not have
any importance.
• They result in indirect AT2-receptor activation.
ACE inhibitors result in depression of both
AT1- and AT2-activation.
Angiotensin Receptor Blockers –
Losartan
• Competitive antagonist and inverse agonist
of AT1 receptor
• Does not interfere with other receptors
except TXA2
• Blocks all the actions of A-II –
vasoconstriction, sympathetic stimulation,
aldosterone release and renal actions of salt
and water reabsorption
• No inhibition of ACE
Losartan
• Theoretical superiority over ACEIs:
– Cough is rare – no interference with bradykinin and other ACE
substrates
– Complete inhibition of AT1 – alternative remains with ACEs
– Result in indirect activation of AT2 – vasodilatation (additional
benefit)
– Clinical benefit of ARBs over ACEIs – not known
• However, losartan decreases BP in hypertensive which is for long
period (24 Hrs)
– heart rate remains unchanged and CVS reflexes are not interfered
– no significant effect in plasma lipid profile, insulin sensitivity and
carbohydrate tolerance etc.
– Mild uricosuric effect
Losartan
• Pharmacokinetic:
– Absorption not affected by food but unlike ACEIs its
bioavailability is low
– High first pass metabolism
– Carboxylated to active metabolite E3174
– Highly bound to plasma protein
– Do not enter brain
• Adverse effects:
– Foetopathic like ACEIs – not to be administered in
pregnancy
– Rare 1st dose effect hypotension
– Low dysgeusia and dry cough
– Lower incidence of angioedema
• Available as 25 and 50 mg tablets
ANGIOTENSIN RECEPTOR BLOCKERS
Theoretical superiority over ACEIs: free from side effects
Cough is rare – no interference with bradykinin and other
ACE substrates
No angioedema, urticaria and taste disturbance
No effect on heart rate and cardiac reflexes
Metabolic and prognostic advantages
Clinical benefit of ARBs over ACEIs (??)
But, combination therapy: Total suppression of RAS
A-II generated by non ACE mechanisms – ARBs block
ACEIs produce bradykinin related vasodilatation – ARBs do
not
ARBs cause compensatory increase of A-II – ACEIs block
ARBs indirect activation of AT2 – ACEIs block
Proved useful in CHF and non-diabetic renal disease –
haemodynamic and symptomatic benefit in CHF
 Drugs acting on the SNS
a) Beta-blockers
(β1) (β1 & β2 ) (β & α )
Atenolol Bopindolol Carvedilol
Acebutolol (β1 ISA) Propranolol (antioxidant)
Bisoprolol Oxprenolol (β1 ISA) Labetalol
Celiprolol (β2 ISA) Pindolol (with β1 ISA)
Metoprolol
Nebivolol releases NO
Mechanism of antihypertensive effect
•Blockade of β1-adrenoceptors in heart
reduces heart rate and
•Blockade of renal juxtaglomerular β1-
receptors reduces renin secretion.
•Blockade of presynaptc β2-adrenoceptors
inhibits exocytose of NA.
•Carvedilol and labetalol also block
a-receptors and produce vasodilation.
Beta-blockers
(–)
AP
Ca2+
(–)
Receptor
Cell
wall VDCC ROCC
Ca2+
AP – action potential, NA – noradrenaline

Sarcoplasmatic
VDCC – voltage dependent calcium channels
reticulum
ROCC – receptor operating calcium channels
Lipophilic β-blockers (e.g. propranolol) are
well absorbed from the gut, but undergo
extensive first-pass metabolism in the liver,
with considerable variability.
Hydrophilic β-blockers (e.g. atenolol) are
less completely absorbed from the gut and
are eliminated unchanged by the kidney.
The dose range to maintain effective plasma
concentrations is narrower than that of drugs
which undergo metabolism and the clinical
response is more predictable.
Beta-adrenergic blockers
• Advantages:
– No postural hypotension
– No salt and water retention
– Low incidence of side effects
– Low cost
– Once a day regime
– Preferred in young non-obese patients, prevention of sudden cardiac
death in post infarction patients and progression of CHF
• Drawbacks: Rebound hypertension
– Raised LDL and lowered HDL and impaired carbohydrate tolerance in
diabetics
– Fatigue, lethargy (low CO?) – decreased work capacity
– Loss of libido – impotence
– Cognitive defects – forgetfulness and nightmares etc.
– Difficult to stop suddenly
– Therefore cardio-selective drugs are preferred now
Adverse reactions of β-blockers
•Blockade of β1-receptors may cause
bradycardia, AV block, heart failure.
•Blockade of β2-receptors may cause
bronchospasm, intermittent claudication
(reducing peripheral blood flow) and
hypoglycemia.
Beta-blockers
(-)
AC PDE
ATP cAMP 3’,5’ AMP
•CNS effects: sleep disturbance, dreams
and hallucinations (more common with
lipophilic drugs which cross the BBB).
•Most β-blockers raise plasma concentration
of triglycerides and lower concentration of
antiatherogenic HDL (probably β3-effect).
•Indurations penis plastic (fibrosis …)
•Sudden withdrawal syndrome:
beta-blockers should be stopped gradually.
Nebivolol
Selective β1-blocker, releases NO (causes vasodialtion)
It has 24 h effect.
Selectivity
β1/β2-blocking
β-blockers
activity
Atenolol 15
Bisoprolol 50
Metoprolol 25
Nebivolol 293
Propranolol 1,9
BETA-ADRENERGIC BLOCKERS
Overall: beta-blockers as first line of drug
No postural hypotension
No salt and water retention
Low incidence of side effects
Low cost
Once a day regime
Cardioprotective potential
Preferred:
In young non-obese patients
Prevention of sudden cardiac death in post infarction
patients and progression of CHF
Angina pectoris and post angina patients
Post MI patients – useful in preventing mortality
In old persons, carvedilol – vasodilatory action can be given
b) Postsynaptic α1-blockers
Blockade of postsynaptic α1-receptors
lowers blood pressure by:
•Lowering tone in arteriolar resistance vessels.
•Dilating venous capacitance vessels, which
reduces venous return and cardiac output.
•Selective α1-adrenoceptor antagonists
the presynaptic α2-adrenoceptors and do
not produce strong tachycardia.
Postsynaptic α1-blockers
Doxazosin
Prazosin
Prazosin
•It has potentially beneficial effect:
- an increase in HDL;
- a reduction in triglycerides
•Adverse reactions (AR):
- postural hypotension due to
relaxation of the veins
(this can be troublesome after the
first dose)
- tolerance
Prazosin
– Fluid retention in monotherapy
– Headache, dry mouth, weakness, blurred vision, rash,
drowsiness and failure of ejaculation in males
• Current status:
– Several advantages – improvement of carbohydrate
metabolism – diabetics, lowers LDL and increases HDL,
symptomatic improvement in BHP
– But not used as first line agent, used in addition with
other conventional drugs which are failing – diuretic or
beta blocker
• Doses: Available as 0.5 mg, 1 mg, 2.5 mg, 5 mg etc. dose:1-
4 mg thrice daily (Minipress/Prazopress)
Doxazosin
Indications: arterial hypertension and
hyperplasia of the prostate gland (men > 45 years old)
Selective postsynaptic alpha-1А-blocker:
It blocks alpha-1А-receptors into the smooth muscles of the
prostate gland,
and the
prostatic
part of the
urethra.
c) α2a-agonists
There are several different α2-adrenoceptor
subtypes have been identiﬁed: α2a, α2b and etc.
α2a-adrenoceptors appear to mediate sedation,
analgesia and hypotension while the
α2b-adrenoceptor mediates vasoconstriction
and hypertension (i.e. postsynaptic
α2-adrenoceptors are probably of the α2b subtype).
The stimulation of presynaptic α2a-receptors
in CNS inhibits NA release, reduces sym-
pathetic influence on the vasomotor centre;
reduces peripheral arterial and venous tone.
• Clonidine ( HCl)
- xerostomia (dry mouth)
- withdrawal phenomenon
- sedation
- postural hypotension
• Methyldopa
(prodrug: α-methyl-NA is an α2a-agonist)
Dopegyt®
Clonidine
(α-methyl-DOPA) α-methyl-NA
(+)
CENTRALLY ACTING DRUGS
Clonidine: Imidazoline derivative, partial agonist of
central alpha-2A receptor in CNS – once popular
(moderately potent)
• Frequent side effects– sedation, depression, impotence, salt and
water retention, supersensitivity and rebound hypertension
• Not frequently used now because of tolerance and withdrawal
hypertension
• Used rarely as 3rd or 4th choice drug – with diuretics
Methyldopa: a prodrug
• Precursor of Dopamine and NA
• MOA: Converted to alpha methyl noradrenaline which acts on
alpha-2 receptors in brain and causes inhibition of adrenergic
discharge in medulla – fall in t.p.r and fall in BP
• Also inhibits dopadecarboxylase – no NA synthesis
• Various adverse effects – cognitive impairement, postural
hypotension, positive coomb`s test etc. – Not used
therapeutically now except in Hypertension during pregnancy
d) I1 (Imidazoline-1)-agonists
(> t1/2: 1 time daily p.o.)
The stimulation of I1-receptors:
•in CNS reduces sympathetic tone
and lowers blood pressure;
•in kidney increases secretion of ANP
(atrial natriuretic peptide)
• Moxonidine
• Rilmenidine
e) Adrenergic
neuron
blockers
•Guanethidine
•Reserpine
– Numerous
adverse
reactions
(out of date)
Adrenergic neuron blockers
use the active transport
mechanisms for monoamines to
accumulate in the adrenergic nerve
terminal. Inside the cell they prevent
the release of NA from vesicles.
 Calcium antagonists
(calcium channel blockers)
They block calcium influx through voltage-
dependant calcium channels in the smooth
muscles. They dilate
coronaries and
peripheral arteries
and reduce
heart afterload.
AP
Calcium
antagonists
NA
Ca2+
(–) Receptor
Cell
wall VDCC ROCC
Ca2+
Sarcoplasmatic
reticulum
VDCC – voltage-dependent calcium channels
Regulation of intracellular calcium
In the cell membranes there are
three types of calcium channels:
 Voltage-dependent (L, N, O, P, Q, R, T)
 Receptor operating
 Stretch activated
Calcium antagonists block predominantly L-type
calcium channels, localized in the myocardium
and myocytes
Plateau phase of AP
of blood
vessels.
L-type channels
are connected
to the plateau
of the AP.
Calcium antagonists reduce coronary and
peripheral vascular resistance, decrease
blood pressure and myocardial oxygen
consumption.
Dihydropyridines (nifedipine, amlodipine,

etc) don’t have cardionegative inotropic,
chronotropic, and dromotropic effect in
comparison with verapamil and diltiazem.
Calcium Channel Blockers –
Classification
 Dihydropyridines
● Norm frequent (with normal heart rate) and
24-hours long effect: Amlodipine, Felodipine
● Other dihydropyridines produce tachycardia
(increase baroreflex sensibility):
Isradipine, Lacidipine,
Nicardipine, Nifedipine,
Nisoldipine, Nitrendipine
● cerebral vasodilators (Nimodipine)
 Phenylalkylamines: Verapamil
 Benzotiazepines: Diltiazem
 Flunarizine type (cerebral vasodilators)
Cinnarizine, Flunarizine
Amlodipine
norm frequent dihydropyridine
t1/2 31-47 h, 55-91% bioavailability
5-10 mg/24 h p.o. (once daily)
Nifedipine (tachycardia!)
– effective in vasospastic angina
Diltiazem (in SR dosage forms)
Verapamil (Isoptin SR® – tabl. 240 mg)
(22% bioаvailability, first pass effect –
extensive liver metabolism; constipation)
Mechanism of action
• Three types Ca+ channels in smooth muscles – Voltage sensitive,
receptor operated and leak channel
• Voltage sensitive are again 3 types – L-Type, T-Type and N-Type
• Normally, L-Type of channels admit Ca+ and causes depolarization
– excitation-contraction coupling through phosphorylation of
myosin light chain – contraction of vascular smooth muscle –
elevation of BP
• CCBs block L-Type channel:
– Smooth Muscle relaxation
– Negative chronotropic, inotropic and chronotropic effects in
heart
• DHPs have highest smooth muscle relaxation and vasodilator action
followed by verapamil and diltiazem
• Other actions: DHPs have diuretic action
Calcium Channel Blockers
• Advantages:
– No haemodynamic effect – physical work capacity
– No effect on lipid profile, uric acid level and electrolyte
imbalance
– No renal and male sexual function impairment
– Can be given to asthma, angina and PVD patients
– Unlike diuretics no adverse metabolic effects but mild
adverse effects like – dizziness, fatigue etc.
– No sedation or CNS effect
– No adverse fetal effects and can be given in pregnancy
– Minimal effect on quality of life
current status
• CCBs are not 1st line of antihypertensive unless
indicated – ACEI/diuretics/beta blockers
• However its been used as 1st line by many because
of excellent tolerability and high efficacy
• Preferred in elderly and prevents stroke
• CCBs are effective in low Renin hypertension
• They are next to ACE inhibitors in inhibition of
albuminuria and prevention of diabetic nephropathy
• Immediate acting Nifedipine is not encouraged
anymore
Adverse reactions
•Arterial dilation: headache, flushing and
dizziness, ankle edema (resistant to diuretics)
•Bradycardia and AV block (verapamil
and diltiazem), constipation (verapamil)
•Verapamil has potentially hazardous
additive effects with beta-blockers, reducing
the force of myocardial contraction and
slowing the heart rate.
•Tachycardia (nifedipine, nisoldipine).
•Constipation (verapamil 8%; nifedipine 3%)
Gingivitis haemorrhagica
 Arterial hypertension
a) Dihydropyridines
b) Verapamil and Diltiazem
 Coronary heart disease
Main indications
a) Dihydropyridines
b) Verapamil and Diltiazem
 Ischemic cerebral stroke
Cinnarizine, Flunarizine, Nimodipine
 SV tachyarrhythmias: Verapamil, Diltiazem (i.v.)
 Migraine (in remission periods)
Flunarizine, Verapamil
Beta-blockers + dihydropyridines: YES (OK)
Beta-blockers + Verapamil or Diltiazem = NO
• Contraindications:
– Unstable angina
– Heart failure
– Hypotension
– Post infarct cases
– Severe aortic stenosis
• Preparation and dosage:
– Amlodipine – 2.5, 5 and 10 mg tablets (5-10 mg
OD) – Stamlo, Amlopres, Amlopin etc.
– Nimodipine – 30 mg tab and 10 mg/50 ml
injection – Vasotop, Nimodip, Nimotide etc.
 Diuretics (in low daily dose)
Hydrochlorothiazide Amiloride
Chlorthalidone Triamterene
Indapamide Spironolactone
5% 3%
Indapamide 20-30%
•Vasodilator Furosemide
•It does not influence Torasemide
serum level of Na+,
K+, Mg2+ and Ca2+
Diuretics
• Drugs causing net loss of Na+ and water in urine
• Mechanism of antihypertensive action:
– Initially: diuresis – depletion of Na+ and body fluid
volume – decrease in cardiac output
– Subsequently after 4-6 weeks, Na+ balance and CO is
regained by 95%, but BP remains low!
– reduction in total peripheral resistance (TPR) due to
deficit of little amount of Na+ and water (Na+ causes
vascular stiffness)
– Similar effect is seen with sodium restriction (low
sodium diet)
Thiazide diuretics – adverse effects
– Hypokalaemia – muscle pain and fatigue
– Hyperglycemia: Inhibition of insulin release due to K+
depletion (proinsulin to insulin) – precipitation of diabetes
– Hyperlipidemia: rise in total LDL level – risk of stroke
– Hyperurecaemia: inhibition of urate excretion
– Sudden cardiac death – tosades de pointes
(hypokalaemia)
– All the above metabolic side effects – higher doses (50-
100 mg per day)
– But, its observed that these adverse effects are minimal
with low doses (12.5 to 25 mg) – Average fall in BP is 10
mm of Hg
Thiazide diuretics – current status
• Effects of low dose:
– No significant hypokalaemia
– Low incidence of arrhythmia
– Lower incidence of hyperglycaemia, hyperlipidemia and hyperuricaemia
– Reduction in MI incidence
– Reduction in mortality and morbidity
• Recommendation:
– low dose of thiazide therapy (12.5-25 mg per day) in essential
hypertension
– Preferably should be used with a potassium sparing diuretic as first
choice in elderly
– If therapy fails – another antihypertensive but do not increase the
thiazide dose
– Loop diuretics are to be given when there is severe hypertension with
retention of body fluids
Diuretics
• K+ sparing diuretics:
– Thiazide and K sparing diuretics are combined
therapeutically
• Modified thiazide: indapamide
– Indole derivative and long duration of action (18 Hrs) –
orally 2.5 mg dose
– It is a lipid neutral i.e. does not alter blood lipid
concentration, but other adverse effects may remain
• Loop diuretics:
– Na+ deficient state is temporary, not maintained round –
the-clock and total peripheral resistance not reduced
– Used only in complicated cases – CRF, CHF marked fluid
retention cases
 Other antihypertensive vasodilators
(used in hypertensive emergencies)
•Sodium nitroprusside
(direct NO donor): i.v. infusion
•Diazoxide: bolus i.v.
(ADRs: hyperglycemia)
•Nifedipine: sublingually
•Clonidine: sublingually, i.m.
•Nitrolingual® or Isoket® spray:
sublingually
Nitroprusside is an inorganic nitro-
vasodilator with a mechanism of
action similar to that of organic nitrates.
It is reserved for hypertensive emergencies.
It dilates arterioles and veins, reducing
both peripheral resistance and venous
return. It is given by i.v. infusion and
has a duration of effect of less than 5 min.
Metabolism to cyanide within red blood
cells terminates its effects. ADRs: Confusion,
psychosis, metabolic acidosis.
Sodium Nitroprusside
• Rapidly and consistently acting vasodilator
• Relaxes both resistance and capacitance vessels and reduces t.p.r
and CO (decrease in venous return)
• Unlike hydralazine it produces decrease in cardiac work and no
reflex tachycardia.
• Improves ventricular function in heart failure by reducing preload
• MOA: RBCs convert nitroprusside to NO – relaxation also by non-
enzymatically to NO by glutathione
• Uses: Hypertensive Emergencies, 50 mg is added to 500 ml of
saline/glucose and infused slowly with 0.02 mg/min initially and
later on titrated with response (wrap with black paper)
• Adverse effects: All are due release of cyanides (thiocyanate) –
palpitation, pain abdomen, disorientation, psychosis, weakness and
lactic acidosis.
Vasodilators – Hydralazine
• Directly acting vasodilator
• MOA: hydralazine molecules combine with receptors in the
endothelium of arterioles – NO release – relaxation of vascular
smooth muscle – fall in BP
• Subsequenly fall in BP – stimulation of adrenergic system leading to
– Cardiac stimulation producing palpitation and rise in CO even in
IHD and patients – anginal attack
– Tachycardia
– Increased Renin secretion – Na+ retention
– These effects are countered by administration of beta blockers
and diuretics
Uses: 1) Moderate hypertension when 1st line fails – with beta-blockers
and diuretics 2) Hypertension in Pregnancy, Dose 25-50 mg OD
Vasodilators – Minoxidil (rogaine,
regaine, mintop)
• Powerful vasodilator, mainly 2 major uses – antihypertensive and
alopecia
• Prodrug and converted to an active metabolite which acts by
hyperpolarization of smooth muscles and thereby relaxation of SM
– leading to hydralazine like effects
• Rarely indicated in hypertension especially in life threatening
ones
• More often in alopecia to promote hair growth
• Orally not used any more
• Topically as 2-5% lotion/gel and takes months to get effects
MOA of hair growth:

• Enhanced microcirculation around hair follicles and also by direct
stimulation of follicles
• Alteration of androgen effect of hair follicles
 Rational antihypertensive combinations
•ACE inhibitor + thiazide diuretic
•Sartan + thiazide diuretic
•Beta-blocker + thiazide diuretic
•Beta -blocker + amlodipine or felodipine
Sexual function
Inhibit: Do not influence: Inhibitors of PD5 (p.o.):
•Diuretics •ACE inhibitors •Sildenafil (Viagra®)
•Alfa-blockers •AT1-blockers
•Tadalafil (Cialis®), Vardenafil
•Alfa2-agonists •Calcium
•Beta-blockers antagonists
•Reserpine-like ... •Nebivolol
ADJUVANT DRUGS
•Platelet antiaggregants
•Antidyslipidemic drugs
•Anxiolytics, etc.
NONPHARMACO-
LOGICAL METHODS
– avoiding of the risk factors
2/3
•Smoking
•Lipid status of the
risk
Risk factors for CVD
•Chomocysteine > 15 mmol/l
•Diabetes mellitus
•Metabolic syndrome
•Sedentary life style
•Tachycardia
•BMI > 30:
>>> saturated fatty acids
>>> salt and >>> sugar
>>> alcohol
<<< fruits and vegetables
•Stress
Treatment of Hypertension
Categories
BP Systolic Diastolic Risk factors
Normal >120 <80 1. Age above 55 and 65 in
Prehypertension 120-139 80-89 Men and Woman
Stage1 149-159 90-99 respectively
Stage2 >160 >100 2. Family History
3. Smoking
4. DM and Dyslipidemia
5. Hypertension
6. Obesity
7. Microalbuminuria
Treatment of Hypertension –
General principles
• Stage I:
– Start with a single most appropriate drug with a low dose.
Preferably start with Thiazides. Others like beta-blockers,
CCBs, ARBs and ACE inhibitors may also be considered.
CCB – in case of elderly and stroke prevention. If required
increase the dose moderately
– Partial response or no response – add from another group
of drug, but remember it should be a low dose combination
– If not controlled – change to another low dose combination
– In case of side effects lower the dose or substitute with
other group
• Stage 2: Start with 2 drug combination – one should be diuretic
Treatment of Hypertension –
combination therapy
• In clinical practice a large number of patients require
combination therapy – the combination should be
rational and from different patterns of hemodynamic
effects
– Sympathetic inhibitors (not beta-blockers) and vasodilators +
diuretics
– Diuretics, CCBs, ACE inhibitors and vasodilators + beta
blockers (blocks renin release)
– Hydralazine and CCBs + beta-blockers (tachycardia countered)
– ACE inhibitors + diuretics
• 3 (three) Drug combinations: CCB+ACE/ARB+diuretic;
CCB+Beta blocker+ diuretic; ACEI/ARB+ beta
blocker+diuretic
• Never combine:
– Alpha or beta blocker and clonidine - antagonism
– Nifedepine and diuretic synergism
– Hydralazine with DHP or prazosin – same type of action
– Diltiazem and verapamil with beta blocker – bradycardia
– Methyldopa and clonidine
• Hypertension and pregnancy:
– No drug is safe in pregnancy
– Avoid diuretics, propranolol, ACE inhibitors, Sodium
nitroprusside etc
– Safer drugs: Hydralazine, Methyldopa, cardioselective beta
blockers and prazosin
Hypertensive Emergencies
• Cerebrovascular accident or head injury with high BP
• Left ventricular failure with pulmonary edema due to hypertension
• Hypertensive encephalopathy
• Angina or MI with raised BP
• Acute renal failure with high BP
• Eclampsia
• Pheochromocytoma, cheese reaction and clonidine withdrawal
• Drugs:
– Sodium Nitroprusside (20-300 mcg/min) – dose titration and monitoring
– GTN (5-20 mcg/min) – cardiac surgery, LVF, MI and angina
– Esmolol (0.5 mg/kg bolus) and 50-200mcg/kg/min - useful in reducing
cardiac work
– Phentolamine – pheochromocytoma, cheese reaction nd clonidine
withdrawal (5-10 mg IV)
ANTIANGINAL DRUGS
Angina pectoris is a symptom of reversible
myocardial ischemia and is most frequently
experienced as chest pain on exertion,
which is relieved by rest.
Pain is the consequence of an imbalance
between oxygen supply and oxygen demand
in the ischemic area of myocardium.
– This imbalance may be due to:
• a decrease in myocardial oxygen delivery
• an increase in myocardial oxygen demand
• or both
• The discomfort abates when supply becomes
adequate for demand.
Typically angina lasts for seconds to minutes, up to 15 minutes
Imbalance results from an inability
of the coronary blood flow to meet the
metabolic demands of the heart, due to a
fixed atheromatous narrowing of coronary
artery.
Usually
reversible
coronary
artery
spasm
participates too.
Factors affecting
Myocardial Oxygen Delivery
• Coronary artery blood flow is the primary determinant of oxygen delivery
to the myocardium
– Myocardial oxygen extraction from the blood is nearly complete, even at rest
• Coronary blood flow is essentially negligible during systole and is
therefore determined by:
– Perfusion pressure during diastole (aortic diastolic pressure)
– Duration of diastole
– Coronary vascular resistance:
is determined by numerous factors including:
• Atherosclerosis
• Intracoronary thrombi
• Metabolic products that vasodilate coronary arterioles
• Autonomic activity
• Extravascular compression
Factors Affecting Myocardial
Oxygen Demand
• The major determinants of myocardial oxygen consumption include:
– Ventricular wall stress
• Both preload (end-diastolic pressure) and afterload (end-systolic pressure) affect
ventricular wall stress
– Heart rate
– Inotropic state (contractility)
– Myocardial metabolism (glucose vs fatty acids)
• A commonly used non-invasive index of

myocardial oxygen demand is the
“double product”:
– [Heart rate] X [Systolic blood pressure]
– Also known as the “rate pressure product”
ECG
Stress
Test
(10-20 min)
Non-
Invasive
method
Types of Angina
1. Classical angina:
 Stable
 Unstable
2. Variant, or Prinzmetal`s, angina
Myocardial infarction
Ischemic necrosis of a portion of myocardium due to
acute and complete occlusion of a coronary artery –
due to coronary thrombosis
Stable Angina
• Stable angina (common form) is also known as:
– Exertional angina/Typical or classic angina/Angina
of effort/Atherosclerotic angina
• The underlying pathology is usually atherosclerosis (reduced oxygen
delivery) giving rise to ischemia under conditions where the work load
on the heart increases (increased oxygen demand)
• Anginal episodes can be precipitated by exercise, cold, stress,
emotion or eating
• Subendocardial crunch develops
Therapeutic goals: Increase myocardial blood flow by dilating coronary
arteries and arterioles (increase oxygen delivery), decrease cardiac load
(preload and afterload; decrease oxygen demand), decrease heart rate
(decrease oxygen demand), [alter myocardial metabolism?]
Subendocardial Crunch – Image
Unstable Angina
• Unstable angina is also known as:
– Preinfarction angina
– Crescendo angina
– Angina at rest
• Caused by recurrent episodes of small platelet clots at the site of a
ruptured atherosclerotic plaque which can also precipitate local
vasospasm
• Associated with a change in the character, frequency, and duration
of angina in patients with stable angina, and episodes of angina at
rest
• May be associated with myocardial infarction
Therapeutic Goal: Inhibit platelet aggregation and thrombus
formation (increase oxygen delivery), decrease cardiac load
(decrease oxygen demand), and vasodilate coronary arteries
(increase oxygen delivery) and Statins
Vasospastic
Angina
• Vasospastic angina (uncommon form) is also known as:

– Variant angina
– Prinzmetal's angina
• Caused by transient vasospasm of the coronary vessels
• Attack occurs even at rest or during sleep
• Usually associated with underlying atheromas, abnormally reactive
or hypertrophied segments in coronary artery
• Chest pain may develop at rest
Therapeutic Goal: Decrease vasospasm of coronary vessels (calcium
channel blockers are efficacious in >70% of patients; increase oxygen
delivery)
Antianginal drugs increase oxygen supply
by improving coronary blood flow or reduce
oxygen demand by decreasing cardiac work.
They can be given to relieve rapidly the

ischemia during an acute attack, or as
prophylaxis to reduce the risk of
subsequent episodes.
Antianginal Agents
Three major classes of agents are used individually or in
combination to treat angina:
1. Organic nitrates:
• Vasodilate coronary arteries
• Reduce preload and aferload
2. Calcium channel blockers:
• Vasodilate coronary arteries
• Reduce afterload
• The non-dihydropyridines (verapamil and diltiazem) also decrease heart
rate and contractility
3. Beta-adrenergic blockers:
• Decrease heart rate and contractility – decrease in cardiac work and O2
consumption
• Improve myocardial perfusion due to decrease in heart rate – decreased
in ventricular wall tension
• Exercise tolerance
Classification of Antianginal Agents
1. Nitrates:
a) Short acting (10 minutes): Glyceryl trinitrate (GTN and Nitroglycerine) -
EMERGENCY
b) Long acting (1 Hour): Isosorbide dinitrate, Isosorbide mononitrate,
Erythrityl tetranitrate, Pentaerythritol tetranitrate
2. Calcium Channel Blockers:
a) Phenyl alkylamine: Verapamil
b) Benzothiazepin: Diltiazem
c) Dihydropyridines: Nifedipine, Felodipine, Amlodipine, Nitrendipine
and Nimodipine
3. Beta-adrenergic Blockers: Propranolol, Metoprolol, Atenolol and
others
4. Potassium Channel openers: Nicorandil
5. Others: Dipyridamole, Trimetazidine
Major sites of actions of antianginal drugs
I. Organic nitrates –
indirect donors of NO
Glyceryl-
3-nitrate
Isosorbide
dinitrate
Organic nitrates are vasodilators which
relax vascular smooth muscle.
They connect with thiol groups (-SH)
and release nitric oxide (NO).
NO combines with thiol groups in
vascular endothelium to form nitrosothiol
(R-SNO). Nitrosothiol activates guanylate
cyclase which raises the concentration of
cyclic GMP. This reduces the availability
of intracellular calcium and produces
vasodilation in three main vascular beds.
Mechanism of Action of Nitrovasodilators
Nitrates become denitrated by glutathione S-transferase
to release
Nitric Oxide
activates
Guanylate Cyclase
converts
GTP
cGMP
activates
cGMP-dependent protein kinase
Activation of PKG results in phosphorylation

of several proteins that reduce intracellular calcium
causing smooth muscle relaxation
Endothelium Smooth muscle
Organic
nitrate
(R-ONO2)
Ca2+
Celullar action of nitrates

SR – sarcoplasmatic reticulum
GTP – guanosine triphosphate
GMP – guanosine monophosphate
Organic nitrates dilate:
•Venous capacitance vessels and lower
left ventricular filling pressure (“preload”)
•Arterial resistance vessels and reduce
ventricular emptying (“afterload”).
This is less important than venodilation
during long treatment but it lowers blood
pressure, decreases cardiac work and
contributes to reduced oxygen demand.
•Coronary arteries.
Nitrates have little effect on the total
coronary flow but they improve the
blood flow through collateral vessels.
Nitrates also relieve coronary artery
spasm. The net effect is increased
blood flow supply to ischemic areas
of the myocardium.
Actions of Nitrates
1. Preload reduction:
 Dilatation of veins more than arteries – peripheral pooling of Blood –
decrease venous return
 Will lead to reduction in preload – decreased end diastolic size – decrease
in fiber length
 Less wall tension to develop for ejection (Laplace`s law) – less oxygen
consumption and reduction in ventricular wall pressure (crunch abolished)
2. Afterload reduction:
 Some amount of arteriolar dilatation – Decrease in peripheral Resistance
(afterload reduction) – reduction in Cardiac work (also fall in BP)
 Standing posture – pooling of Blood in legs – reflex tachycardia (prevented
by lying down and foot end raising)
 However in large doses opposite happens – marked fall in BP – reflex
tachycardia – increased cardiac work – precipitation of angina
Actions of Nitrates
3. Increased Myocardial Perfusion:
 Dilatation of bigger conducting coronary arteries all over the heart
+ dilatation of autoregulatory ischemic vessels due to ischemia +
normal tone of non-ischemic zone vessels – Redistribution of blood
in Myocardium to ischemic zone
 However total blood flow in coronary vessels is almost unchanged
with Nitrates
4. Mechanism of angina relief:
 Variant angina – coronary vasodilatation
 Classical angina – reduction in Cardiac load
 Increased exercise tolerance
5. Other actions: Cutaneous vasodilatation (flushing occurs),
meningeal vessels dilatation (headache) and decreased renal
blood flow
Pharmacokinetics – Nitrates
• All Nitrates share same action – only Pharmacokinetic differences
• All are highly lipid soluble and absorbed well from buccal mucosa,
orally and skin
• Rapidly denitrated by glutathione reductase and mitochondrial
aldehyde dehydrogenase
• Hepatic first-pass metabolism is high and oral bioavailability is
low for nitroglycerin (GTN) and isosorbide dinitrate (ISDN)
– Sublingual or transdermal administration – avoids the first-pass
effect
• Isosorbide mononitrate is not subject to first-pass metabolism and is
100% available after oral administration
• Hepatic blood flow and disease can affect the pharmacokinetics of
GTN and ISDN
Comparison of Pharmacokinetic
Properties of Nitrates
Property GTN ISDN 5-ISMN

Half-life (min) 3 10 280
Plasma clearance (L/min) 50 4 0.1
Apparent volume of 3 4 0.6
distribution (L/kg)
Oral bioavailability (%) <1 20 100
Glyceryl trinitrate is the most widely used
organic nitrate. It is well absorbed orally
but undergoes extensive first-pass metabo-
lism in the liver to inactive metabolites.
Usually glyceryl trinitrate is given by one
of three routes to avoid first-pass effect
and hence increases its bioavailability:
(1) Sublingually (as a tablets). Its effect
begins after 1-2 min and lasts 18-20 min.
Tablets lose their potency with prolonged
storage.
Sublingually (as a spray). A metered
dose aerosol spray is equally effective
and more stable.
(2) Transdermal: glyceryl trinitrate
is absorbed well through the skin and
can be delivered from an adhesive
patch, via a rate-limited membrane or
matrix. The anti-anginal effect is stable
for at least 24 hrs.
(3) Intravenous infusion.
Glyceryl trinitrate
•Nitrolingual® spray: 0.4 mg/dose
•Nitroglycerin®: ling. 0.5 mg
®
•Nitroderm TTS
•Perlinganit® - i.v. inf.
(+ Heparin)
Glyceryl trinitrate (GTN,
Nitroglycerine)
– Rendered nonexplosive by adsorbing in inert matrix of a
tablet
– Stored in a tightly closed Glass container
• Formulations: Oral, SL, IV and ointment
1) SL (0.5 mg) – to terminate an Ongoing attack
• Crushed under the tongue and spread over the buccal mucosa
• Action starts within 1-2 minutes
• Effects disappear within minutes but its metabolite – dinitrate
stays (1 hr)
2) IV transfusion: in acute MI
3) Patches: Ointment and patches – at night application
Isosorbide dinitrate
(prodrug)
•Isoket®: spray and tabl. (sub linguam)
•Isodinit : tablets 20 mg
®
•Kardiket : tabl. 20 mg
®
Isosorbide-5-mononitrate
•t1/2 4-5 h (Olicard® 40 retard: 12 h)
Adverse reactions of nitrates:
•Venodilation may lead to postural hypo-
tension, dizziness, syncope, tachycardia.
•Arterial dilation causes throbbing
headache and flushing, but tolerance is
common during treatment with long-acting
nitrates (retard tablets).
Organic nitrates are contraindicated
in patients with elevated intracranial
pressure
Nitrate Tolerance
• Tolerance to the therapeutic effects. Continuous or
frequent exposure to nitrates can lead to the
development of complete tolerance
• The mechanism of tolerance is not completely
understood:
– May be related to the enzymes involved in converting the
nitrates to NO
– This may be due to depletion of vascular thiol groups
– or to the enzyme that produces cGMP
It can be avoided by a “nitrate-low”

period of 10-12 h each day.
Nitrates
• Drug Interaction: Sildenafil (Viagra)
and other PDE-5 inhibitors used for
erectile dysfunction can potentiate
the actions of nitrates because they
inhibit the breakdown of cGMP (they
should not be taken within 6 hours of
taking a nitrovasodilator).
Nitrates – Therapeutic Uses
1. Angina pectoris: Classical and variant Types
2. Acute Coronary syndromes: Unstable angina and associated
with MI (Combination Drugs)
3. Myocardial Infarction: IV administration is useful in relieving
congestions of chest and favouring blood supply to ischemic
zone
4. CHF and LVF: Pooling of blood
5. Biliary colic: SL administration
6. Oesophageal spasm: Reduction in oesophageal tone (achalasia)
7. Cyanide Poisoning: Nitrates counter cyanide by producing
Methaemoglobin – then Cyanomethaemoglobin (Sod. Thiosulfate
is given to form Sod. Thiocyanate)
II. Beta-adrenoceptor
antagonists (b-blockers)
(b1) (b1 & b 2 ) (b & a )
Atenolol Propranolol Carvedilol

Acebutolol Oxprenolol (antioxidant)
Bisoprolol Pindolol
Celiprolol
Metoprolol
Beta-blockers
(–)
AP
Ca2+
(–)
Receptor
Cell
wall VDCC ROCC
Ca2+

Sarcoplasmatic
VDCC – voltage dependent calcium channels
reticulum
Beta-blockers
• Though most beta-blockers do not cause coronary
vasodilatation like the nitrovasodilators or calcium channel
blockers, beta-blockers are important in the treatment of
angina because of their effects on the heart
• Desired effects of beta-blockers
– Reduce myocardial oxygen consumption by reducing
contractility and heart rate
• Reducing cardiac output also reduces afterload
• Some β-blockers can cause vasodilatation directly or by acting as
α-blockers
– Improve myocardial perfusion by slowing heart rate (more time
spent in diastole)
Beta-blockers
• Benefits:
– Decreased frequency and severity of attacks
– Increased exercise tolerance (classical angina) –
cardioselectives are preferred
– Lowers sudden cardiac death
• ADRs and contraindications:

– May exacerbate heart failure
– Contraindicated in patients with asthma
– Should be used with caution in patients with diabetes since
hypoglycemia-induced tachycardia can be blunted or blocked
– May depress contractility and heart rate and produce AV block
in patients receiving non-dihydropyridine calcium channel
blockers (i.e. verapamil and diltiazem)
All b-blockers act as competitive antagonists
of catecholamines at beta-adrenoceptors:
•decrease heart rate
•reduce the force of cardiac contraction
•lower blood pressure
•reduce oxygen demand
Lipophilic b-blockers (e.g. propranolol) are
well absorbed from the gut, but undergo
extensive first-pass metabolism in the liver,
with considerable variability among
individuals.
Hydrophilic beta-blockers (e.g. atenolol) are
less completely absorbed from the gut and
are eliminated unchanged by the kidney.
The dose range to maintain effective plasma
concentrations is narrower than that for drugs
which undergo metabolism and the clinical
response in angina pectoris is more
predictable.
Adverse reactions of beta-blockers
•Blockade of beta1-receptors may cause
bradycardia, AV block, heart failure.
•Blockade of beta2-receptors may
cause bronchospasm, intermittent
claudication (reducing peripheral
blood flow) and hypoglycemia.
•CNS effects: sleep disturbance, dreams and
hallucinations (more common with
lipophilic drugs which cross the BBB).
•Most β-blockers raise the plasma concentration of
triglycerides and lower the concentration of HDL.
•Induratio penis pastica (fibrosis …)
•Sudden withdrawal syndrome: Beta-blockers
should be stopped gradually.
III. Calcium antagonists
Calcium is essential for excitation and
contraction in muscle cells. Free calcium
must either enter the cell or be released
from intracellular stores.
Calcium antagonists have widely different
chemical structures.
Calcium Channels
1. Voltage Sensitive Channels (-40mV) o Voltage sensitive Calcium
2. Receptor operated Channel (Adr and channels are
other agonists) heterogeneous (membrane
3. Leak channel (Ca++ATPase) spanning funnel shaped):
– L-Type (Long lasting
current) – SAN, AVN,
Conductivity, Cardiac and
smooth muscle
– T-Type (Transient
Current) – Thalumus,
SAN
– N-Type (Neuronal) –
CNS, sympathetic and
myenteric plexuses
Calcium antagonists block predominantly L-type
calcium channels, localized in myocardium
and myocytes
Plateau phase of AP
of blood vessels.
L-type channels
are connected
to the plateau
of the AP.
AP Calcium
antagonists
NA
Ca2+
(–) Receptor
Cell
wall VDCC ROCC
Ca2+
Sarcoplasmatic
reticulum
VDCC – voltage-dependent calcium channels
• Phenylalkylamines: Verapamil
• Dihydropyridines (DHPs):
1st generation: Nifedepine
2nd generation: Nicardipine, Nimodipine,
Felodipine, Isradipine
3rd generation: Amlodipine
• Benzothiazepines: Diltiazem
• Diarylaminopropylamine
ethers: Bepridil
• Benzimidazole-substituted
tetralines: Mibefradil
Calcium antagonists
cause a reduction
in coronary and
peripheral resistance,
lower the blood pressure
and oxygen demand.
Dihydropyridine derivatives
(e.g. amlodipine, felodipine, nifedipine,
nisoldipine) have no negative
chronotropic effect and do not impair
Effects on Vascular Smooth Muscle
• Ca++ channel blockers inhibit mainly L-type
• Little or no effect on receptor-operated channels or on release
of Ca++ from SR
• “Vascular selectivity” is seen with the Ca++ channel blockers
– Decreased intracellular Ca++ in arterial smooth muscle results in
relaxation (vasodilatation)  decreased cardiac afterload (aortic
pressure)
– Little or no effect of Ca++-channel blockers on venous beds  no
effect on cardiac preload (ventricular filling pressure)
– Specific dihydropyridines may exhibit greater potencies in some
vascular beds (e.g. nimodipine more selective for cerebral blood
vessels, nicardipine for coronary vessels)
– Little or no effect on nonvascular smooth muscle except bronchial,
uterine, biliary, vesical and intestinal
Effects on Recovery
Cardiac Cells
Resting Activated Inactivated
Nonconducting of conducting NC
C++ Ca++ Ca++
• Negative Inotropic, Chronotropic and Dromotropic

• Negative inotropic effect (myocardial L-type channels) –
WMC and ventricular fibres
• Negative chronotropic /dromotropic effects (L- and T-type
channels)
• Verapamil and diltiazem shows such effects but not DHPs
• Verapamil, diltiazem, and mibefradil depress SA node and AV
conduction – depression of pacemaker and conduction
• Dihydropyridines have minimal direct effects on SA node and AV
conduction – more selective for vascular smooth muscles
• Magnitude and pattern of cardiac effects depends on the
class of Ca++channel blocker
Amlodipine
normal frequently dihydropyridine
t1/2 31-47 h, 55-91% p.o. bioavailability
5-10 mg/24 h p.o. (once daily)
Nifedipine (tachycardic dihydropyridine)
– effective in vasospastic angina
Diltiazem (in SR dosage forms)
Verapamil (Isoptin SR® – tabl. 120 mg)
(22% p.o. bioаvailability, first pass effect –
extensive liver metabolism)
Verapamil
• Arteriolar dilatation and alpha blocking action – decrease in
total peripheral resistance – but modest lowering of BP
• Direct Cardiac depressant action (countered by reflex effects of
above)
• Overall, decrease in HR, slowed AV conduction and increased
coronary flow
• Available as 40, 80, 120 etc. tabs and also injections
• Drug Interactions:
– Verapamil and beta blockers – sinus depression and conduction
defects (asystole)
– Digoxin – digitalis toxicity (by decreasing excretion)
– Quinidine – Cardiac depression
Relative Cardiovascular Effects of
Coronary Suppression Suppression Suppression

Compound vasodilatation of cardiac of of
contractility SA node AV node
Verapamil ++++ ++++ +++++ +++++

Diltiazem +++ ++ +++++ ++++
Nifedipine +++++ + + 0
Nicardipine +++++ 0 + 0
ADRs of calcium antagonists
•Arterial dilation: headache, flush, dizziness,
ankle swelling (resistant to treatment with
diuretics but not with ACE inhibitors).
•Bradycardia and AV block (verapamil).
•Verapamil + beta-blockers: potentiate
cardiodepression.
•Tachycardia (nifedipine, nisoldipine).
•Constipation
(verapamil 8%, nifedipine 3%)
•Haemorrhagic gingivitis
(inhibition of collagen synthesis)
Adverse effects
• Patients with ventricular dysfunction, SA node or AV
conduction disturbances, WPW syndrome, and systolic
blood pressures below 90 mm Hg should not be treated
with verapamil or diltiazem
• Immediate-release forms of dihydropyridines (Nifedipine)
may increase mortality in patients with myocardial
ischemia – longer acting Nifedipine is used
– Also cause increase in angina frequency
– Cerebral Ischemia – rapid bringing down of BP
– Bladder relaxation – voiding difficulty
– Decrease in Insulin release
Pharmacokinetics
• High oral absorption, but high first pass metabolism (except
amlodipine) – individual variation and highly plasma protein bound
• Extensively distributed in tissues and metabolized in liver and
excreted in urine, eliminated in 22-6 Hrs (except amlodipine)
Drug Bioavailability Vd (L/kg) Active Elim. half life
% metabolite (hr)
Verapamil 15-30 5.0 Y 4-6
Diltiazem 40-60 3.0 Y 5-6
Nifedepine 30-60 0.8 M 2-5
Felodipine 15-25 10.0 None 12-18
Amlodipine 60-65 21.0 None 35-45
Desired Therapeutic Effects of
Calcium Channel Blockers for Angina
 Reduce frequency and severity of Classical and Variant angina
 Classical angina
• reduction in cardiac work by reducing afterload
• Increased exercise tolerance
• Coronary flow increase – less significant (fixed arterial block)
• But: short acting DHPs cause Myocardial Ischemia – due to
decreased coronary blood flow secondary to fall in mean BP,
reflex tachycardia and coronary steal
• Verapamil/Diltiazem a reduce O2 consumption by direct effect –
do not aggravate angina
 MI – Verapamil/Diltiazem as alternative to β-blockers
 Variant angina: Benefited by reducing the arterial spasm
CCBs – other Therapeutic Uses
• Hypertension
• Cardiac arrhythmia
• Hypertrophic Cardiomyopathy:
verapamil
• Nifedipine – Preterm labour (?) and
Raynaud`s disease; Verapamil –
migraine and nocturnal leg cramps
Pharmacotherapy of Angina Pectoris
Aim: 1. Relief and prevention of Individual attack; 2. Chronic Prophylaxis;
3. Measures to prevent Progression
1. Prevention of Individual attack:
• Short acting Nitrate as and when required basis
• GTN is the drug of Choice in all kinds of angina
• Dose: 0.3-0.6 mg SL
• If symptoms not relieved quickly – additional tabs at 5 min. interval (not more than 3 tabs at 5
minutes interval)
• Discard the remnant tab soon relieved – hypotension
• Acute Prophylaxis: GTN 15 minutes before a period of increased activity – exercise, sexual
activity etc. – lasts for upto 2 Hrs
2. Chronic Prophylaxis:
• Monotherapy with either of the 3 groups of Drugs – depends on stage and
associated cardiac disease
• May be Nitrates/Ca++ blockers/beta-blockers – beta blockers are preferred
• When Monotherapy fails: Go for combination of those Drugs (two drugs)
• When Two Drugs fails – go for all above 3 drugs
Combination Therapy of Angina
Use of more than one class of antianginal agent can reduce specific
undesirable effects of single agent therapy
Beta-Blockers or Nitrates Plus

Effect Nitrates Alone Channel Blockers Beta-Blockers or
Alone Channel Blockers
Heart Rate Reflex Increase Decrease* Decrease
Afterload Decrease Decrease Decrease
Preload Decrease Increase None or decrease
Contractility Reflex increase Decrease* None
Ejection time Decrease Increase None
Undesireable effects are shown in italics

* Dihydropyridines may cause the opposite effect due to a reflex increase in
sympathetic tone
4. Potassium Channel Openers –
Nicorandil, Pinacidil,
Minoxidil, Diazoxide
• MOA:
– Activation of ATP sensitive K+ channel – hyperpolarization of vascular smooth
muscle – relaxation of Smooth muscle
– Also acts as NO donor and increases cGMP – Arterio-venous relaxation
– Dilatation of all types of coronary vessels
• Benefits in angina (equipotent to nitrates, beta blockers and Ca++ channel
blockers)
– Reduced angina frequency
– Increased exercise tolerance
– Ischemic preconditioning for Myocardial stunning , arrhythmia and infarct size
(Mitochondrial K+ATP channel opening)
• ADRs: Flushing, palpitation, nausea, vomiting, aphthous ulcer
• Dose: available as 5, 10 mg tabs and also injection
5. Metabolic cardioprotective agents
Trimetazidine (Preductal MR®) has prolonged
concentration plateau lasting up to 11 h.
It increases ATP synthesis and decreases acidosis
in ischemic tissues.
The heart receives energy in the form of ATP molecules, which are
synthesized in cardiomyocytes through the oxidation of energy
substrates in mitochondria. The main energy substrates for
cardiomyocytes are: fatty acids, glucose and lactate (2/3 of ATP
are synthesized from fatty acids, 1/3 – from glucose and lactate).
Glucose oxidation requires less oxygen than fatty acids. The
accumulation of fatty acids and their metabolites in cardiomyocytes
during hypoxia has a cytotoxic effect on cell membranes,
additionally reduces the synthesis of ATP.
Trimetazidine inhibits the fatty acid oxidation enzyme –
acetylcoenzymA-acetyltransferase (thiolase) in the
mitochondria of cardiomyocytes, changes energy production
from fatty acid oxidation to glucose oxidation.
Blocking beta-oxidation, reducing Trimetazidine

the concentration of acidic
metabolic products in the cell
6. If-blockers
delays pulse rate with

Ivabradine
is a selective blocker of If channels of sinus node cells Inhibitor of
incoming ion current through mixed Na/K channels, which
• determine pacemaker activity,
• activated at the time of hyperpolarization, participate in the
occurrence of a phase of spontaneous slow diastolic depolarization
in the cells of the sinus node
• determine the heart rate.
Ivabradine – blocks If channels and reduces heart rate (by 10 beats
/min) without reducing the strength of heart contractions.
Its activity is comparable to propranolol, but it does not cause
bronchospasm and other side effects.
Causes visual disturbances (blocks retinal channels related to If
channels Ih – blurred image, increased brightness).
Contraindicated in AV block, bradycardia (less than 50 beats/min).
OTHER DRUGS
USED IN CORONARY
HEART DISEASE (CHD)
•Platelet antiaggregants
•Antifibrinolytics (Alteplase – t-PA)
•Antidyslipidemic drugs
•Anxiolytics, etc.
Pharmacotherapy
of MI
1. Aim:
 Emergency life saving management of the patient (ICU)
 Subsequent Treatments
2. Pain, anxiety and apprehension: Morphine, Pethidine parenteral
3. Oxygenation: assisted respiration
4. Maintenance of Blood Volume, tissue perfusion and microcirculation: slow
IV fluid with saline
5. Correction of acidosis: Sodibicarb IV
6. Prevention of Arrhythmia: Beta blockers early (arrhythmia and infarct size)
7. Pump Failure: Furosemide, NG IV/Nitroprusside and Dobutamine
8. Prevention of Thrombus extension and thrombo-embolism
9. Thrombolysis and reperfusion: Streptokinase, urokinase etc.
10. Prevention of future attacks: beta-blockers, aspirin, anti-hyperlipidemia
•Smoking 2/3 Risk factors
•Lipid status of the
risk for CVD
•Chomocysteine > 15 mmol/l
•Tachycardia
•body mass index (BMI) > 30:
>>> salt and >>> sugar
>>> alcohol
•Stress
Additional Measures
1. Hyperlipidemia, Diabetes and Hypertension -
Statins
2. Dietary Restriction – saturated fats
3. Smoking cessation
4. Lifestyle change – obesity reduction
5. Physical exercise
6. Daily intake of Vit. C and Vit. E
7. Antiplatelete Drugs – Aspirin etc.
ALTERNATIVE METHODS
FOR TREATMENT OF
ISCHAEMIC
HEART DISEASE
Rotational atherectomy (Rotablation) –
Chronic narrowing's or blockages may become calcified or have a lot
of atheroma in them making them very difficult to treat with just a
balloon. Rotablation is a procedure where, once again, a very fine
wire is guided through the narrowing and then a catheter with a small
device called a burr, similar to drill, mounted at its tip is guided to the
beginning of the narrowing. The burr is connected to an external
device which when activated by the cardiologist causes the burr to
spin at very high speeds inside the narrowing, thereby creating a
channel wide enough for a balloon or stent to then be used.
ANTI-GOUT
DRUGS
GOUT
A familial metabolic disease
characterized by recurrent episodes
of acute arthritis due to deposits of
monosodium urate in joints and
cartilage.
Associated with hyperuricemia.

Uric acid is a poorly soluble major
end product of purine metabolism.
GOUT
Treatment aims to:
 Relieve acute gouty attacks

- Colchicine, NSAIDs, corticosteroids
 Prevent recurrent gouty episodes

- Uricosuric agents
- Allopurinol
Pathophysiologic events in a gouty joint
CLASSIFICATION of
antigout drugs
1. Colchicum alkaloids
Colchicine
2. Nonsteroidal anti-inflammatory
drugs
Naproxen, indomethacin,
phenylbutazone, ibuprofen
3. Uricosuric agents
Probenecid, sulfinpyrazone
4. Urate synthesis inhibitors
Allopurinol, Febuxostat
COLCHICINE
An alkaloid (colchicum autumnale)
Relieves pain and inflammation of gouty
arthritis in 12-24 hrs
MOA
 inhibits the polymerization of tubulin (a
structural protein necessary for motility)
– inhibits leukocyte migration
 reduces the phagocytosis of urate
crystals by leukocytes
Pharmacokinetics
 Given orally, rapidly absorbed

from GIT.
 Metabolized in liver and GIT
 Partially metabolized and

excreted in urine and part of the
drug is recycled in the bile and is
excreted unchanged in feces.
Clinical uses
 Selective for an acute attack of

gouty arthritis, alleviating the
pain within 12 hours.
 Prophylaxis of recurrent attacks
of acute gout.
 In preventing attacks of acute
Mediterranean fever.
 Hepatic cirrhosis.
Colchicine
 Reliefpain and inflammation

of gouty arthritis within 12-24
hours.
 Has no analgesic effect

Adverse Effects
 Diarrhea – bloody
 Nausea, vomiting and abdominal pain
 Hair loss
 Bone marrow depression
 Peripheral neuritis
 Myopathy
 Acute intoxication: burning throat pain,

bloody diarrhea, shock, hematuria
 Fatal ascending CNS depression
Contraindication and
Precaution
 Contraindicated in pregnancy
 Should be used with caution in
hepatic, renal or cardiovascular
diseases.
NSAIDs:
 Anti-inflammatory (inhibiting urate crystal
phagocytosis) and analgesic effects
 Indomethacin is most commonly used NSAID –
uricosuric
 All NSAIDs except acetylsalicylic acid (aspirin),
salicylates and tolmetin
Aspirin in therapeutic doses is contraindicated as it

compete with uric acid secretion in proximal tubule
URICOSURIC AGENTS
PROBENECID
SULFINPYRAZONE
Organic acids
MOA
 inhibit the reabsorption of uric acid in the
proximal part of the nephron
 may also reduce secretion of uric acid
into the nephron (proximal tubule), but
reduction of reabsorption is the dominant
(and therapeutic) effect
Pharmacokinetics
 Probenecid is reabsorbed by the

renal tubules and slowly
metabolized.
 Sulfinpyrazone and its active
metabolite are excreted rapidly
through kidney.
 The duration of their effect after oral
administration is nearly the same
(4-6 hours).
CLINICAL USES
 Chronic gout (urine volume should

be maintained at a high level, and
urinary pH kept alkaline).
 Probenecid is a general inhibitor of
the tubular secretion of organic
acids, so it is used to prolong
action of other weak organic acids
as some antibiotics e.g. penicillin.
Adverse effects
 Gastrointestinal irritation, more with
sulfinpyrazone.
 Allergic dermatitis, more with
probenecid.
 Nephrotic syndrome with probenecid.
 Both of them rarely cause aplastic

anaemia.
ALLOPURINOL
Standard of care therapy in the intercritical

period
Reduces total uric acid body burden
MOA
 Allopurinol is converted to alloxanthine by
xanthine oxidase
 Inhibits the production of less soluble uric
acid by xanthine oxidase from more soluble
xanthine and hypoxanthine
 Those purine ribonucleotides not
incorporated into nucleic acids and
those derived from nucleic acid
degradation are converted to
xanthine or hypoxanthine and
oxidized to uric acid.
 Allopurinol inhibits the last step
decreasing the uric acid pool and
plasma uric acid.
Pharmacokinetics
 80% absorbed after oral administration.

 Metabolized to active metabolite
alloxanthine.
 Given once daily.
 Drug and its metabolite are excreted in
the feces and urine.
 short half-life (1-2 hours), but
metabolite alloxanthine (oxipurinol) has
a half-life of about 15 hours
CLINICAL USES
 Primary hyperuricemia
 Secondary hyperuricemia
 Recurrent renal stones
 In hyperuricemia secondary to
renal disease or after treatment
with chemotherapeutic agents
 When serum urate levels are
greatly increased
Adverse effects
 Acute attacks of gouty arthritis (prophylactic
treatment with NSAIDs or colchicine)
 GI intolerance
 Peripheral neuritis
 Necrotizing vasculitis
 Bone marrow depression
 Aplastic anemia
 Hepatic toxicity, Interstitial nephritis
 Allergic skin reactions-exfoliative dermatitis
 Cataract formation
Interactions
 Inhibits the metabolism of 6-
mercaptopurine and azathioprine so their
dosage must be reduced by 75%
 Prolongs t1/2 of warfarin and probenecid
(inhibits metabolism)
 May enhance the bone marrow toxicity of
cytotoxic drugs (cyclophosphamide)
Caution: Safety in children & during
pregnancy has not been established
FEBUXOSTAT
 Recently approved first non-purine

inhibitor of xanthine oxidase
 Safe in renal disease as highly
metabolized to inactive metabolites in
the liver
ANTIARRHYTHMIC
DRUGS
Cardiac Physiology
• Recall: to function
efficiently, heart needs to
contract sequentially
(atria, then ventricles)
and in synchronicity
• Relaxation must occur between contractions (not true for other

types of muscle [exhibit tetany  contract and hold contraction for
certain length of time]
• Coordination of heartbeat is a result of a complex, coordinated
sequence of changes in membrane potentials and electrical
discharges in various heart tissues
Myocardial Cells • 2 types – Pacemaker and non
pacemaker
– Pacemaker and conducting
cells – SAN, AVN, Bundle of
His and Purkinje`s fibers
– Non pacemaker – Working
Myocardial Cell
• Sinus rhythm means rhythm
originates in SAN
• Sinus tachycardia means
tachycardia but rhythm originates
in SAN – fever, exercise etc.
• Tachycardia = heart rate > 100 per
minute
• Sinus Bradycardia = heart rate < 60
per min.
BASIC ELECTROPHYSIOLOGY
Myocardial cells maintain transmembrane
ion gradients by movement of the Na+, Ca2+
and K+ through membrane channels.
The resting potential of a cardiac cell is
– 90 mV compared to the extracellular
environment.
Depolarization is initiated by a rapid influx
of Na+ (phase 0).
Rapid repolarization
Plateau
Depolarization
Final repolarization
Resting potential Spontaneous

depolarization
Cardiac Action Potential
• Divided into five phases (0,1,2,3,4)
– Phase 4 – resting phase
(resting membrane potential)
• At (-90mv) stable
• Phase cardiac cells remain in until stimulated
• Associated with diastole portion of heart cycle
• Addition of current into cardiac muscle (stimulation) causes
– Phase 0 – opening of fast Na channels and rapid depolarization
• Drives Na+ into cell (inward current), changing membrane potential
– Phase 1 – initial rapid repolarization
• Closure of the fast Na+ channels
• Phase 0 and 1 together correspond to the R and S waves of the
ECG
Cardiac Na+ channels
• Phase 2 – plateau phase

– sustained by the balance between the
inward movement of Ca++ and outward
movement of K+
– Has a long duration compared to other
nerve and muscle tissue
– Normally blocks any premature stimulator
signals
– Corresponds to ST segment of the ECG.
• Phase 3 – repolarization
K+ channels remain open, allows K+ to build up outside the cell, causing
the cell to repolarize K+ channels finally close when membrane potential
reaches certain level corresponds to T wave on the ECG
Cardiac action potential –
in relation with ECG
S
Cardiac Electrophysiology
Contraction of
ventricles
ECG
showing Contraction
Repolarization
of ventricles
wave segments of atria
In the AV node depolarization is
due to the slower influx of calcium ions.
This results in slower conduction of the
impulse through the AV node than in
other parts of the heart.
Cardiac Action Potential –
Pacemaker Cells
• PCs – slow, continuous

depolarization during rest
• Slow depolarization
during 0 phase
• Continuously moves
potential towards threshold
for a new action potential
(called a phase 4
depolarization)
•Funny current (If)
During the period between phase 0 and the
end of phase 2, the cell is refractory to the
further depolarization (absolute refractory
period) since the sodium channels are
inactivated.
During phase 3, a sufficiently large stimulus
can open enough sodium channels to over-
come the potassium efflux. This is the
relative refractory period.
Rapid repolarization
Plateau
Depolarization
Absolute Final repolarization

refractory period Relative refractory period
Threshold potential
Spontaneous depolarization
Resting membrane
potential
The cardiac action potential
Cardiac Arrhythmias
• Cardiac dysrhythmia (arrhythmia)
– there is abnormal electrical activity in the heart
– The hearts too fast or too slow, and may be regular or
irregular
– Results in rate and/or timing of contraction of heart muscle
that is insufficient to maintain normal cardiac output (CO)
• Result from disorders of impulse formation,
conduction, or both
• Causes of arrhythmias
– Cardiac ischemia
– Excessive discharge or sensitivity to autonomic transmitters
– Toxic substances
– Other
Cardiac Arrhythmias –
Clinical Classification
• Heart rate (increased / decreased)
– Tachycardia – heart rate fast (>100 beats/min)
– Bradycardia – heart rate slow (<60 beats/min)
• Heart rhythm (regular / irregular)
• Site of origin (supraventricular / ventricular)
• Complexes on ECG (narrow / broad)
PR interval, QRS complex, ST segment or QT complex
etc.
Irregularity in Cardiac Rhythm
• Bradyarrhythmia: Failure of impulse
generation resulting in slow heart rates
• Heart Block: Results from failure of impulse
to propagate normally from atrium to ventricle
– usually defect in AV node or His-Purkinje
system
• Tachyarrhythmias: Abnormally rapid
heart rhythms
Causes of Arrhythmia
Root causes: When the normal sequence of impulse
generation and propagation is perturbed
Cardiac Arrhythmias – Mechanism
1. Enhanced or ectopic pacemaker activity
– Catecholamine over activity
– Injury current in damaged myocardial
cells, e.g. Myocardial ischemia
2. After-depolarization
– Depolarization at phase 3
– Related to Ca++ current, e.g. digitalis
toxicity
3. Reentry Phenomenon
Arrhythmias –
pacemaker acticity
• Enhanced Automaticity: Pacemaker cells or

ordinary fibres
– Results due to patholgical increase in phase 4 slope –
accelerated pacemaker rate
– May result from current of Injury
– Physiology: ACh reduces such pacemaker rate – by
decreasing phase 4 and hyperpolarization
– Ventricular wall cells (WMCs) may also show such
pace maker activity – due to ischaemia
•AUTOMATICITY
Subsidiary (or ectopic)
Spontaneous depolarization
pacemakers may
develop when a site
in the myocardium
develops a more
rapid phase
4 depolarization Threshold potential
than the SA node,
e.g. as a result
of ischemia.
Triggered
Activity
• A normal AP interrupted/followed by a abnormal
depolarization (a triggering rhythm)
Delayed After Depolarization: Caused by Digoxin toxicity,
Myocardial Ischaemia or Adrenergic stress or Heart
failure – due to Ca++ overload
Early After Depolarization: Due to interruption in
phase 3 repolarization
 Causes: Slow heart rate, Hypokalaemia and drugs prolonging QT
interval – quinidine, sotalol, procainamide etc. (block IK channel)
Torsades de pointes: due to marked prolongation of APD
– polymorphic ventricular tachycardia – long QT interval
and frequent changing of QRS
After
depolarization
– EAD and DAD
MECHANISMS OF ARRHYTHMOGENESIS
Arrhythmias can arise as the result of

abnormal impulse generation or abnormal
impulse conduction. The main mechanisms:
•RE-ENTRY (the most frequently): if an

impulse arrives at an area of tissue when
it is refractory to the stimulus, this impulse
will be conducted by an alternative route.
If the impulse again reaches the “blocked”
tissue distally when it has had sufficient
time to recover, the same impulse will be
conducted retrogradely (re-entry).
This retrograde
conduction
is slow, because
to initiate a circuit
of electrical acti-
vity, the healthy
tissue has to be
given time
to repolarize.
Such a mechanism can initiate a
“loop” of electrical activity which
acts as a pacemaker.
The re-entry circuit can be localized
within small a area of the myocardium
or it can exist as a large circuit, for
example between the atria and
ventricles.
Functionally defined
reentry
Ventricular fibrilation
Atrial fibrillation
Reentry Phenomenon –
Accessory pathway (WPW syndrome)
Fractionation of Impulse
• Increased Vagal activity – Atrial ERP brief
and inhomogenous
• Premature impulses get conducted by
fibres having short ERP – then to the
fibres with longer ERP and so on
• Asynchronous activation of atrial
fibres – inhomogenicity – Atrial
fibrilation etc.
Arrhythmia Conditions
• Extrasystole: abnormal automaticity/after depolarization
• Paroxysmal Supraventricular Tachycardia: 150-200/minute (1:1),
reentry phenomenon (AV node)
• Atrial Flutter: 200-350/minute (2:1), reentrant circuit in right atrium
• Atrial Fibrillation: 350-550/min, electrophysiological inhomogenicity
of atrial muscles (bag of worms)
• Ventricular tachycardia: 4 or more consecutive extrasystole of
ventricles
• Ventricular Fibrillation: rapid irregular contractions – fatal (MI,
electrocution)
• Torsades de pointes: polymorphic ventricular tachycardia, rapid
asynchronous complexes, rise and fall in baseline of ECG
• Atrio-ventricular Block (A-V Block): vagal influence or ischemia –
1st, 2nd and 3rd degree
Antiarrhythmic Drugs
• Biggest problem – antiarrhythmics can cause arrhythmia!
– Example: Treatment of a non-life threatening tachycardia
may cause fatal ventricular arrhythmia
– Must be vigilant in determining dosing, blood levels, and in
follow-up when prescribing antiarrhythmics
• Mechanism of action:
– Sodium channel blockade
– Blockade of sympathetic autonomic effects
– Blockade of Effective Refractory Period (ERP) –
increase ERP/APD ratio
– Calcium Channel Blockade
Antiarrhythmic Drugs
Vaughan-Williams classification:
• Class I – Na+ Channel Blockers

• Class II – Beta-adrenergic Blockers
• Class III – Prolong Repolarization
• Class IV – Calcium Channel Blocker
Vaugham-Williams
classification
• Class I – Na+ Channel Blockers
– 1a: quinidine, procainamide, disopyramide
– 1b: lidocaine, mexilitine, phenytoin
– 1c: propafenone, flecainide, moricizine
• Class II – Beta-adrenergic Blockers – propranolol,
esmolol, acebutalol etc.
• Class III – K+ channel blockers: amiodarone,
sotalol (II + III action) and bretylium
• Class IV – Ca++ channel blockers: verapamil,
diltiazem
ANTIARRHYTHMIC DRUGS (AAD)
I. AAD used in tachyarrhythmias
The Vaughan William’s

Classification of AAD
is based on their
effects on the cardiac
action potential (AP).
Class I – antiarrhythmics
Class I antiarrhythmics: are further classified to
Ia, Ib and Ic – based on repolarization and potency of Na+
blockade – state dependant manner
Na+ blockade: Ic>1a>1b ERP: 1a>2c>1b

Class I (membrane stabilizers)
These AAD slow the rate of raise of phase 0
of AP by inhibiting fast sodium channels.
The class is subdivided according to the
effects of drugs on the duration of AP.
Indications: SV and ventricular arrhythmias.
IA IB IC
Increase Decrease No effect on
the duration of AP the duration the duration
IA IB IC
Disopyramide Lidocaine Propafenone

Procainamide Mexiletine Flecainide
Ajmaline Phenytoin
- weak negative inotropic effect
Quinidine
ADRs: Bradycardia, AV block, (–) inotropic
effect, disturbances of GIT, rashes
Cinchona succirubra Rauwolfia serpentina
•Quinidine •Ajmaline
•Chinine •Reserpine
Subclass – IA – quinidine,
procainamide, disopyramide
• Binds to Na+ channels in open state and prevent conduction of

ions (Refractory – Rest – Open – Refractory) – Moderate sodium
channel blockade in open state
• Prolong refractoriness by blocking several types of potassium
channel
• Delayed Na channel recovery
• Delayed AV conduction
• Useful in conditions where Na+ channels open frequently –
ectopic beats – atrial tachycardia and atrial fibrillation and
ventricular arrhythmias
• Abolish reentry – unidirectional block to bidirectional block
• Electrophysiology changes: Lengthen action potential, slow rate
of rise of phase 0, Prolong repolarization ---------------- also
prolong AV node ERP – ECG changes: Prolong PR, QRS, QT
Subclass – IB – lidocaine,
mexiletine, phenytoin
• Lowest potency for Na+ channel blocker
– inactivated state
• Do not delay channel recovery
• EP changes: Shorten action potential, Limited
effect on rate of rise of phase 0, Shorten
repolarization ------------- no ERP effect on
AV node (shorten)
• ECG: Shorten QT
• Used in Treatment and prevention of ventricular
tachycardia and fibrillation after Myocardial
Infarction – lidocaine IV
Subclass – IC – flecainide,
propafenone, moricizine
• Marked Na+ channel blockade in open state – with longest recovery
time
• Refractory period of AV node is increased – marked delay in
conduction
• Electrophysiology changes: No effect on length of action potential,
Markedly reduces rate of rise of phase 0 and ---------- marked delay
in AV conduction with little effect on repolarization
• ECG: markedly prolong PR and QRS complex
• Prolong refractoriness by blocking outward-rectifying potassium
channels
• General reduction in excitability
• Used in life threatening ventricular fibrillation since they have highest
affinity to Na+ channels involving AV node – WPW syndrome and
Paroxysmal atrial fibrillation
Antiarrhythmic Drugs – Quinidine
• Dextroisomer of Quinine: Na+ channel blocking and antivagal action
• Actions:
– Inhibition of Na channel – slanted 0 phase and Decreases phase 4
– Net result is delay in conductivity and increase in refractoriness
– Other actions include – alpha blockade, decreased skeletal muscle
contractility, vomiting and diarrhoea etc.
• Kinetics: well absorbed orally, half life – 10 Hrs
• Uses:
– Broad spectrum antiarrhythmic
– Atrial fibrillation and flutter, AF after direct current cardioversion to
maintain sinus rhythm, prevention of PSVT and prevention of
ventricular tachycardia
• Adverse effects: it is rarely used now for adverse effects like
Proarrhythmia (torsades de pointes), sudden cardiac arrest, cinchonism.
Antiarrhythmic Drugs – Procainamide
• Procaine derivative (amide)
• Identical action with quinidine except:
– Minimal antivagal action
– Lesser suppression of ectopic automaticity
– Lesser depression of automaticity and AV conduction
– No alpha blocking action
• Kinetics:
– Absorbed orally and bioavailability is 80%
– Metabolized in liver to N-acetyl-procainamide (NAPA) – blocks K
channel and prolongs repolarization
• Dosage – 250 mg tabs and 1gm/ml injections
– Antiarrhythmic – 0.5 to 1 gm oral followed by 0.25-0.50 mg every 2 Hrs
• Uses: Mainly for monomorphic VTs and to prevent recurrences
Antiarrhythmic Drugs – Lidocaine
• Popular antiarrhythmic and also local anaesthetic (membrane
stabilizing action)
• Lowest potency for Na+ channel inactivated state – ECTOPIC Foci
– Enhance phase – 4 depolarization in partially depolarized or stretched
PF – After depolarization antagonized – no effect on SAN
– Practically no action on Atrial fibres
– Rate of 0 phase in AVN and ventricles – not affected
– Reduction in APD in PF and ventricular myocardium
• Actions:
– Selective action on partially depolarized and cells with long APD –
normal ventricular and conducting fibres – not affected
– Suppression of automaticity in ectopic foci (reentry) – one way or two
way block
– Enhanced phase-4 depolarization in partially depolarized or stretched
PF (APD long)
– Little effects on cardiac contractility and arterial BP
Antiarrhythmic Drugs – Lidocaine
• Kinetics: Ineffective orally, given IV lasts for 10-20 minutes.

Therefore given as IV bolus 50-100 mg followed by 20-40
mg every 10-20 minutes. Half-life prolonged in CHF (coz.
Vd decreases) and 70-80% metabolized by liver
• Adverse effects: Neurological – drowsiness,
paresthesia, blurred vision, nystagmus and fits etc.
– No proarrhythmic effects – no cardiotoxicity
• Uses: 50-100 mg bolus and 10-20 mg every 20 minutes
– 1st line of drug in Arrhythmia following acute MI and cardiac
surgery
– Prevention of ventricular tachycardia
– Digitalis toxicity – no AV block
Treatment: Lidocaine, Ajmaline
Ventricular fibrillation, characterized
by irregular undulations without
clear ventricular complexes.
Treatment: Lidocaine or
electrical defibrillation
Ventricular flutter
Class II (-adrenoceptor antagonists)
Reduce the rate

of spontaneous depo-
larization of sinus
and AV nodal tissue
by indirect blockade
( cAMP)
of calcium channels.
Indications: SV and Pindolol, Propranolol
ventricular arrhythmias. Atenolol, Esmolol
• Block beta-1 receptor in heart and decreases heart rate
• Adrenaline causes ventricular extrasystole and
fibrillation by increasing the slope of phase 4
depolarization
– Also increases spontaneous firing of SA node
• AV conductions also needs sympathetic activity – Beta
blockers prevent these activity
• Drugs used are beta-blockers: Propranolol, Esmolol,
Acebutlol etc.
• Propranolol – Membrane stabilizing effect like quinidine
on heart – high doses – clinical dose: cardiac
adrenergic blockade
• Clinical doses (antiarrhythmic effect) – Block beta-1
receptor in heart and decreases heart rate
1. Decrease in phase 4 depolarization and automaticity in SA
node, AVN, PF and other ectopic foci (Adrenaline causes
ventricular ES and fibrillation by increasing the phase 4
depolarization !!!)
2. Prolongation of ERP of AVN – impede AV conduction
• Uses:
– Reduce mortality after MI
– Arrhythmias associated with increased sympathetic activity –
sinus tachycardia, atrial extrasystoles provoked by emotion and
exercise
– Less effective in PSVT than adenosine and verapamil
Uses of Propranolol
• Arrhythmias associated with increased sympathetic activity
– sinus tachycardia, atrial extrasystoles provoked by
emotion and exercise
• Less effective in PSVT than adenosine and verapamil
• Propranolol is used to treat sympathetically mediated
arrhythmias – phaeochromocytoma and halothane
anaesthesia
– Sinus tachycardia, atrial and nodal extrasystole and nodal
extrasystole provoked by exercise
Does not abolish AF or Afl but decreases ventriculsar rate
• Reduce mortality after MI – anti-ischaemic action
• Esmolol IV – quickly terminates AF and flutter and used in
emergency control of arrhythmia due to anaesthetics
Esmolol
(short action)
Atrial flutter with a 4:1 conduction ratio

Class III
These AAD prolong
the duration of the AP
and increase the abso- Amiodarone (p.o.; i.v. inf.)
t1/2 20–100 days ADRs: bradycardia,
lute refractory period. hypo/hyper thyreoidism,
This is the result of corneal micro-deposits under
reduced influx of K+ pupil, neuritis n. opticus,
pulmonary fibrosis.
into the cell. Dronedarone (contains no iodine
Ind: SV and ventri- but has hepatotoxic effect)
cular arrhythmias. Sotalol, Bretylium
Class III
• Class III drugs K channel blockers prolong repolarization

(increase refractoriness) by blocking outward potassium
conductance
– Prolongation of Cardiac action potential
– Also have interaction with the ANS
– Diverse Pharmacology which is poorly understood
• Drugs – amiodarone, dronedarone, sotalol (II + III action)
and bretylium
• Bretylium is used only in life threatening arrhythmias
Class III – Amiodarone
Long acting and highly lipophilic and Iodine containing
compound
MOA: multiple actions
1. Blocking of delayed rectifier K+ channel – prolongs APD
2. Weak class I (lidocaine like) – depresses conduction in
partially depolarized and long APD
3. II (beta-blocker) – NC alpha and beta; and class IV actions
4. Also direct coronary and peripheral vasodilator
• Overall – Slowed conduction and suppressed automaticity
Kinetics: Incompletely and slowly absorbed – daily oral dose is
given for several days for actions to develop, t1/2 = 3-8 weeks
Dose: 400-600 mg/day p.o for many days followed by 100-200
mg/day as maintenance (100-300 mg slow IV)
Class III – Amiodarone
Uses:
• Most tachyarrhythmic conditions – ventricular and
supraventricular
• Recurrent VT and VF
• WPW syndrome
Adverse effects:
• Photosensitization – skin pigmentation
• Peripheral neuropathy – weak shoulder and pelvic muscles
• Myocardial depression – bradycardia
• Pulmonary alveolitis and fibrosis – kept below 200 mg
• Corneal micro deposits – on long term use
• Hypothyroidism, goiter – inhibition of T4 to T3
Drug Interactions: Digoxin and warfarin (reduced renal clearance)
Class IV (calcium channel antagonists)
Mainly Verapamil
(22% oral availability)
and Diltiazem (i.v.) from
calcium antagonists
have specific action
on the SA and AV
nodes. They decrease
the duration of AP. ADRs: headache, edema,
Ind: SV arrhythmias. bradycardia, AV block
Class IV – Antiarrhythmics
• Three important classes:
– Phenylalkylamines – hydrophilic Verapamil
– Dihydropyridines – lipophilic Nifedepine
– Benzothiazepines – hydrophilic Diltiazem
• Verapamil and diltiazem: are useful in Arrhythmia
• Relatively selective AV nodal L-type calcium
channel blockers – depression of Ca++ mediated
depolarization and delay recovery
– Slows SA node automaticity
– reduced phase 4 depolarization in SAN and PF – extinction
of latent pacemakers and DAD
– Prolongation of AVN ERP – reentry terminated
– Negative ionotropic action
Class IV – Antiarrhythmics
• Relatively selective AV nodal L-type calcium channel blockers – slow sinus rhythm,
prolong PR interval, no effect on QRS complex
(Verapamil, Diltiazem)
– Sinus Bradycardia – SA node and PF
– AV block – no reentry
– Negative inotropic effect – interference with Ca++ mediated contraction
• MOA:
– Block L-type channels – Phase 4 depolarization of SA and PF reduced
– Reduce slow inward current and force of contraction
– Also slow conduction of AV node due to calcium channel blockade
• Uses: Verapamil
– PSVT:
– For termination of attack – 5 mg IV over 2-3 minutes (reflex bradycardia)
– For prevention of attack 60-120 mg orally tds
– Reduce ventricular rate in Atrial fibrillation (AF) and Atrial flutter – with digitalis
Atrial fibrillation
Other drugs used in tachyarrhythmias
Digoxin reduces conduction
through the AV node and is useful in the
control of atrial flutter and atrial fibrillation.
Adenosine inhibits AV conduction.

The duration of effect is less than 60 s.
•used as an i.v. bolus in
•SV tachycardia with narrow QRS complex.
Adenosine
• Endogenously produced important chemical mediator used in PSVT
• MOA:
– Activation of ACh sensitive K+ channel - membrane hyperpolarization
– of SA node (G-protein coupled adenosine receptor A1)
– depression of SA node and also slowing of AV conduction
– shortening of action potential in atrium and reduced excitability
– Also indirectly reduces Ca++ current in AV node – depression of reentry in
PSVT
• Very short half life – 20-30 sec. – Uptake by RBCs and endothelial cells
– Administered intravenously
– 6 mg given as a rapid intravenous bolus (administered over a 1-2 second
period)
– If the first dose does not result in elimination of the supraventricular tachycardia
within 1-2 minutes – 12 mg should be given as a rapid intravenous bolus
• ADR: bradycardia, AV block, chest tightness, dyspnoea, fall in BP and flushing etc.
When Antiarrhythmics?
• Asymptomatic and those which do not interfere
haemodynamics – AES, VES, 1st degree block
and bundle branch block – no need of
treatment
• Therapy needed:
– Life threatening VT, TdP and VF
– Causing breathlessness, hypotension and
cardiac failure
– Marked palpitation – PSVT, VT, AF and TdP
– Myocardial infarction
Non-pharmacological treatment
• Acute
– Vagal manoeuvres
– DC cardioversion
• Prophylaxis
– Radiofrequency ablation
– Implantable defibrillator
• Pacing (external, temporary,
permanent)
II. AAD used in bradyarrhythmias
Atropine is given
by bolus i.v. inj.
in sinus brady-
cardia and AV
block. It blocks
M2-receptors and
increases conduction
through the AV node.
Isoprenaline
is used in AV block
The Pacemaker
• Surgical implantation of electrical leads
attached to a pulse generator
1) Leads via subclavian vein and advanced to
the chambers on the vena cava (right) side of
the heart
2) 2 leads – right atrium, and right ventricle
3) Pulse generator containing microcircuitry and
battery are attached to leads and placed into a
“pocket” under the skin near the clavicle
4) Pulse generator sends signal – to contract
atria, then ventricles
• Pulse generator – sense electrical
activity – only deliver electrical impulses
when needed.
• Pacemakers: can only speed up a heart
experiencing bradycardia, cannot alter a
condition of tachycardia
III. AAD used in Digitalis arrhythmia
Phenytoin
Digitalis purpurea Potassium
(foxglove) chloride
Magnesium
aspartate
•Digoxin-
specific FAB
(Fragment
AntiBody)
Digitoxin Digoxin
PROARRHYTHMIC ACTIVITY OF AAD
All AAD have the potential to precipitate
serious arrhythmias, particularly ventri-
cular tachycardia or fibrillation.
Mainly the AAD from class IA prolong
the Q-T interval which predisposes to the
development of a polymorphic ventricular
tachycardia known as “torsades de pointes”.
Torsades de Pointes
Polymorphic ventricular tachycardia
with a twisting axis on the ECG
ECG: The frequency of the ventricular rhythm is from 200
to 300 per minute and above, the amplitude of the
complexes is different, their direction alternates: they are
either above or below the baseline, as if they are rotating,
"dancing a pirouette" around it.
QRS complexes
expanded 0.12 s;
The RR intervals are
not the same,
fluctuations in the
range of 0.2-0.3
seconds;
Outside of the
attack, the length of
the QT interval is
greater than normal.
Arrhythmias torsades de pointes may appear when
treated with the following drugs in large doses:
antiarrhythmic drugs that prolong the QT interval:
quinidine, procainamide, sotalol, disopyramide,
amiodarone;
psychotropic drugs (antidepressants);
beta-adrenomimetics: salbutamol, terbutalin,
phenoterol
antibacterial drugs: erythromycin and other macrolides;
antihistamines: astemizole, terfenadine;
diuretics: furosemide, indapamide;
prokinetics: metoclopramide;
antifungal drugs: ketoconazole, fluconazole.
Polymorphic ventricular tachycardia
with a twisting axis on the ECG – Dangerous
arrhythmia, can lead to fibrillation and death.
Torsades de Pointes: Treatment
Treat hypokalemia if it is the precipitating factor and administer
magnesium sulfate in a dose of 2-4 g i.v. initially.
Magnesium is usually very effective, even in the patient with a
normal magnesium level. If this fails, repeat the initial dose, but
because of the danger of hypermagnesemia (depression of
neuromuscular function) the patient requires close monitoring.
Other therapies include overdrive pacing and isoprenaline infusion.
Most (75-82%) torsade de pointes rhythms are started by a
pause. Pacing at rates up to 140 bpm may prevent the ventricular
pauses that allow torsade de pointes to originate.
The patient with torsade who is in extremis should be treated
with electrical cardioversion or defibrillation .
HEMATOPOIETIC DRUGS
Hematopoiesis (formation of blood)
a complex process of proliferation, differentiation, and
maturation of cellular components of blood
(erythrocytes, leucocytes and platelets) from the bone
marrow stem cells. It is regulated by balanced
interaction between endogenously derived
hematopoietic growth factors and exogenously
supplied essential nutrients (hematinics). Inadequate
supply of either the growth factors or the hematinics
results in deficiency of normal blood cells which is
manifested as anemia, thrombocytopenia or
neutropenia.
Hematopoietic growth factors
are glycoproteins that control and maintain the
production of various blood cell lineages from
pluripotent hematopoietic stem cells and multipotent
progenitors. A number of these factors (also called
cytokines) have been cloned and produced for
clinical use: Erythropoietin; Myeloid Growth Factors
(Colony Stimulating Factors) – Granulocyte-
Macrophage Colony Stimulating Factor (GM-CSF) and
Granulocyte Colony Stimulating Factor (G-CSF); and
Megacariocyte (Thrombopoietic) Growth factors –
Interleukin-11 and Trombopoietin.
Hematinics (iron, vitamin B12 and folic acid) and
accessory hematinics (vitamin C, riboflavin,
pyridoxine and certain minerals like Cu, Co and
Mn) are also necessary for blood cell maturation
and physiological turnover under basal conditions
and on demand.
Thrombocytopenia and neutropenia are not rare
and CSF therapy is used for their prevention and
treatment in patients with immune deficiency,
being on radiotherapy or receiving
myelosuppressive chemotherapy.
Anaemia is the most common objective sign of a
deficiency in oxygen-carrying erythrocytes. It is classified
according to the size of erythrocytes (microcytic and
macrocytic or megaloblastic) and their haemoglobin
content (hypochromic or hyperchromic) or to the cause of
the condition: haemorrhagic anaemia (due to acute or
chronic blood loss), haemolytic anaemia (due to
damaged red cell membranes and destruction of
erythrocytes), aplastic and hypoplastic anaemia (caused
by bone marrow damage), deficiency of essential
nutrients (iron deficiency anemia, megaloblastic
anemias) and genetic alteration in the hemoglobin
molecule (hemoglobin-S in Sickle cell anemia).
Erythropoiesis in bone marrow
Classification of hematopoietic drugs
A. Drugs for Anemia
1. Drugs for treatment of iron deficiency (microcytic, hypochromic) anemia
 Oral preparations of iron (Fe2+)
 Ferrous sulfate: Ferro-gradumet, Hemofer prolongatum (film-tabl.
325 mg, 105 mg Fe2+; 1 tab. b.i.d. after meals), Tardyferon depot (80
mg Fe2+ included in mucoprotein obtained from intestinal mucosa of
sheep; absorption continues 7 h; 1-2 tab. q.d.)
 Ferrous glutamate: Glubifer
 Ferrous aspartate: Ferrospartin (tab. 350 mg, 50 mg Fe2+)
 Ferrous fumarate: Ferronat
 Ferrous gluconate: TOTHEMA® (amp. Fe2+ gluconate 50 mg; Mn2+
gluconate; Cu2+ gluconate)
 Ferric hydroxide polymaltose complex: Maltofer (1 ml sol. contains
50 mg unionized Fe3+ hydroxide polymaltose complex)
A. Drugs for Anemia
1. Drugs for treatment of iron deficiency (microcytic, hypochromic) anemia
 Parenteral preparations of iron (Fe3+)
 Iron sucrose complex: Venofer
 Iron isomaltoside: Monofer
 Iron dextran: Dexferrum®*, Ferrum Lek®
 Sodium ferric gluconate complex: Ferrlecit®
 Cobalt agents:
 Coamid – amp. 1%-1 ml
 Fercoven
2. Drugs for treatment of megaloblastic (macrocytic, hyperchromic) anemias
 Vitamin B12 (Cyanocobalamin) – amp. 250 mcg/1 ml i.m.
 Folic acid
Iron chelators: Deferoxamine (Desferal), Deferasirox (Exjade)
B. Hematopoietic Growth Factors
1. Erythropoietins
 Erythropoietin: Epoetin alfa (Eprex), Epoetin beta (Recormon)
 Darbepoetin alfa (Aranesp)
 Methoxy polyethylene glycol-epoetin beta (long-acting erythropoietin
receptor activator): Mircera
2. Myeloid growth factors
 Granulocyte Colony Stimulating Factor (G-CSF): Filgrastim
(Neupogen), Lenograstim (Granocyte)
 Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF):
Molgramostim (Leucomax), Sargramostim (Leukine)
3. Megakaryocyte (Thrombopoietic) Growth Factors
 Oprelvekin (IL-11): Newmega
 Thrombopoietin
1. Drugs for treatment of iron deficiency
Iron deficiency anemia is microcytic

hypochromic anemia, caused by insufficient
supply of iron. It is the most common type of
anemia. Iron deficiency in normal conditions
may occur more often in women (with menstrual
blood loss or pregnancy), in adolescents
(increased demand) and in vegetarians or
persons with malnutrition (inadequate dietary
iron intake).
Pharmacokinetics of iron
The total body iron is about 3.5-4 g in men and 2.5 g in women, and over
70% of it circulates in the blood as haemoglobin. About 15-18% is stored in
the liver, spleen and bone marrow mainly as ferritin and haemosiderin.
Maximum iron absorption occurs by active transport in the duodenum and
proximal jejunum. Absorption rate depends on the ratio of apoferritin (a
protein) to ferritin (apoferitine-iron complex) in the intestinal mucosa. The so
called “mucosal block” is a mechanism that prevents the entry of excess iron
in the body. Ascorbic acid and SH-group containing amino acids (in gastric
juice) facilitate Fe3+ to Fe2+ conversion and promote its absorption. Iron
absorption is hindered by coffee, tea, antacid agents, phosphates (rich in
egg yolks), tetracyclines, etc. In the body iron is distributed into:
haemoglobin (Hb) – 66%; iron storages (ferritin and haemosiderin) – 25%,
myoglobin in muscles – 3%, and parenchimal iron (as prostetic group in
cytochrome, peroxidases, catalases, xanthine oxidases and other cellular
enzymes) – 6%. Haemoglobin contains 0.33% iron and 50 mg elemental iron
is averagely lost with the loss of 100 ml blood (15 g Hb).
The preferred route of iron administration is oral.
Elemental iron quantity per dose should be taken into
consideration. Oral preparations contain ferrous
(Fe2+ ) salts (sulfate, glutamate, aspartate, fumarate,
gluconate, succinate, etc.). Ferric (Fe 3+) salts are also
available (Ferric hydroxide polymaltose complex, Iron
polysaccharide, etc.), but ferrous (Fe2+) salts are
supposed to be better absorbed. A number of iron
combinations (with vitamins, minerals, amino acids,
etc.) are marketed, but should be considered irrational
due to lower iron content.
About 50-100 mg of iron can be incorporated into
hemoglobin daily, and about 25% of oral iron can be
absorbed. Full haemopoetic response in adults is
usually achieved with administration of 200 mg
elemental iron daily p.o. in 2 or 3 divided doses
after or in between meals. Absorption of iron is much
better when taken in empty stomach, but side effects
may limit patient compliance. For prophylactic use, a
daily dose of 30 mg elemental iron is sufficient.
In severe anemia, treatment with oral iron should be
continued for at least 3 months after correction to
replenish iron stores.
Parenteral iron preparations are indicated only in
case of:
• severe deficiency with chronic bleeding
• intolerance to oral iron
• malabsorption or inflammatory bowel disease
• erythropoietin therapy (to meet the increased
needs of induced erythropoiesis)
Parenteral forms contain organically complexed salts of
unionized iron: Iron dextran, Iron sucrose complex, etc.
A sensitivity test with a small test dose must be performed before
parenteral administration of iron to avoid any risk of
hypersensitivity reactions.
Iron – side effects
• Iron salts can cause constipation, diarrhea (rarely),
epigastric pain, heart burns, nausea, vomiting, metallic
taste, and staining of teeth (mainly with oral liquid or
chewable preparation).
• Local reactions: Pain at the site of action, skin
pigmentation, sterile abscess.
• Systemic side effects: Fever, headache, joint pain,
urticaria, lymphadenopathia; anaphylactoid reaction
(palpitation, chest pain, dyspnoea, cardiovascular
collapse) may occur with iron-sorbitol preparations, but
rarely with other preparations).
Iron – toxicity
Acute iron toxicity occurs mostly in young children after
accidental ingestion of iron tablets. Severe intoxication is
clinically presented with necrotizing gastroenteritis (vomiting,
abdominal pain, haematemesis, diarrhoea), lethargy, cyanosis,
dehydration, convulsion, shock and metabolic acidosis. Coma
and death may result (12-36 Hours). Unfortunately, activated
charcoal, does not work here.
• Desferrioxamine (Deferoxamine), an iron chelator, is a specific antidote
that is given systematically to remove iron: 0.5 to 1 g IM repeated 4-12
Hourly or IV 10-15 mg/kg/Hour (max 75 mg/day) till serum levels fall.
• Prevent further absorption: Induce vomiting or gastric lavage with
NaHCO3 – to render Iron insoluble and also Egg yolk and Milk orally
• Supportive: Fluid and electrolyte, correction of acidosis and Diazepam
Iron – toxicity
Chronic iron toxicity (hemochromatosis) occurs in
persons with an inherited abnormality of iron absorption
or with frequent transfusions (eg, thalassemia major).
Iron chelators (deferoxamine or the oral agent
deferasirox) are used in the treatment of chronic iron
overload.
2. Drugs for treatment of
megaloblastic anemias
Megaloblastic anemia is clinically manifested with a
deficiency in serum hemoglobin and erythrocytes in
which the erythrocytes are hyperchromic, fragile and
abnormally large. It results from either folate or vitamin
B12 deficiency. Pernicious anemia is a form of
megaloblastic anemia resulting from reduced intestinal
absorption of vitamin B12 (extrinsic factor) due to
deficiency of intrinsic factor (a protein produced by
parietal cells of the gastric mucosa). Parenteral
injections of vitamin B12, but not oral preparations, are
effective for treatment of pernicious anemia.
Vitamin B12
Cyanocobalamin (vitamin B12 – amp. 250 mcg/1 ml i.m.).
Cyanocobalamin and hydroxocobalamin are complex
cobalt-containing compound present in diet and referred to
as vitamin B12. Vitamin B12 is essential for cell growth and
multiplication. Along with folic acid, it is involved in the DNA
synthesis as a cofactor in the transfer of 1-carbon units.
Two biochemical reactions require vitamin B12: conversion
of methylmalonyl-coenzyme A (CoA) to succinyl-CoA and
conversion of homocysteine to methionine.
Methylcobalamin and deoxyadenosylcobalamin are the
active forms of the vitamin.
Vitamin B12
Conversion of homocysteine to H4 folate and methionine is
conjugated with the conversion of cobalamin to methylcobalamin.
Vitamin B12 deficiency results in deficiency of folate cofactors for
DNA synthesis and megaloblastic anemia occurs first. This
biochemical interaction explains why high doses of folic acid can
improve the anemia, caused by insufficient supply of vitamin B12.
Conversion of methylmalonyl-CoA to succinyl-CoA requires
desoxycobalamin. Vitamin B12 deficiency results in accumulation
of methylmalonyl-CoA, synthesis of abnormal fatty acids and
neurologic defects, which may become irreversible if not treated
promptly. The disruption of methionin synthesis is also supposed
to be involved in the neuronal damage.
Vitamin B12
Absorption: Present in food as protein conjugates – released by
cooking/proteolysis – intrinsic factor (Castle) forms a complex with
Vit. B12 – attaches to specific receptor in mucosa – absorbed by
active transport
Transport: In combination with transcobalamin II (TCII) –
congenital absence/abnormal protein (liver disease) – defective
supply to tissues
Storage: In liver – 4/5th of Body`s Vit.B12
Degradation: Not degraded in body – excreted mainly in bile –
enterohepatic circulation
Parenteral – completely absorbed – IM and SC administration –
excreted via urine
The minimal requirement: ≈ 1 μg/day.
Vitamin B12
Vitamin B12 deficiency is manifested by megaloblastic
anaemia, glossitis, peripheral neuritis, paresthesias, poor
memory, mood changes, hallucinations, etc. It is clinically
used for treatment of megaloblastic anaemia, tobacco
amblyopia, neuropathies and psychiatric disorders.
Hydroxocobalamin is highly protein-bound and longer
acting, but is associated with the development of
antibodies (hence lesser in use).
Vitamin B12 and folic acid – Side effects and toxicity
Both substancies are well tolerated and neither their form
has significant toxicity.
Folic acid
Humans do not synthesize folic acid and meet theirs
requirements from green leafy vegetables, fruit, mushrooms,
liver, meat, kidney, eggs, milk and yeast. In the intestinal
mucosa of jejunum folic acid is reduced by dihydrofolate
reductase to tetrahydrofolic acid. Tetrahydrofolic acid through
1-C carbon transfer reactions is involved in the synthesis of
purines and pyrimidines which are essential for DNA
synthesis.
Deficiency of folic acid leads to megaloblastic anaemia and
teratogenic effects (spina bifida, etc.). Vitamin B9
prophylactically can be used during pregnancy and lactation
– 0.4 mg p.o. daily)
Folate Deficiency:
1) Increased Demand (pregnancy

and lactation)
2) Poor Absorption
caused by pathology of
the small intestine
3) Alcoholism
4) Treatment with drugs that are
Dihydrofolate Reductase
Inhibitors – Methotrexate,
Trimethoprim, Co-trimoxazole
[Sulfamethoxazole +
Trimethoprim]
3. Haematopoetic Growth Factors
Erythropoetin: Epoetin alfa and Epoetin beta (Recormon).
Erythropoietin stimulates erythrocyte proliferation and
differentiation by acting on specific receptors (JAK-STAT-kinase)
present on red cell progenitors and promotes the release of
reticulocytes (alters phosphorylation of intracellular proteins and
activates transcription factors to regulate gene expression). It is
used to treat anemia in chronic renal failure or anemias secondary
to cancer chemotherapy or HIV treatment, bone marrow
transplantation, AIDS, cancer.
Erythropoietin can provoke an increase in hematocrit, blood
viscosity and peripheral vascular resistance. Hypertension,
thrombotic complications and flu-like symptoms (rare) may occur.
For prevention of CV complications, it is recommended to maintain
hemoglobin levels < 12 g/dL.
Myeloid Growth Factors (Colony
Stimulating Factors – CSFs)
Granulocyte (G) and Granulocyte-Macrophages (GM) CSFs are
cytokines. They accelerate the formation of matured leucocytes by
acting on many progenitor cells.
Filgrastim (recombinant G-CSF), Lenograstim (rG-CSF),
Molgramostim (rGM-CSF) and Sargramostim (rGM-CSF) are used:
• to reduce the severity and duration of neutropenia induced by
cytotoxic chemotherapy, radiotherapy or following bone marrow
transplant
• to treat congenital neutropenia, cyclic neutropenia and
neutropenia associated with aplastic anaemia
Pegfilgrastim is a PEGilated (covalently conjugated to PolyEthylene
Glycol polymer chain) form of filgrastim with a much longer t1/2 than
the recombinant G-CSF.
Filgrastim (G-CSF) is lineage-specific growth factor –
supports Proliferation, Differentiation and Functional
Activity of neutrophils causing a rapid rise in leucocytes
within 2-3 days in patients with normal bone marrow
function or 7-14 days in patients with bone marrow
suppression.
Clinical uses: to decrease incidence of infection
• after cancer chemotherapy for non-myeloid malignancies
• chronic severe neutropenia
• after bone marrow transplantation in cancer patients
• agranulocytosis, pancytopenia, acute leukaemia
myelodysplastic syndrome
• hematologic toxicity with drug therapy
Molgramostim (GM-CSF) has broader actions than G-CSF.
• stimulates Proliferation and Differentiation of Granulocytic
Progenitor Cells as well as Erythroid and Megakaryocyte
progenitors
• increases functional activity of mature neutrophils, enhancing
phagocytosis
GM-CSF acts together with IL-2 to stimulate T cell proliferation
and appears to be a locally active factor at the site of
inflammation.
• mobilizes peripheral blood stem cells, but it is significantly less
efficacious than G-CSF in this regard
• enlarges the extent of expression of “respiratory explosion”
(ensuring formation of 90% active forms of O2 and which is
one of the most important mechanisms of phagocytosis)
Side effects of Myeloid Growth Factors: G-CSF is better
tolerated than GM-CSF. It may cause fever, bone pain
(10-15%), myalgia, and vasculitis. GM-CSF is more likely
to provoke fever, arthralgia, myalgia and skin rash.
Megakaryocythe Growth Factors. Oprelvekin (IL-11)
and Thrombopoietin stimulate the growth of
megakaryocytic progenitors and increase the number of
peripheral platelets. They are used to treat
thrombocytopenia following cancer chemotherapy.
Side effects: IL-11 treatment is associated with dizziness,
headache and fatigue. Recombinant human trombopoietin
is supposed to be better tolerated.
DRUGS ACTING ON BLOOD CLOTTING
AGENTS USED FOR PROPHYLAXIS AND
TREATMENT OF THROMBOSIS
1. PLATELET AGGREGATION INHIBITORS
2. ANTICOAGULANTS
3. THROMBOLYTIC AGENTS
Haemostasis
BLEEDING
Haemostasis: Arrest of Bleeding – The Physiological mechanism
which results in stoppage of bleeding after an injury
Primary haemostasis: platelet aggregation – platelet plug
formation (plus local vasospasm) – sealing of gap
Blood clotting:
• Intrinsic: within blood vessels
• Extrinsic pathway: extravagated blood
Secondary haemostasis: Stabilizes
– Intrinsic: prevents further escape of Blood
– Extrinsic: plugs the gap in the blood vessels
Weak blood clot: Without platelet aggregation
Platelet Aggregation
• Glycoprotein (GP) integrin Receptors
• Platelet Activation: Collagen reacts with GPIa and GPIb
receptors via vWF
• Release of TXA2, ADP and 5-HT etc.
• Conformational changes at GPIIb/IIIa – binding of
fibrinogen – cross linkage – Platelet PLUG formation
• Thrombus in arteries – only mass in Arteries; In veins –
Red tail – antiplatelet drugs are useful
• Balance between PGI2 and TXA2 – controls intavascular
Thrombus
The role of platelets
Coagulation cascade
N (12-14 s) N (26-32 s)
The activated partial thromboplastin time (aPTT or APTT)

The prothrombin time (PT) are blood tests that characterizes coagulation of the blood
Thrombus and Embolus
Blood clots – a clot adheres to blood vessels (usually arteriole) –
Thrombus – Pathological!!!
Thrombus dislodges and floats in blood vessels from arteries and
veins – Embolus (Pathological)
Emboli can block arterioles in the lung and pulmonary circulation
–Thromb: May lead to Deep vein thrombosis, Myocardial
infarction, Unstable angina, rheumatic heart disease
–Arterial Thrombosis: Adherence of platelets to arterial wall –
White in color – Often associated with MI, stroke and ischemia
(fibrin clot)
–Venous Thrombosis: In areas of stagnated blood flow (deep
vein thrombosis), Red in color – Associated with Congestive Heart
Failure, Cancer, Surgery
Thrombus formation and pharmacological interventions in
the coagulation cascade
Antiplatelet Drugs
a) Irreversible inhibitors of platelet COX-1, which
prevent TxA2 production: Acetylsalicylic acid (Aspirin)
(100-150 mg/24 h), Indobufen
b) Platelet ADP inhibitors (tienopyridines, P2Y12
Receptor Blockers): Clopidogrel, Prasugrel, Ticlopidine
c) Inhibitors of GP IIb/IIIa fibrinogen receptors
(disintegrins): Abciximab, Eptifibatide, Tirofiban (i.v.
infusion with heparin)
d) Analogues of PGs: Alprostadil (PGE1), Iloprost (PGI2)
e) Inhibitors of Phosphodiesterase: Dipyridamole
Thrombus formation and pharmacological interventions in
the coagulation cascade
PLATELET AGGREGATION
INHIBITORS
(ANTIPLATELET AGENTS)
Indications:
• myocardial infarction (Low doses of aspirin or
aspirin/clopidogrel are used to reduce mortality and to prevent
reinfarction)
• unstable angina (aspirn/clopidogrel), coronary bypass
implants (antiplatelet agents are used to maintain the patency
of implanted bypass vessel)
• prosthetic heart valves and arterio-venous shunts
• venous thromboembolism and peripheral vascular disease
• cerebrovascular transient ischaemic attacks
(aspirin/clopidogrel or aspirin/dipyridamole)
The platelet aggregation cascade
Inhibitors of platelet aggregation
Acetylsalicylic acid
(Aspirin)
MOA: Acetylates COX 1 and TX-synthase – irreversible inactivation – in

portal circulation (Deacetylation of Aspirin) occurs in liver
• TXA2 formation suppressed – fresh enzyme synthesis takes time – at low
doses
• Prolongation of bleeding time for 5-7 days
• Cumulative effect – 40 mg/day – max. at 160 mg
• Low doses – only TXA2 but higher doses both TXA2 and PGI2 (Clinically
irrelevant)
• In vessel wall – PGI2 suppression – can synthesize new enzymes
• At low doses (75-150 mg/day) – selective suppression of TXA2 – higher
doses – both TXA2 and PGI2
• Also inhibition of ADP – sticking interfered
Acetylsalicylic acid – major use
• Secondary prevention of transient
ischaemic attack (TIA), ischaemic
stroke and myocardial infarction
• Prevention of ischaemic events in
patients with angina pectoris
• Prevention of coronary artery bypass
graft (CABG) occlusion
Ticlodipine
Thienopyridine derivative – Prodrug (active
metabolites in liver): Alters surface receptors on
Platelets and inhibits ADP and fibrinogen induced
platelet aggregation
MOA:
1. Gi coupled P2Y12 (P2YAC ) receptor mediates ADP induced adenylyl cyclase
inhibition – blocked – platelet activation interfered
2. Also prevents binding of fibrinogens to platelets – but does not interfere GPIIb/IIIa
receptors
3. TXA2 is not affected – but bleeding time prolonged – platelet survival in extra-
corporeal circulation increased
4. Synergistic action with aspirin
Kinetics: Well absorbed orally – converts to active metabolite in body – single

dose Half life 8 hrs – cumulates – peak effect 8-10 days – lasts for 5-6 days
P2Y Receptors
Ticlodipine – Uses
• Secondary prevention of Stroke, TIA, Intermittent
claudication
• Unstable angina
• PCI (percutaneous coronary intervention)
• Coronary artery bypass surgery
• Prophylaxis of MI
• With aspirin prevents restenosis after PCI and
stent
ADRs: Diarrhoea, vomiting, abdominal pain,
headache, tinnitus, skin rash
Bleeding, neutropenia, thrombocytopemia and jaundice
Limited Use – replaced by Clopidogrel
Clopidogrel
Similar MOA to Ticlodipine – irreversible blockade of platelet
function – Safer and better tolerated than Ticlodipine
Advantages over Aspirin in Ischaemia – lower incidence of
ischaemic events
Synergistic action with aspirin – prevention of Ischaemic episodes
Kinetics: Prodrug like Ticlodipine, 50% absorbed orally
Only a fraction slowly activated in liver by CYP2C19 slow acting
CYP2C19 – genetic polymorphism – interindivdual variability in
antiplatelet action
Takes 5-7 days for action
ADRs: Bleeding most common, neutropenia and
thrombocytopenia rarely
Dose: 75 mg OD
Prasugrel
Newer, most potent and faster P2Y12 purinergic receptor blocker
Preferred in Acute Coronary Syndromes (ACS) and when strong antiplatelet
action required
Prodrug – but faster and complete absorption – completely activated
CYP2C19 substrate – but Genetic polymorphism related decrease and DI with
Omeprazole is rare
Uses: STEMI, ACS to cover angioplasty
• Comparison with clopidogrel in ST-elevation MI (STEMI) or a non-ST
elevation MI (NSTEMI)– Prasugrel – better in reduction in death due to
CVS causes
• Superior results in reduction of STENT thrombosis
ADRs: Bleeding complications – severe, Intracranial haemorrhage – in TIA
and stroke patients
CI: Ischaemic stroke and TIA
Dose: 10 mg OD (available as 5 and 10 mg tablets)
Dipyridamole – Vasodilator – used in angina
Powerful coronary dilator – increases total
coronary flow
MOA:
• Phosphodiesterase enzyme inhibitor
• increases cAMP conc.
• Inhibits uptake of Adenosine in Platelets – increase c AMP cAMP – Overall, Resistance
Potentiates PGI2 (prostacyclin) vessels
• Levels of TXA2 and PGI2 are not altered – life span increased
Uses: Used to enhance the action of Warfarin and Aspirin in TE events

– Risk of stroke in TIA – 150-300 mg / day
– To decrease the incidence of
thromboemboism in prosthetic heart valve
– TIA – risk of stroke reduced
– As vasodilator: myocardial perfusion
imaging (Thallium scanning)
Dipyridamole (Curantil, Persantine) – Kinetics
• Incompletely absorbed from the gastrointestinal tract with peak
plasma concentration occurring about 75 minutes after oral
administration
• More than 90% bound to plasma proteins A terminal half-life of
10 to 12 hours
• Metabolised in the liver
• Mainly excreted as glucuronides in the bile; a small amount is
excreted in the urine
• Available as 75 mg and 100 mg preparations
Pentoxifylline (Trental)
inhibits PDE, decreases platelet and
erythrocytes aggregation, has
desaggregational properties, enhances
fibrinolysis, lowers viscosity, improves
microcirculation.
GPIIb/IIIa receptor antagonists
Newer potent platelet aggregation inhibitor –
Abciximab, eptifibatide and tirofiban
Blocks the key receptor involved in platelet
aggregation
Collagens, thrombin, TXA2 and ADP etc. – acts
through – GLP IIb/IIIa is an adhesive receptor
(integrin) on platelet surface
GLP IIb/IIIa antagonists block platelet
aggregation
GPIIb/IIIa-receptor antagonists –
mechanism of action
mechanism of action
mechanism of action
mechanism of action
mechanism of action
ABCIXIMAB
ReoPro 2 mg/ml
IV injection
a Humanized Monoclonal Antibody

directed against the platelet
Glycoprotein IIb/IIIa Receptor Complex and
inhibits platelet aggregation
Abciximab
Chimeric monoclonal antibody against – GPIIb/IIIa receptor But
nonspecific – binds to some other proteins also
Available only in IV form – intravenous bolus dose followed by
continuous IV – with aspirin + heparin during PCI (reduced restenosis –
MI and Death)
After a bolus dose: action remains for 12-24 Hrs, t1/2 – 10-30 min
After continuous infusion: after stoppage – clears rapidly in 6 Hrs – then
slowly – remains in blood for 15 days
ADRs: Haemorrhage, Thrombocytopenia – should not be repeated 2nd
time, paralytic ileus, constipation, arrhythmia – nonantigenic
Drawback: Expensive
Uses: Unstable angina and as an adjuvant to coronary
thrombolysis/PCI with Stent application
Eptibatide
• Synthetic – selective to platelet GPIIb/IIIa
receptor
• Longer plasma half life – but inhibition of
platelet reverses sooner (6 hours)
Uses: Unstable angina, coronary angioplasty
– Given with aspirin and heparin
ADR: Bleeding, thrombocytopenia,
anaphylaxis
Uses of Antiplatelets
Coronary Artery Disease:
• MI: Immediately after MI low dose aspirin
• Aspirin: routinely used after thrombolytic therapy to prevent reocclusion;
to cover PCI with heparin
• Unstable angina: Aspirin reduces risk of MI
• Primary and secondary prevention of MI: Evidence of coronary artery
disease – aspirin
Cerebrovascular Disease: Do not have much effect but prevents TIAs
Coronary angioplasty, stents etc.: patency of re-canalized artery or
implant bypass vessels improved – re-occlusion reduced
Prosthetic Heart Valve and Arteriovenous shunts: reduce formation of
microthrombi in heart valves
Venous Thromboembolism
Peripheral Vascular Disease
Coagulation Cascade
Coagulants
a) Local Haemostatics
• Sterile, gelatin-base haemostatic sponges: Gelaspon® (applied
topically as an adjunct to haemostasis when the control of bleeding
by conventional procedures is ineffective to reduce capillary ooze or
is impractical)
• Sterile, collagen-base haemostatic sponges: Tachocomb® (a local
haemostatic agent; composed of fibrinogen, thrombin, and aprotinin
integrated into the surface of a collagen fleece)
• Fibrin Sealants (obtained from human plasma) are used in dental
procedures
• Vasoconstrictors for temporary haemostasis: to stop epistaxis by
packing a cotton gauze with 1% Epinephrine or 0.5% Oxymetazoline
• Miscellaneous: Solutio Hydrogenii peroxydi diluta 3% (Solution of
Hydrogen Peroxide 3%)
b) Systemic Coagulants
• Calcium salts (Ca2+ – clotting factor IV): Calcium chloride (i.v.),
Calcium gluconate
• Vitamin K: Phytomenadionе (vitamin K1 is fat-soluble, obtained from
leafy vegetables), Menaquinone (vitamin K2) is synthesised by intestinal
bacterial flora), Menadionе (vitamin K3 is a synthetic analogue).
Vitamin K is required for the synthesis of four clotting factors from the liver cells: II
(prothrombin), VII (proconvertin), IX (Cristmas factor) and X (Stuart factor).
Indications of phytomenadion:
• prolonged antibiotic use
• overdose of oral anticoagulants
• newborns of or premature infants (because they have low level of prothrombin and
other clotting factors)
• malabsorption syndrome/obstructive jaundice
• liver diseases (cirrhosis, viral hepatitis)
10 mg IM – 5 mg 4 hrly
ADRs: Flushing, breathlessness, fall in BP and sense of constriction in chest.
Menadione K3 – haemolysis – G6PD deficiency
Coagulating (Clotting) Factors
a) For treatment of Haemophilia- A or B:
Blood coagulation factor VII (Pronconvertin)
b) For treatment of Haemophilia-A: Blood
coagulation factor VIII (Antihaemophilic factor-A)
c) For treatment of Haemophilia-B: Blood
coagulation factor IX (Antihaemophilic factor-B)
d) For prophilaxis or treatment of
haemorrhagic diathesis in hypo- or
afibrinogenemia: Fibrinogen (clotting factor I)
Intrinsic Pathway Extrinsic Pathway
Blood Vessel Injury Tissue Injury
XII XIIa Tissue Factor

Recall !
Thromboplastin
XI XIa
IX IXa VIIa VII
X Xa X
Prothrombin Thrombin
Factors affected
By Heparin Fibrinogen Fribrin monomer
Vit. K dependent Factors Fibrin polymer
Affected by Oral Anticoagulants XIII
Anticoagulants
• To reduce the coagulability of blood
• Blood clots – Thrombus
Arterial Thrombosis:
• Adherence of platelets to arterial walls – “White” in color – Often
associated with MI, stroke and ischemia
Venous Thrombosis:
• Develops in areas of stagnated blood flow (deep vein thrombosis),
“Red” in color – Associated with Congestive Heart Failure,
Cancer, Surgery
• Thrombus dislodge from arteries and veins and become an embolus
• Venous emboli can block arterioles in the lung and pulmonary
circulation
• Thromboembolism
Anticoagulants
Indications: Anticoagulants reduce blood clotting which
can help prevent deep vein thrombosis, pulmonary
embolism, myocardial infarction and ischemic stroke.
A. Parenteral anticoagulants
a) Group of Heparin (indirect thrombin inhibitors)
▼Low molecular weight heparins (s.c. application):
Enoxaparin, Nadroparin (Fraxiparine), Parnaparin etc.,
incuding synthetic low molecular weight heparins
(Fondaparinux − s.c.)
▼Sodium salts of Heparin (i.v. infusion or s.c.
application).
b) Prepararations of antithrombin:
Antithrombin III
c) Direct thrombin inhibitors (used in heparin-
induced thrombocytopenia): Argatroban,
Bivalirudin (synthetic analogue of Hirudin),
Hirudin (peptide in the saliva glands of Hirudo
medicinalis), Lepirudin (r-Hirudine)
B. Oral anticoagulants
a) Oral indirect-acting anticoagulants
(Vitamin K antagonists)
▼Coumarin derivatives
Heparin
• Mixture of straight chain mucopolysaccharides
with MW 10,000 to 20,000 D
• Contains polymers of two sulfated disaccharides:
D-glucosamine-L-iduronic acid and
D-glucosamine-D-glucoronic acid
• Strongest organic acid in our body – strong
electronegative charge
• Mast cells – all tissues (75,000)
• Get from – lung and intestine of Pig
Heparin: origin, structure and mechanism of action
Heparin
Mechanism of action: Antithrombin III (AT-III) plays a crucial
role in natural endogenous anticoagulant mechanisms by
blocking the activity of activated clotting factors XII (Hageman
factor or contact factor), XI (Plasma thrombopastin antecedent),
X (Stuart factor or thrombokinase), IX (Christmas factor) and II
(thrombin). Heparin accelerates AT-III activity 1000 folds
especially against clotting factors IIa and Xa, but low molecular
weight heparins and fondaparinux accelerate AT-III activity only
against clotting factors Xa (thrombin is not).
Antiplatelet action: high doses
prevents platelet aggregation
prolongs bleeding time.
Heparin mechanism of action
Heparin
Antithrombin III
Heparin
Kinetics: Highly ionized, not absorbed orally – given IV (instant
action) and SC (slow action)
Does not cross BBB or placenta (In contrast to coumarins and is not
associated with foetal malformationpregnancy – in thrombophlebitis !)
Mast cell release – destroyed by macrophages
100 U/kg dose half life – 1 hr after IV – long among cirrhotic and
kidney diseases
Unitage: Variable molecular size – bioassay
1 U = prevents 1ml of citrated sheep plasma for 1 hr (0.2 ml of CaCl2 1%)
Heparin sodium: 1 mg – 120-140 U
Dosage: IV Bolus followed by continuous IV (e.g. 5000 to 10,000
U followed by 750-1000 U/hr continuous IV)
Not IM, SC may be used – haematoma
Heparin
Adverse effects:
• Bleeding due to overdose – haematuria is 1st sign.
Excessive bleeding may be managed by suspending the drug or
treating with protamine sulfate
• Heparin-induced thrombocytopenia and thrombosis
(HITT): abnormal antibodies activating platelets – aggregation of
platelets
• Hypersensitivity – urticaria, rigor, fever and anaphylaxis
• Alopecia and osteoporosis
Contraindications: Bleeding disorders, Severe hypertension,
GIT ulcer, malignancy, Ocular and neurosurgery, Chronic
alcoholism, cirrhosis etc.
Aspirin and antiplatelet drugs – caution
Protamine sulfate
• Strongly basic drug with low MW Source Fish sperm
• 1 mg neutralizes 100 U of heparin
• Administration needs judgment of heparin administered
and metabolized
• Used infrequently – action of heparin disappears itself –
whole blood transfusion
• Mainly used to terminate heparin action quickly – after
cardiac surgery
• In heparin absence – itself is weak anticoagulant
• Releases histamine – hypersensitivity
Dosage of Heparin
Unitage: Expressed in units as it is standardized by
bioassay – variable molecular size
1 •mg = 120-140 U activity
Administered
• as IV bolus 5000-10,000 U followed by
1000 U/hr IV drip – adjusted with aPTT value
• Pretreatment aPTT value and followed by 1.5 to 2.5 times
during therapy
Alternate: 10,000-20,000 deep SC every 8 Hrly (fine
needle)
•
Or, Low dose SC – 5000 SC 8-12 Hry before and after
surgery to prevent deep vein thrombosis (DVT)
Clinical uses of Heparin:
 Pulmonary Embolism and Deep Vein Thrombosis
 Myocardial Infarction and Unstable Angina
 Prevention of Thromboembolism
 Intravascular Catheters
 Anticoagulation during pregnancy

Low Molecular Weight Heparin (LMWH)
MW: 2000 to 6000
Fraxaparin – syringe 0.3 ml, 0.5 ml, 1 ml (1 ml-9,500 IU),
Enoxaparin
MOA: Acts only by interfering with Xa – inducing conformational change in AT III – smaller
effect on aPTT – whole blood clotting time
Lesser antipatelet action and lower incidence of haemorrhagic complications
–
Better Bioavailability on SC administration (once daily dosing)
Better half life (4-6 Hrs) –
Laboratory monitoring not needed (aPTT and – clotting time affected little)
Uses:
• Prophylaxis of DVT and Pulmonary embolism in Surgery, stroke and
immobilized patients
• DVT
• Unstable angina and MI
• Rheumatic heart disease and Atrial fibrillation
• Haemodialysis patients
Direct Thrombin Inhibitors
Lepirudin: Recombinant preparation of Hirudin –

Leech (Hirudinaria granulosa)
• Injected IV in heparin induced thrombocytopenia
• No antidote
Bivalirudin and argatroban – similar
▼Coumarin derivatives
Neodicumarin, Acenocoumarol and Warfarin
Mechanism of action: These drugs competitively inhibit vitamin-K
Epoxide reductase, resp. synthesis of clotting factors II
(prothrombin, resp. thrombin), IX (Christmas factor or plasma
thromboplastin component or antihaemophilic factor-B) and X
(Stuart factor or thrombokinase) by the liver. The anticoagulant
effect develops within 1-3 days.
Antidote: Phytomenadione (vitamin K1). Fresh frozen plasma or
factor IX concentrate, which contains large amounts of
prothrombin complex, can also be i.v. infused.
Acenocoumarol (Sintrom – t1/2 8-11 h) Tab 2 and 4 mg
Neodicumarin (Tab 0.05 and 0.1 g)
▼Indandiones: Phenindione – Tab 0.03 g
Clinical Uses of Neodicumarin:
 Thrombophlebitis
 Deep Vein Thrombosis
 Myocardial Infarction
 Artificial Heart Valves
 Atrial Arrhythmias
Warfarin
Tab 2 and 10 mg
In vivo, not in vitro
MOA: Competitive antagonist of
Vit.K – lowers the plasma level of vit.
K dependent clotting factors
– Inhibits VKOR needed to generate active
Vit.K
•
Synthesis of clotting factors
diminishes within few hours – at
different
• times by diff. factors
But anticoagulant action starts in 1-3 NAD – Nicotinamide adenine dinucleotide
days only NADH – its reduced form
Commercially, mixture of R and S

enantiomers
Warfarin
Kinetics: Completely absorbed from intestine and 99%
plasma protein bound – only 1% free which results in their
low Vd. It is a reason for unwanted drug interactions (incl.
displase of plasma proteins from co-trimoxazole, aspirin,
indometacin, phenytoin, probenecid). t1/2 40 h
Dosing: Risk – calculate risk-benefit ratio
• Dose is individualized by repeated measurement of PT
• Optimum ratio of PT: 2-2.5 in prophylaxis of DVT, 2-3 in DVT
treatment and 3-3.5 in MI etc.
Uses: DVT, Pulmonary embolism, myocardial infarction,
unstable angina, after placing artificial heart valves, persistent
forms of atrial fibrillation (drug of choice – 3-4 wks before and
after conversion)
Warfarin
ADRs: Bleeding – epistaxis, haematuria, GIT bleeding,
Intracranial haemorrhage
Minor bleeding – Vit K (takes long)
Fresh blood transfusion or blood factors
Other: transient alopecia, dermatitis, diarrhoea
Contraindications: Same as heparin
Coumarin derivatives cross the placenta and can lead to
haemorrhagic disorders in the foetus, Foetal warfarin
syndrome: skeletal abnormality – hypoplasia of nose, eye
socket, hand bones and growth retardation
Warfarin
• Factors enhancing warfarin effect: (1) Debility,
malnutrition etc. (2) Liver diseases, chronic alcoholism (3)
Newborn (4) prolonged antibiotic therapy
• Factors decreasing warfarin effect: Pregnancy, Nephrotic
syndrome and genetic warfarin resistance
• Drugs enhancing anticoagulant action: Broad spectrum
antibiotics, Aspirin (platelet aggregation inhibition and
hypoprothobinemic action), Newer cephalosporins
(hypoprothobinemic; Chloramphenicol, allopurinol,
tolbutamide and phenytoin (inhibits metabolism)
• Drugs reducing effect: Barbiturates, carbamazepine,
Rifampicin
b) Oral direct-acting anticoagulants (used for the
prevention of venous thromboembolism in adult patients
undergoing elective hip or knee replacement surgery). They
does not require frequent blood tests for international
normalized ratio monitoring, while offering similar results in
terms of efficacy.
Direct factor Ха inhibitors: Apixaban, Rivaroxaban
Direct thrombin inhibitors: Dabigatran (Pradaxa®). It offers an
alternative to warfarin as the preferred orally administered
anticoagulant ("blood thinner"), including to prevent strokes in
those with atrial fibrillation due to causes other than heart
valve disease, and at least one additional risk factor for stroke
(congestive heart failure, hypertension, age, diabetes, and
prior stroke)
FIBRINOLYTIC (THROMBOLYTIC) DRUGS
I. Non-selective Activators of
Profibrinolysin:
Streptokinase
Urokinase
Streptodekase
II. Selective activators of Profibrinolysin:
Alteplase
Fibrinolytics
Drugs used to lyse thrombi/clot to
recanalize
• occluded vessels – coronary
artery
MOA: Produce more plasmin – dissolves
fibrin thread
Drugs: Streptokinase, urokinase,
alteplase (rt-PA), reteplase and
tenecteplase
Streptokinase – once popular
– Binds to plasminogen and generate plasmin

– Non-specific – activates circulating + fibrin bound
plasminogen – non-specific fibrinogen depletory – but less
effect than newer ones in fibrinolysis
Fibrinolytics
Mechanism of action: Fibrinolytics block activiation of
plasminogen to plasmin, which in turn dissolves the fibrin
network as the wound gets healed. As compared to arterial
thrombi, venous thrombi are lysed more easily, and recent
thrombi are lysed better than older ones.
Indications: Fibrinolytics used to treat acute myocardial
infarction, peripheral arterial thrombosis/embolism and for
unclotting catheters and shunts.
ADRs: Haemorrhage is the major side effect of this drugs. As a
result, an unsuspected peptic ulcer may bleed following their
use. Unfortunately, increased availability of a local thrombus at
the site of fibrin clot, may enhance rethrombosis after the lysis of
the initial clot. The allergenicity to Streptokinase is the highest.
Alteplase (Tissue Plasminogen Actiavator – t-PA) is now prepared by
recombinant DNA technology using human tissue culture. However, alteplase
has short t1/2 (5-10 min) and shows high incidence of reocclusion, thus
necessitating concomitant use of i.v. Heparin also. It is expensive.
Reteplase is also a recombinant tissue plasminogen activator, but it has a
longer t1/2 (15-20 min).
Streptokinase is a protease enzyme, obtained from beta-haemolytic
streptococci. It has t1/2 1 h. As a foreign protein, hypersensitivity reactions
(rashes, fever, hypotension) are frequent (about 3%). Prior presence of
antistreptococcal antibody may reduce its efficacy and it cannot be repeated
within one year. However, it is the least expensive.
Tenecteplase is a genetically engineered mutant from alteplase, but with a
longer t1/2 (2 h). It is given as a single bolus injection over 5 sec. It is very
expensive!
Urokinase is a protease enzyme which is now produced from cultured
human kidney cells. It is nonallergenic, nonpyrogenic and does not produce
hypotension (unlike streptokinase).
Streptokinase (amp 250,000 and 500,000 IU) –
a non-selective Activator of Profibrinolysin,
the enzyme extracted from cultures of
Hemolytic Streptococci.
It activates Plasminogen (Profibrinolysin) of thrombus and
serum to form Plasmin (Fibrinolysin), which
degrades fibrin
and break up
thrombi.
Alteplase and Tenecteplase
Recombinant tissue plasminogen activator (rt-PA) – human
tissue
• culture – costlier than Streptokinase
MOA: tissue specific thrombolytic (acts on fibrin bound
plasminogen within thrombus) – also interferes with circulating
plasminogen (50%) – inactivated by PAI-1
Plasma half life 5 minutes – given slow IV (heparin needed)
MI: 1o mg IV bolus – followed by rest 90 mg infusion for 90
minutes Pulmonary embolism: 100 mg slow IV for 2 Hrs
Tenecteplase: genetically engineered, higher fibrin
selectivity, not inactivated by PAI-1, can be injected
over 10 seconds single bolus
Uses of Thrombolytics
• AMI – alternative to PCI with stent

placement – aspirin + heparin co-
administered to prevent re-occlusion
• DVT: leg, pelvis and shoulder
• Pulmonary embolism
• Stroke: selected patients
Agents to Treat Bleeding (Hemostatics)
1. Agents enhancing Coagulation of blood:
for Local Application:
Thrombin – amp 125 AU
Sponges hemostatic
System Action:
Gelatin
Fibrinogen
Calcium chloride, Calcium gluconate
Adroxon
Dicynon (Etamsylat)
Vitamin K
Protamine sulfate
Adroxon (amp. 0.025% 1 ml)
• Hemostatic action
• It is used to stop capillary and parenchymatous
bleeding in traumas, during surgery and for
prevention of post-operative bleeding and
haematomas.
Adroxon is used:
a) Locally – gauze bandage or tampon moistened with
0.025% solution
b) IM or SC 0.025% 1 ml 1-4 times during or after
surgery
Ethamsylate (Dicynon) – amp. 12.5% 2 ml IV or IM,
Caps. 0.25 g
Antihyaluronidase Action – improves Capillary Wall stability
• Inhibits PGI2 production
• Corrects abnormal platelet function
Clinical uses: Prevention and Treatment of Capillary Bleeding in:
• Menorrhagia, after Abortion, Postpartum Haemorrhage
• Epistaxis (nosebleed)
• Malena (tarry stool)
• Haematuria
• After tooth extraction.
Antifibrinolytics
Mechanism of action: The aminoacid agents competitively
inhibit activation of plasminogen to plasmin and inhibit
fibrinolysis. Aprotinin inhibits plasmin, kallikrein and platelet
activation.
ADRs: Unwanted deep vein thrombosis.
a) Aminoacids: Aminomethylbenzoic acid, Aminocapronic
acid, Tranexamic acid. The aminoacid agents are used in
haemophilic patients who may be prone to bleeding, after
surgery, as the wound is healing.
b) Protease inhibitors: Aprotinin is used in
hyperplasminaemia caused by fibrinolytic drugs overdose and
also to prevent blood loss during cardiac bypass surgery.
ANTIFIBRINOLYTIC AGENTS
Inactivation of the Fibrinolytic System
can be achieved by Plasmin Inhibitors:
Aminocaproic acid (5% sol.-100 ml)
Tranexamic acid
Aminomethyl Benzoic acid (Amben, Pamba)
(amp. 1% sol.-5 ml)
Aprotinin (Contrical, Trasylol)
All agents inhibit

plasminogen activation.
Angioprotectors (Vasoprotectors)
a) Capillarotonic drugs
Bioflavanoids: Peflavit C, Rutin (a plant glycoside which
is being used to prevent capillary bleeding with vitamin C)
Synthetic agents: Doxium (used in retinopathy);
Ethamsylate increases capillary wall stability by exerting
anti-hyaluronidase activity and also by inhibition of PGI2
synthesis and promoting platelet aggregation. It is used to
prevent bleeding in postpartum haemorrhage,
menorrhagia and tooth extraction.
b) Venotonic drugs: Detralex, Endotelon, Troxevasin
(semi-synthetic agents)
DRUGS USED
IN THE TREATMENT
OF CARDIAC FAILURE
Cardiac failure
develops as a
result of decreased
cardiac output,
when the heart
becomes unable to
provide adequate
amount of blood to
the organs according
to their needs.
Echocardiography
– ejection fraction
(EF) < 45%
Cardiac failure
• Systolic – In IHD, Valvular incompetence,
cardiomyopathy and myocarditis etc.
• Diastolic – In Hypertension, aortic stenosis,
congenital heart disease and hypertrophic
cardiomyopathy
Reduced efficiency of the

heart as a pump –
reduced Cardiac Output
Cardiac failure
I. CONGESTIVE HEART FAILURE (CHF)
The treatment of CHF aims to reduce preload

and afterload and to increase myocardial
contractility mainly by administration of:
ACE inhibitors, diuretics, beta-blockers,
alpha-blockers, cardiac glycosides,
organic nitrates, cardioprotecors, etc.
1. Cardiac glycosides (CGs)
France, UK Nativelle
(1869)
•Digitoxin
Digitalis purpurea (Foxglove) W. Withering (1785)

Cardiac Glycosides – Introduction
Drugs having the cardiac inotropic property –
increase in force of contraction
– They increase the myocardial contractility and
improves cardiac output without proportionate
increase in Oxygen consumption
– Do not increase the heart rate
• Digitalis is the genus name for the family of
the plants that provide most of the
medically useful cardiac glycosides –
Digoxin
Sources – Cardiac glycosides
Cardenolides (Cardanolides):
Digitalis purpurea – Digitoxin, Gitoxin and Gitalin
Digitalis lanata – Digitoxin, Gitoxin and Digoxin
Strophanthus gratus – Ouabin
Thevetia nerifolia – Thevetin
Convallaria majalis – Convallotoxin
Bufadienolides:
Bufo vulgris – Bufotoxin
Images of Cardiac Glycosides
Digitalis purpurea Digitalis lanata
Strophanthus gratus
Images of Cardiac Glycosides
Urginea maritima Thevetia nerifolia
Convallaria majalis
Chemistry
All Cardiac glycosides
– aglycone (genin) part (active
pharmacologically)
– sugar (glucose or digitoxose)
attached at Carbon 3 of
nucleus
Aglycone – Steroid ring
(cyclopentanoperhydrophenan
threne ring) and lactone ring
attached at 17th position
(Aglycon)
(Glycon)
Cardiac glycosides – Pharmacokinetics
• Absorption and Distribution:
– Vary in their absorption, distribution, metabolism and excretion characteristics
– Presence of food in stomach delays absorption of Digoxin and Digitoxin
– Digitoxin is the most lipid soluble
– Vd of Cardiac glycosides are very high
– All are concentrated in heart, skeletal muscles, liver and kidney
• Metabolism:
– Digitoxin is partly metabolized in liver and excreted in bile
– Cardioactive metabolite (digoxin) and other metabolites are reabsorbed in gut
wall - enterohepatic circulation – long half life
– No relation with renal impairment
– Digoxin is primarily excreted unchanged in urine and rate of excretion parallels
creatinine
– So, renal impairment and elderly – long half life
– All CGs are cumulative – steady state is attain after 4 half lives (1 week for
– Digoxin and 4 weeks for digitoxin)
* Ouabain is administered parenterally and is excreted unchanged in urine
Cardiac glycosides –
Pharmacokinetics
* Ouabain is administered parenterally and is excreted unchanged in urine

Digoxin:
•Positive inotropic effect
without increasing of oxygen consumption
•Positive batmotropic effect
•Negative chronotropic effect
•Negative dromotropic effect
ARs: bradycardia, AV block,
Extrasystoles arrhythmias,
accumulation and intoxication.
Pharmacological Actions on Heart
Acts on Failing Heart:
• Failing Heart
– Inability of the heart
to pump sufficient
blood to meet the
metabolic demands
of the body
– Reduced efficiency
of the heart as a
pump
Pharmacological actions on Heart
Overall actions:
• Direct Effects – Myocardial contractility and
electrophysiology
• Vagomimetic effect
• Reflex action – alteration of hemodynamic
• CNS effects – altering sympathetic activity
Force of Contraction:
• Dose dependent increase in force of contraction in
failing heart – positive inotropic effect
• Increased velocity of tension development and higher
peak tension
• Systole is shortened and prolonged diastole
Tone: is Maximum length of fibre in a given filling pressure (Resting
tension)
• Not affected by digitalis
• Decreasing end diastolic size of failing ventricle
Rate: Rate decreased because of improved circulation restored by
vagal tone and abolished sympathetic over activity
• Additionally decreases heart rate by vagal and extravagal action
Vagal tone is increased by:
1) through reflex sensitization of baroreceptor;
2) direct stimulation of vagal centre and;
3) sensitization of SA node to ACh
Extravagal action: Direct depressant action on SA and AV nodes
(extravagal)
Electrophysiological actions
Qualitative and quantitative difference on different fibers
Action Potential:
WMC: Excitability enhanced – RMP progressively decreased, shifted towards
isoelectric
Due to reduction in gap between RMP and threshold potential
But decreased at toxic doses – below critical level
AV and BoH: Rate of “0 phase” depolarization is reduced
PF: Phase 4 slope is increased – latent pacemaking activity (extrasystoles)
SAN AND AVN AUTOMATICITY – REDUCED
Higher doses: Oscillation at phase 4 –
coupled beats:
delayed afterdepolarization (DAD)
APD is reduced – at phase 2
Amplitude of AP is diminished
Mainly via 2 actions – autonomic and direct action
• Direct action:
– At therapeutic doses
• Early brief prolongation of action potential
• Followed by period of shortening of action potential – mainly platue
phase
• Shortening of action potential contributes to shortening of
refractoriness of atria and ventricles – excitability increases
– At higher doses
• Reduced resting membrane potential – less negative
• Extrasystoloes – oscillatory afterpotentials appear following normal
action potentials
• In the event of below threshold action potentials (less negative) –
afterpotentials interfere with normal conduction
• At further stage – after potentials themselves reach the threshold to
elicit action potential (ectopic beat) coupled with preceding normal one
Afterpolarization
Afterpolarization actions – ouabain

ERP: (Minimum interval between 2 propagated
action potentials)
Atrium: decreased by vagal action and increased by direct
action – overall decreased – inhomogenicity
AVN and BoH: Increased by direct, vagomimetic and
antiadrenergic action
Ventricles: abbreviated
Conductivity: Slowed in AVN and BoH fibres
ECG:
Increased PR interval
Decreased QT (shortening of systole)
Decreased/inversion of – T wave
Digitalis –
• Autonomic actions:
– Involves both Parasympathetic and sympathetic
systems
– At therapeutic doses – cardio selective
parasympathomimetic action
– Sensitization of baroreceptors, central vagal
stimulation and falicitation of muscarinic transmission
at cardiac muscle cells
– More prominent action in atria and AV nodal function
than Purkinje fibers
– However sympathetic action is increased in toxic doses
Digitalis –
Digitalis action – Blood vessels
• Mild vasoconstrictor and increased PR in Normal
individuals
• In CHF – compensated by improvement of increased in
cardiac output-decrease in sympathetic overactivity –
decrease in Peripheral resistance occurs
• Improved venous tone in CHF
BP: No prominent action in Systolic and diastolic BP – no
contraindication in hypertensive (rise in systolic and
decreased in diastolic in CHF)
Coronary vessels: No significant action on coronary
vessels – not contraindicated in patient with coronary
artery disease
Digitalis – mechanism of action
• Inhibition of Na/K
ATPase
• blunting of Ca2+
extrusion
• Ca2+ sarcomere
shortening
Mechanism of positive inotropic action of GS
1. Depolarization
X Ca++
5. Blocked
4. NCX
6. Na+ more
Ca++<<
Depleted K+
2. Release Ca++
3. Contraction
1. Binds to extracellular face of the Na+/K+ ATPase of heart muscles (alpha)
and Inhibits this enzyme – progressively accumulation of intracellular Na+
2. Normally, During depolarization (action potential) Ca++ channels open
Ca++ ions enter into the cytosol via concentration gradient. Again this results
in triggering release of Ca++ from sarcoplasmic reticulum
All these will result in increase conc. of Ca++ in cytosol nad contraction of
cells
3. After contraction Ca++ falls and relaxation of Myocardial cells -
concentration of Ca++ falls due to entering into the SR and partly by extrusion
outside the cell
5. Driving out of cells – 3:1 Na++: Ca++
Now due to the Na+/K+ ATPase blockade by digitalis there is slight increase
in Na++ inside the cell and therefore transmembrane gradient of Na++ is
slightly changed to drive out excess Ca++ - increase in Ca++ conc.
SR – Sarcoplasmic reticulum, TnC – Troponin C
Digitalis action – other tissues
• Kidney:
– Diuresis due to the improvement of circulation
– No diuresis in Normal persons
• Other smooth muscles:
– Inhibition of Na+/K+ ATPase – increased spontaneous
activity – anorexia, nausea, vomiting and diarrhoea
• CNS:
– No major visible action in therapeutic doses
– High doses – stimulation of CTZ - nausea and vomiting
– Toxic doses – central sympathetic stimulation, mental
confusion, disorientation and visual disturbance
Digitalis – Adverse effects
Cardiac and Extracardiac:
• Extracardiac:
– GIT: nausea, vomiting and anorexia etc.
– CNS: CTZ stimulation, headache, blurring of
vision (Flashing light, Altered color vision),
mental confusion etc.
– Serum Electrolyte: K+ : Digitalis competes for K
binding at Na/K ATPase
• Hypokalemia: increase toxicity
• Hyperkalemia: decrease toxicity
– Mg2+: Hypomagnesemia: increases toxicity
– Ca2+: Hypercalcemia: increases toxicity
Potassium and calcium have antagonistic action.
Hypokalemia and hypercalcemia potentiate
the action of CGs.
Specific antidote for digitalis
intoxication are Digoxin-specific
Fab-antibody (Digoxin Immune Fab – Digibind®,
DigFab®) in the form of intravenous infusion.
Antibodies interact also with
Digitoxin.
One vial of Digibind® (38 mg) or
DigFab® (40 mg) associated
approximately 0,5 mg
Digoxin or Digitoxin.
Digitalis – Adverse effects
Cardiac: All Arrhythmias
Tachyarrythmias: Heart rate abnormally increased due
to prolong diuretic and digitalis therapy (K
depletion) – Potassium chloride 20 m.mol IV/hr or
orally
Digitalis toxicity – don’t give K+
Serum K+ estimation
Ventricular arrhythmia: Excessive ventricular
automaticity: Lidocaine IV (or Phenyton)
PSVT: Propranolol IV or Adenosine
AV block: Atropine – 0.6 to 1.2 mg IM
Digitalis – Common Drug interactions
• Diuretics: Hypokalaemia (K+
supplementation required)
• Calcium: synergizes with digitalis
• Adrenergic drugs: arrhythmia
• Propranolol and Ca++ channel blockers:
depress AV conduction and oppose
positive ionotropic effects
• Metoclopramide, sucralfate and antacids
– reduced absorption
Digitalis – contraindications
• Hypokalemia: Toxicity
• Myocardial Infarction
• WPW syndrome: VF may occur (due to
reduced ERP of bypass)
• Elderly, renal or severe hepatic disease:
more sensitive to digitalis
• Ventricular tachyarrhythmias
• Partial AV block: Complete block
• Thyrotoxicosis
Digitalis – therapeutic Uses
• Congestive Heart Failure
• Cardiac Arrhythmias
CGs are effective in CHF, occuring with
normal or accelerated heart rhythm,
especially in cases of atrial fibrillation.
Preparations of Digitalis (foxglove)
Digitoxin (t1/2 168 h)
Digoxin (t1/2 40 h): p.o. or i.v.
Semisynthetic derivatives of Digoxin
– Acetyldigoxin (Lanatilin®): p.o.
– Methyldigoxin (Lanitop®): p.o.
Preparations of Strophanthus gratus
– Strophanthin G (Ouabain®) – i.v.
Digitalis – Congestive Heart Failure
Systolic dysfunction: dilated ventricles and unable to develop
sufficient wall tension – IHD, Valvular disease, Myocarditis etc.
Diastolic dysfunction: Thickened wall, filling is impaired and low
output – prolonged hypertension, CHD, hypertrophic myopathy
Long standing CHF patients have both the types of dysfunctions
Acts primarily on systolic dysfunction
Failing heart is unable to pump sufficient blood at normal
filling pressure
More blood remains in ventricles – Frank-Starling
compensation applied – but, Congestion starts
Digitalis therapy improves the conditions in CHF: Na+ and
water retaining stops – however, neither arrest progression nor
reverse pathological change
Reduction in Oxygen consumption
Digoxin Digitalization
• Digoxin has low therapeutic window and margin of safety is very
low
• Therapeutic level of digoxin is 0.5-1.5 ng/ml
• It is administered such a way that patient gets maximum
benefits with minimal adverse effects
• Previously rapid digitalization was done but obsolete now
• Slow digitalization:
– Administer digoxin 0.25 mg (or even 0.125mg) daily in the evening
– full response in 5-7 days
– If no improvement administer administer 0.375 for 1 week
– If no, administer 0.5 mg in next week
– Monitor patient for blood levels, if no monitor in improvement of
signs and symptoms
– If bradycardia, stop the drug
Digitalization
• Rapid digitalization (oral):
– Administer 0.5 to 1 mg stat
– 0.25 mg every 6 Hrly
– Monitor for toxicity
– Patient is digitalized within 24 Hrs
• Rapid IV: Seldom used now
– As desperate measure in CHF and atrial fibrillation
– 0.25 mg slow IV stat followed by 0.1 mg every Hrly
Digoxin – Cardiac Arrhythmias
• Cardiac dysrhythmia (arrhythmia)
– Large and heterogeneous group of conditions in which there is abnormal
electrical activity in the heart
– The hearts too fast or too slow, and may be regular or irregular
• Atrial fibrillation is the most common type of arrhythmias
although not life threatening
– Often irregular and rapid atrial contractions originating in atrial muscles
– Ultimately interferes with ventricular contractions (heart beat)
– If treated, it is not life threatening
– Generally occurs above 50 years of age
– Digitalis action:
• Acts by decreasing the number of impulses passing down the AV node –
direct, vagomimetic and sympathetic action
• Decreases average atrial ERP – increases fibrillation frequency
• Decreases the ventricular rate and pulse deficit is abolished
• Can bring down ventricular rate to 70-80/min
Digoxin – Cardiac Arrhythmias
• Atrial flutter:
– Regular and synchronous contractions
– Atrial rate is less than AF (200-350)
– Digoxin enhances AV block and reduces ventricular rate
– Converts atrial flutter to fibrillation – reduction in atrial
ERP
• PSVT:
– Heart rate is 150-200/min
– A-V conduction is 1:1 due to reentry in SA or AV node
– IV injection of Digoxin prevents this by increasing vagal
tone
Pharmacotherapy of CHF – Goal
Relief of congestive/Low output symptoms and
restoration of Cardiac performance:
Inotropic: Digoxin, Dopamine, Dobutamine, Amrinone/Milrinone
Diuretics: Furosemide, thiazides
Vasodilators: ACE inhibitors/ARBs, Hydralazine, Nitroprusside
and Nitrates
Beta-blockers: Metoprolol, Bisoprolol, Carvedilol
Arrest/Reversal of disease progression and
prolongation of survival
ACE inhibitors/ARBs, Beta-blockers
Aldosterone antgonist: Spironolactone
Non-pharmacological measures: Rest and salt
restriction (for all grades of CHF)
Heart failure – classification
• Class I (Mild): No limitation of physical activity. Ordinary
physical activity does not cause undue fatigue, palpitation, or
dyspnea (shortness of breath).
• Class II (Mild): Slight limitation of physical activity.
Comfortable at rest, but ordinary physical activity results in
fatigue, palpitation, or dyspnoea.
• Class III (Moderate): Marked limitation of physical activity.
Comfortable at rest, but less than ordinary activity causes
fatigue, palpitation, or dyspnoea.
• Class IV (Severe): Unable to carry out any physical activity
without discomfort. Symptoms of cardiac insufficiency at rest.
If any physical activity is undertaken, discomfort is increased.
2. Thiazides and loop diuretics
They increase salt and water loss,
reduce blood volume
and lower excessive venous filling pressure,
reduce circulating blood volume and preload.
The congestive features of oedema, in the lungs
and periphery, are alleviated,
cardiac output is also increased.
Diuretics are administered together with
ACE inhibitors and other drugs.
Hydrochlorothiazide
Chlorthalidone
Indapamide
5%
20–30%
3. Potassium-sparing diuretics
(aldosterone antagonists)
In cases of severe heart failure low
doses of Spironolactone are added to the
therapy while regularly checking creatinine
and electrolyte levels. Spironolactone is a weak
diuretic. It blocks aldosterone
receptors in the distal renal tubules
and reduces increased aldosterone
levels in CHF.
Spironolactone
• Rise in plasma aldosterone level in CHF leads to
– Increase in preload due to ECF rise
– Risk of arrhythmia due to hypokalaemia – sudden
death
– Pathological remodeling of myocardium
– Enhancement of sympathomimetic activity
• Spironolactone antagonizes all the above effects –
mobilization of edema fluid, prevents hypokalaemia
• Prevents hypokalaemia induced by diuretics
• Serum K+ monitoring required – risk of
hyperkalaemia
In low doses (25 mg/24 h) Spironolactone
potentiates the effects of ACE inhibitors.
It also saves K+ and Mg2+ and has anti-
arrhythmic activity. Spironolactone
prevents myocardial fibrosis, caused by
aldosterone, and in this way increases
Similar to spironolactone is another
aldosterone antagonist – Eplerenone.
4. АСЕ inhibitors
Angiotensin
Renin
Angiotensin I
() ACE
ACE inhibitors
()
Angiotensin II
Breakdown
ACE
Kinins
AT1- AT2-
receptor receptor (kininase II)
ACE inhibitors reduce pre- and afterload.
They are administered in lower doses alone
or together with diuretics, cardiac glycoside,
antiischemic agents, etc. in all stages of CHF,
due to systolic dysfunction.
• Reduction of facilitation of sympathetic
nervous system
• Reduction of cardiac hypertrophy
In preparations with t1/2 ≥ 24 h (Perindopril,

Ramipril, Trandolapril) the risk of lowering
blood pressure after the first dose is avoided.
5. Beta blockers
• Cardioselective beta-blockers Bisoprolol and Metoprolol decrease
with 31% mortality in patients with CHF, if used in combination
with diuretics, ACE inhibitors and Digoxin.
• Initially reduce cardiac contraction and stroke volume i.e.,
ejection fraction – but slowly Ef increases
1. Prevention of ventricular wall stretching – prevent
remodeling
2. Prevention of Renin-angiotensin system
• Used in mild and moderate cases of heart failure with dilated
cardiomyopathy and systolic dysfunction
• No use in severe decompensate heart, other drugs should be
continued
• Useful in class II and Class III failures
• Dose: start as low dose, metoprolol – 200 mg/day
6. Beta- and alpha-blocking agents
Carvedilol is a blocker of β- and α-

receptors. It also has antioxidant, vasodilating
and cardioprotective effects. It decreases
cardiac output, peripheral vascular resistance
and afterload. Carvedilol lowers mortality
with 25–67%, but it is contraindicated in CHF,
occuring with cor pulmonale. The treatment
begins with low doses (3.125 mg/12 h).
7. Оrganic nitrates
Organic nitrates dilate capacity vessels,
reduce preload and myocardium oxygen
needs. They connect with thiol groups (SH)
and release nitric oxide (NO).
NO combines with new thiol groups in
vascular endothelium to form nitrosothiol
(RSNO). Nitrosothiols activates guanylate
cyclase which raises the concentration of
cyclic GMP. This reduces the bioavailability
of intracellular calcium and produces
vasodilation.
Endothelium Smooth muscle
Organic
nitrate
(RONO2)
Ca2+
Celullar action of nitrates

SR  sarcoplasmatic reticulum
GTP  guanosine triphosphate
GMP  guanosine monophosphate
In congestive left-ventricular
heart failure Isosorbide dinitrate
and Isosorbide-5-mononitrate are
prescribed.
To prevent tolerance
development are necessary
8-12 hours intervals without nitrates.
8. Prazosin
is a postsynaptic alpha-1-blocker which reduces afterload.
It is used for treatment of resistant CHF in low
doses together with diuretics and cardiac glycosides.
9. Metabolic cardioprotective agents
Trimetazidine has prolonged concentration
plateau lasting up to 11 h. It increases ATP
synthesis and decreases acidosis in ischemic
tissues. It supplies energy for Na+/K+
transmembrane pump.
Levocarnitine is a N-containing amino
acid in muscle, which has antioxidant activity.
It is indicated in cardiomyopathy and muscle
dystrophy caused by carnitine deficiency.
Preparations containing Coenzyme Q10

(a part of the mitochondrial redox system),
stimulate ATP synthesis and improve
myocardial contractility in CHF.
10. Calcium sensitizers
Levosimendan (Simdax®) increases
sensitivity of troponin in the heart
to calcium. This results in increased
myocardial contractility. It is infused
i.v. for short treatment of severe heart failure.
II. Acute heart failure (AHF)
1. Phosphodiesterase III inhibitors (PDE):
Amrinone, Enoximone, Milrinone
These agents are indicated in severe congestive
AHF, resistant to other drugs; usually for short
i.v. treatment. They have positive inotropic effect,
but they increase oxygen consumption.
ARs: ventricular and SV arrhythmias, angina,
hypotension, headache, hypokalemia.
Amrinone
Enoximone
Milrinone
(–)
AC PDE III
ATP cAMP 3’,5’-AMP
Amrinone: (amicor/inocor/iarditone)
– Selective PDE III inhibitor
– MOA: Prevents intracellular breakdown of cAMP
by PDE III – increases cAMP conc. and Ca++
influx
– Clinically, positive ionotropy and vasodilatation
– Dose: IV Bolus 0.5 mg/kg followed by 5-10
mcg/kg/min
– Adverse Effects: Thrombocytopenia,
hepatotoxicity, arrhythmia, nausea, & vomiting
– Uses: Only for short term therapy of CHF and not
used for maintenance although effective orally
2. Cardioselective beta-1-
adrenomimetic agents
In AHF with cardiogenic shock Dobutamine

(β1-agonist) and Dopamine are administered
by i.v. infusion.
In high doses dopamine may increase
peripheral vascular resistance, while dobutamine
does not influence it.
Dopamine in low doses activates D2-receptors
in renal and mesenterial vessels and in coro-
naries. It causes arterial vasodilation, acti-
vates D5-receptors in myocardium and
increases myocardial contractility. Used in
low doses (2 to 5 mcg/kg/min i.v.) dopamine
does not increase blood pressure. In high
doses (> 5 mcg/kg/min i.v.) its α- and β-effects
dominate.
Dopamine
• 3-10 mcg/kg/min IV
• Acts on pre-junctional D2 and post-junctional
D1 receptors
• Actions: Splanchnic and Renal vasodilatation
(D1) and suppression of NA release (D2 effect)
– increase renal perfusion and increase g.f.r
• Uses: Patient in shock, adjunct to frusemide in
refractory cases (short term only)
• Adverse effects: tachycardia, arrhythmias and
peripheral vasoconstriction
Dobutamine
2-8 mcg/kg/min:
– Beta-1 agonist and acts via cAMP and increase in
Ca++ conc.
– Relatively do not increase heart rate
– Further Beta-2 effects – muscle vasodilatation
– Less change in heart rate and BP
– Cardiac workload decreases – low oxygen demand
– Uses: acute heart failure with MI, cardiac surgery and
advanced decompensate CHF
– Adverse effects: Tachycardia (reflex action due to
beta-2 action), tolerance (down regulation of beta
receptors after 72 Hrs)
3. Organic nitrates
They dilate capacity vessels (vein, venules) which
normally can take up to 80% of the total blood volume.
They decrease intraventricular pressure and reduce
myocardial wall distention. Organic nitrates reduce
myocardial oxygen needs too.
Glyceryl trinitrate is prescribed sublingually at
18-20 min intervals in acute left-ventricular
heart failure, but it is more effective when
infused i.v. in doses from 10 to 100 mcg/min.
4. Non-organic nitrates
Sodium nitroprusside
is indicated in resistant to other
pharmacotherapy congestive heart
failure (often in combination with
dopamine) and also in acute
left-ventricular heart failure.
Antidyslipidemic drugs
• CVD (cardiovascular disease)
is the leading cause of death among
the adult population in the world.
• CHD (coronary heart disease) is the main
cause of death in patients with CVD.
• Total plasma cholesterol, high plasma levels
of LDL, low levels of HDL are important
risk factors for CHD.
Lipoproteins are macromolecular aggregates
of lipids and apolipoproteins.
Lipids can be divided into two main groups,
simple and complex.
The two most important simple lipids are
cholesterol and fatty acids.
Lipids become complex lipids when fatty
acids undergo esterification to produce
esters.
Simple lipids
Cholesterol is a soft waxy substance present in all
cells of the body. Most tissues can produce
cholesterol, but it is synthesised primarily in the liver
and small intestine. Approximately 50% of the
cholesterol requirement is synthesised, whilst the
rest is obtained from animal produce in the diet.
Cholesterol is important in the repair of cell
membranes and in the synthesis of steroid
hormones, vitamin D and bile acids.
Fatty acids are the simplest form of lipid found in the
body and are an important energy source. They exist
as saturated, monounsaturated and polyunsaturated
forms, distinguished by the number of bonds
between the hydrocarbon chain and carbon atoms.
The most common fatty acids in the body are stearic
and palmitic (saturated), and oleic
(monounsaturated). Fatty acids exist freely in the
plasma mostly bound to albumin, but are stored in
adipose tissue as triglycerides.
Complex lipids
Triglycerides are mainly stored in adipose tissue and are the main
lipid currency of the body. Phospholipids are glycerol esters
containing two fatty acids. They have a water-soluble and a lipid-
soluble surface and are an important component of the cell
membrane. Cholesterol esters, oleate and linoleate, are the
storage molecules of cholesterol in cells.
Apolipoproteins In order for these water-insoluble lipids to be
transported around the body in the the aqueous medium, blood,
they are aggregated with apolipoproteins to form lipoproteins.
These multimolecular packages consist of a hydrophobic core
containing cholesteryl esters and triglyceride, surrounded by a
hydrophilic surface layer of phospholipids, proteins and some
free cholesterol. While structurally similar, lipoproteins vary in
their proportions of component molecules and the type of
proteins present.
Structure of lipoproteins
Free cholesterol
Phospholipids Triglycerides
Apolipoproteins Cholesterol esthers

Classification of lipoproteins
according to their density
 Chylomicrons
 Very low density lipoproteins (VLDL)
 Intermediate density lipoproteins (IDL)
 Low density lipoproteins (LDL)
 High density lipoproteins (HDL)
Apolipoproteins
They are the main protein ingredient
of lipoproteins with the following functions:
(1) Facilitate lipid transportation
(2) Activate main enzymes in lipid metabolism
– lecithin cholesterol acetyltransferase
– lipoprotein lipase
– liver triglyceride lipase
(3) Connect to receptors on the cell surface
Apolipoproteins
There are eight broad groups of apolipoproteins
that have currently been identified.
These are designated apo A to F, apo H and
apo J.
The form of apolipoprotein B that is made
in the liver (apo B100) is associated with
high levels of LDL and is an important
marker for atherosclerosis.
Atherogenic lipoproteins (LDL or other
apo B-containing lipoproteins) penetrate
the intima.
This renders them susceptible to
oxidation – the auto-oxidation lipid cycle.
Oxidized LDL contains modified apo B
which is not recognized by the normal
receptors.
Instead, it is recognized by the non-
regulated scavenger receptor on the
activated macrophage.
After LDL oxidation free radicals and active oxygen
species are formed and they activate macrophages.
Oxidized LDL contains large amounts
of cholesterol ester.
When macrophages are full of
cholesterol ester they secrete
cytokines (IL-6, CRP, TNFa) which, in
turn, induce vascular inflammation,
cell recruitment, and weakening of the
fibrous cap.
Activated macrophages produce inflammatory cytokines (IL-6,
TNF alpha), which damage endothelium and initiate atherogenesis.
Lipoproteins rich in triglycerides
Hypertriglyceridemia can predict

CHD risk independently to HDL
Fredrickson classification
of dyslipidemias (WHO)
Phenotype Lipoprotein Plasma Plasma Atherogenity Rate
increased cholesterol triglycerides
I Chylomicrons Normal to NO Low
IIa LDL Normal +++ High
IIb LDL and VLDL +++ High
III IDL +++ Medium
IV VLDL Normal to + High
V VLDL and Normal to + Low

Chylomicrons
Notes
1. The Fredrickson classification does not take
into account HDL-C (cholesterol in HDL), whose
low plasma level has a significant atherogenic role.
2. Homocysteine (normal 5-15 mmol/l) is produced in

methionine metabolism. Increased plasma levels of
homocysteine is an independent risk factor for the
development of atherosclerosis and CVD, even in
normal lipid status. High homocysteine plasma
levels are reduced by folic acid (vitamin B9),
pyridoxine (vitamin B6), and vitamin B12.
Dyslipidaemia may be secondary to other disorders or a
primary abnormality.
Common causes of secondary dyslipidaemia: diabetes
mellitus, the nephrotic syndrome, chronic renal failure,
hepatobiliary disease (generally of the obstructive variety)
and hypothyroidism.
Of the primary causes of dyslipidaemia, the most severe

forms are caused by genetic disorders of lipoprotein
metabolism: familial hypercholesterolaemia , polygenic
hypercholesterolaemia and familial combined
hypercholesterolaemia, all of which increase the risk of
premature development of CHD.
I. Drugs inhibiting cholesterol
and lipoprotein synthesis
• Statins
• Fibrates
• Nicotinic acids
 Statins
HMG-CoA reductase
inhibitors
• Atorvastatin
• Lovastatin
• Simvastatin
• Fluvastatin
• Rosuvastatin
• Pravastatin
Statins
Mechanism of action:
1. Competitively reversibly inhibit 3-hydroxy-3-
methylglutaryl-coenzyme A reductase→inhibits
the synthesis of cholesterol at the stage of
mevalonic acid. Cholesterol reserves in the liver
decrease → expression of LDL receptors on
hepatocytes → increased uptake of atherogenic
lipoproteins from the blood.
2. In the liver, the formation of VLDL and their
release into the blood decreases.
3. HDL in blood plasma
Pharmacological properties of statins:
• Hypolipidemic
• Restoration of endothelial function (prevent
LDL endothelial damage)
• Vasodilator (expression of NO synthase)
• Anti-ischemic
• Antithrombogenic (reduction of platelet
aggregation, reduction of thrombin, stimulation
of fibrinolysis)
• Reduction of proliferation of smooth muscles of
blood vessels
• Anti-inflammatory
Adverse reactions of statins
• hepatotoxicity – depends on the dose,
dyspeptic disorders
• insomnia, headache
• myopathy (may vary from an
asymptomatic increase in the level of
creatine phosphokinase (CPK) in the
blood or accompanied by myalgia
and muscle weakness to life-
threatening rhabdomyolysis in
0.61%)
 Fibrates
(induction of lipoprotein lipolysis in the
endothelium, inhibit HMG-CoA reductase)
– Ciprofibrate
– Clofibrate
– Fenofibrate
Mechanism of action: 1. ↑expression of endothelial lipoprotein lipase
→ catabolism of VLDL
2. Inhibit the synthesis of cholesterol in the liver (possibly inhibits
HMG-CoA reductase) and the synthesis of VLDL from cholesterol
3. the density of lipoprotein receptors in hepatocytes increases, the
level of LDL decreases, and HDL increases
Adverse reactions: dyspeptic disorders, blurred vision, headache,
cholelithiasis, myopathy, rarely rhabdomyolysis
 Nicotinic acid
Inhibits lipolysis in adipose tissue, induction of
lipoprotein lipolysis in the endothelium:
– Niacin (Vitamin B3)
Inhibits triglyceride lipase in adipocytes  in adipose tissue, the
formation of free fatty acids that are not captured by the liver
decreases  in the liver, the biosynthesis of triglycerides and the
formation of VLDL from them is disrupted.
The level of VLDL, LDL in the blood decreases, and the level of
HDL ↑
Adverse reactions: increases the concentration of prostaglandins
→ redness of the skin of the face, neck, upper torso,
gastrointestinal and cardiovascular disorders (correction –
take325 mg of Acetylsalicylic acid in 30 minutes)
II. Drugs enhancing cholesterol and lipid
metabolism
 Bile acid sequestrants inhibit bile acid enterohepatic
recirculation:
Colestipol, Colestyramine
Mechanism of action: they form non-absorbable complexes with bile
acids in the intestine. A decrease in the enterohepatic circulation of bile
acids causes an increase in their synthesis in the liver from endogenous
cholesterol. Cholesterol reserves in the liver decrease→ expression of
LDL receptors on the hepatocyte membrane and an increase in the
receptor-dependent endocytosis of atherogenic lipoproteins, their
concentration in blood plasma decreases.
Adverse reactions: flatulence, constipation – at the beginning of taking
in large doses with a shortage of water and fiber
 Phytoproducts: Pectin
Pectivit C® (pectin/vitamin C)
III. Drug, inhibiting intestinal
cholesterol absorption: Ezetimibe
Mechanism of action: inhibits the transporter of
cholesterol and phytosterols in enterocytes – Niemann-Pick
protein type C1 (Niemann-Pick C1-Like1, NPC1L1), which
transfers cholesterol to intestinal epithelial cells and
activates cassette transporters that remove cholesterol from
epithelial cells into the intestinal lumen.
Pharmacological effects:
• hypolipidemic
• anti-inflammatory
Side effects: increased liver enzymes, rhabdomyolysis and
myopathy (0.2%).
IV. Drugs containing polyunsaturated
essential omega-3-fatty acids:
Escimo-3® Cod-liver oil 5 g/12 h p.o. ( A&D)
Omacor®
Arachidonic Eicosapentanoic
acid acid
Escimo-3®
Omacor®
TxA2: potent TxA3: week
trombocyte trombocyte
antiaggregant aggregant
Potent PGI2: potent Week PGI3: potent

inflamma- trombocyte inflamma- trombocyte
tory LTs antiaggregant tory LTs antiaggregant
Control of total serum cholesterol
Normal •Control in 5 years
< 5,2 mM levels
5,2–6,2 mM Borderline •Control in 12 months + diet
levels •In CHD or/and risk factors –
lipid status analysis, diet,
and antidyslipidemic treatment
 6,2 mM High •Control in 6 months with

levels lipid status analysis, diet,
and antidyslipidemic treatment
 •Smoking 2/3
of the Risk factor for CVD
•Lipid status risk
•Homocysteine >15 mmol/l

•BMI >30:
> >>salt and >>> sugar
>>> (or <<<) alcohol
•Stress
 Metabolic syndrome
– high risk for CVD
presence of ≥ 3 risk factors:
•Waist > 102 cm in men and > 85 cm in women
•Triglycerides ≥ 1,7 mmol/l
•HDL-cholesterol
< 1 mmol/l in men or Patients with hypertension
< 1,3 mmol/l in women and concomitant CVD have
•Arterial hypertension increased risk for diabetes
> 130/85 mm Hg mellitus.
•Glucose ≥ 6,1 mmol/l
Caffeine > 300 mg/d:
5-6 coffee cups daily
(–)
AC PD
ATP cAMP 3’, 5’-AMP
(+) Hypercholesterolemia
(+)
Lipolysis Cholesterol synthesis
• treatment (+ 1 to 2
measure of BP) Patient’s compliance
• non-pharmacological
treatment
• physical activity
• dietary regimen Quantum therapy device
• 8-9 h of sleep
• avoidance of risk factors 
Drugs Acting on
Respiratory System
Definition of Bronchial Asthma
• Bronchial asthma is chronic respiratory condition
characterized by
Hyper-responsiveness of
tracheobronchial smooth
muscles to a variety of stimuli
I. Drug Therapy of Bronchial Asthma
The term asthma is derived from the Greek word
meaning difficulty in breathing. Asthma is a
chronic inflammatory allergic disease: the patients
suffer with reversible episodes of airways obstruction
due to bronchial hyper-responsiveness.
In the early (acute) phase there are smooth muscle
spasm and excessive bronchial secretion of mucus.
In the late (chronic) phase, inflammation
continues, accompanied by fibrosis and
oedema of bronchial epithelial cells.
FACTORS THAT EXACERBATE ASTHMA
What are the stimuli? (Triggers)
• Tobacco smoke
• Infections such as colds, flu, or pneumonia
• Allergens such as food, pollen, mold, dust mites, and pet dandruff
• Exercise
• Air pollution and toxins
• Weather, especially extreme changes in temperature
• Drugs (such as aspirin, NSAID, and beta-blockers)
• Food additives
• Emotional stress and anxiety
• Singing, laughing, or crying
• Perfumes or sprays
• Acid reflux
Results in narrowing of
air tubes
Classification – Etiological
1. Extrinsic or allergic: Pollens Dust mite
– History of `atopy` in childhood

– Family history of allergies
– Positive skin test
– Raised IgE level
– Below 30 years of age
– Less prone to status asthmaticus
2. Intrinsic or Idiosyncratic:
– No family history of allergy
– Negative skin test
– No rise in IgE level
Mold Pet dandruff
– Middle age onset
– Prone to status asthmaticus
Bronchial Asthma
• Increased secretion
• Mucosal oedema
• Mucus plugging
All are
Primarily due to
Inflammation
Bronchial Asthma
• Triad of asthma
– Dyspnoea (shortness of breath)
– Wheezing (additional sound)
– Cough (persistent)
– Additionally: limitation of activity
Clinical definition: Bronchial asthma (also called reversible airway obstruction) is a
clinical syndrome characterized by recurrent bouts Bronchospasm. There is increased
responsiveness of the tracheobronchial smooth muscles to various stimuli resulting in
widespread narrowing of the airway.
• May be life threatening !!! - status asthmaticus

The cardinal symptoms of asthma are breathlessness
wheezing, cough and chest tightness with worsening of
these symptoms at night. In the acute attack there are ra-
pid respiratory rate and tachycardia. The majority of patients
suffer with atopic extrinsic asthma, which is associated
with exposure to specific allergen (pollen or house-dust
mite). In non-atopic extrinsic asthma the attack may be
stimulated with some non-specific stimulus, e.g. chemical
irritants. In such cases, antibodies circulate in
the blood but are not attached to the mast cells or
basophils. Neutrophils destroy these antigen-antibidy
complexes.
As a result, the liberated lysosomal enzymes can digest the remaining
mucoproteins.
Drugs which stabilize the lysosomal membrane, e.g. GCS provide
relief to these patients. In contrast, the many patients who acquire
asthma after the age of 40 years have no identifiable external
precipitating factor or immunological basis for asthmatic attack. This
can be described as intrinsic asthma. Many patients suffer from both
extrinsic and intrinsic forms of asthma. In comparison with intrinsic
asthma, extrinsic asthma is episodic and less prone to develop into
status asthmaticus.
Status asthmaticus is a severe acute asthma, which is a life-
threatening condition involving exhaustion, cyanosis, bradycardia,
hypotension, dehydration and metabolic acidosis.
Cardiac asthma is a bronchospasm precipitated by
uncompensated congestive heart failure.
Pathophysiology of Asthma
Antigens (pollen and house-dust mites) sensitize patients
by eliciting the production of IgE type of antibodies, which remain
either circulating in the blood or become attached to the mast cells
of nasal or bronchial tissues and basophils.
On re-exposure the same antigen, the resulting antigen-
antibody reaction in the early phase causes degranulation
of the lung mast cells and releasing of the
Powerful bronchoconstrictors:
histamine, PGD2
and
leucotriens (LTB4, LTC4 and LTD4).
Lung mast cells also release ILs (IL-4, IL-5 and IL-13).
In the late (delayed) phase of asthma, these mediators
activate
additional
inflammatory
cells
(eosinophils,
basophils,
and alveolar
macrophages)
which also
release
LTs and ILs.
Other mediators of inflammation, in delayed phase, are: adenosine (causing
bronchconstriction), neuropeptides (substance P, causing mucus secretion and
increase in Vascular permeability; neurokinin A, causing bronchoconstriction).
The normal tone of bronchial smooth muscle is influenced by a balance
between parasympathetic, sympathetic and non-adrenergic–non-cholinergic
(NANC) mediators activity.
Activation of M3-receptors by the release ACh results in
increase in cGMP levels and leads to bronchoconstriction
and increase in mucus secretion. β2-receptor stimulation
leads to an increase of cAMP levels which results in
bronchodilation.
The main NANC inhibitory neurotransmitter is NO.
The main NANC excitory transmitters are neuropeptides

(neurokinin A and substance P), released from
unmyelinated sensory C-fibres when stimulated
by inflammatory mediators and irritant chemicals
(SO2, cigarette smoke).
What is COPD
(Chronic Obstructive
Pulmonary
Disease)?
• COPD is characterized by airflow limitation caused by chronic

bronchitis or emphysema often associated with long term tobacco
smoking
• This is usually a slowly progressive and largely irreversible process
• Consists of increased resistance to airflow, loss of elastic recoil,
decreased expiratory flow rate, and over inflation of the lung
• COPD is clinically defined by a low FEV1 (forced expiratory volume)
value that fails to respond acutely to bronchodilators, a characteristic
that differentiates it from asthma.
Pathology of Small Airways
i.e. less than 2 mm in diameter
Control Severe COPD

Classification of Antiasthmatic Drugs
1. Bronchodilators
• Selective β2-agonists: Clenbuterol, Salbutamol,
Fenoterol, Formoterol, Salmeterol, Terbutaline
• Nonselective β-agonists: Epinephrine, Isoprenaline,
Orciprenaline; Ephedrine
• M-cholinolytics: Ipratropium, Tiotropium, Oxitropium
• Methyl Xanthines: Theophylline, Aminophylline,
Theotard
2. Mast Cell Stabilizers: Sodium Cromoglycate,
Ketotifen, Nedocromil
3. Glucocorticosteroids (GCS)
• Oral: Prednisone, Methylprednisolone
• Parenteral: Methylprednisolone, Betamethasone
• Inhalational: Beclomethasone, Budenoside,
Fluticasone, Triamcinolone
4. Inhalational β2-agonists/Glucocorticosteroids
Seretide® (fluticasone/salmeterol)
Symbicort® (budenoside/formoterol)
5. Leukotriene Modulators
• 5-Lipoxygenase Inhibitor: Zileuton
• LTD4-antgonists: Zafirlukast, Montelukast
6. Monoclonal Anti-IgE Antibody: Omalizumab
Bronchodilators – relievers (β-agonists,
M-cholinolytics, Methyl Xanthins) provide a rapid
symptomatic relief but they do not control the disease
process.
Selective β2-agonists activate β2-receptors present on

airway smooth muscle and mast cells too. These agents
relax airway smooth muscle, inhibit the release of
bronchoconstricting mediators from the adipocytes
and increase the mucociliary transport by increasing the
mucociliary activity.
ADRs: tremor, tachycardia, desensitization/down-regulation

of β2-receptors that results in diminished responsiveness.
Adrenaline (b1&b2)
(+)
Ex
Gs AC
In
cAMP ATP
PKA Effects
Clinical benefits of Beta-2
stimulation
• Bronchodilatation without tachycardia (beta-1)
• Inhibition of release of chemical mediators by
stabilization of mast cell membrane (beta
receptors)
• Prevention of mucosal edema (vessels)
• Increased ventilatory response to
chemoreceptor stimuli (better exchange)
• Restoration of mucocilliary transport mechanism
in respiratory tract (result of reduction in
secretion)
Results of β2 stimulation
Beta-2-agonists are available as metered-dose aerosol.
Short acting beta-2
agonists: the onset
of effect (per inhalation)
begins after 3 to 5 min
and continues 4-6 h:
•Salbutamol
•Fenoterol, Terbutaline
Highly lipid, soluble long-acting agents

(t1/2 12 h)
Effect: after 15-20 min, duration 12 h:
•Salmeterol, Formoterol
Salbutamol
• Pharmacokinetics:
– Undergoes metabolism in gut wall
– Bioavailability is 50%
– Duration of action: 4-6 Hrs
• Salbutamol: preparation and doses
– Available as 2, 4 and 8 mg tablets
– Syr. As 2mg/5 ml
– As metered dose inhaler (MDI) – 100 μg
– 200 μg as rotacaps
– Muscle tremor, restlessness, palpitation and nervousness
– Vasodilatation – reduction in mean arterial pressure with tachycardia and also
exacerbate pulmonary hypoxia due to mismatched of ventilation and perfusion
– Hyperglycaemia and hyperlacticacidemia
– Worsening of asthma on prolong inhalation
Salmeterol
• Long acting Beta-2 agonist (more lipophilic)
• Available as inhaler: MDI and rotacaps (25 μg)
• Weaker than salbutamol but more beta-2 selective
• Duration of action is 3 Hrs to 12 hrs
• Not useful for acute attacks, only for prophylaxis
• Usually combined with steroids
Formeterol: Long acting and lasts for 12 Hrs

Anticholinergics
in asthma
•Ipratropium
•Tiotropium
Primarily, the site of bronchodilation action of inhaled β2-adrenergic
agonists is mainly the bronchiolar smooth muscle. Atropinic drugs
cause bronchodilation by blocking cholinergic constrictor tone,
act primarily in large airways.
Anticholinergics
Ipratropium bromide and tiotropium
• Airways are innervated by a supply of efferent, cholinergic,

parasympathetic autonomic nerves
• Motor nerves derived from the vagus form ganglia predominate
in the large and medium-sized airways
• Postganglionic fibers supply the smooth muscle and
submucosal glands of the airways as well as the vascular
structures
• Release of acetylcholine (ACh) at these sites results in
stimulation of muscarinic receptors and subsequent airway
smooth muscle contraction and release of secretions from the
submucosal airway glands.
Anticholinergics
• Distinct muscarinic receptors exist within the airways are M1, M2 and
M3 receptors
• M1 – present in peribronchial ganglion cells where the preganglionic
nerves transmit to the postganglionic nerves
• M2 receptors are present on the postganglionic nerves – they are
activated by the release of acetylcholine and promote its reuptake
into the nerve terminal
• M3 are present on smooth muscle larger airways
• Muscarinic receptor activation of these M3 receptors
intracellular cAMP levels contraction of airway smooth
muscle bronchoconstriction
Anticholinergics
• Less efficacious than sympathomimetics
• COPD, asthmatic bronchitis, psychogenic
asthma – respond better
• Drug of choice in COPD
• Slower response – for prophylaxis (2-4 puffs 6
hrly)
• Ipratropium bromide + sympathomimetics =
marked longer lasting bronchodilatation
• Nebulized Ipratropium bromide and
Salbutamol – refractory asthma
Methyl Xanthines
(Theophylline, Aminophylline, Theotard):
a) inhibit phosphodiesterase III (present in airway
muscle) and IV (present in eosinophils and mast cells),
the two specific isoenzymes responsible for the
degradation of cAMP;
b) block the adenosine-1-receptors on airway muscle
and adenosine-3-receptors, present on mast cells.
The main use of methylxanthins is in the management
of asthma and COPD, usually as combination therapy
with beta-2-agonists.
Bronchodilation is promoted by cAMP. Intracellular levels of cAMP can
be increased by – adrenoceptor agonists, which increase the rate of its
synthesis by adenylyl cyclase (AC); or by phosphodiesterase (PDE)
inhibitors such as theophylline, which slow the rate of its degradation.
Bronchoconstriction can be inhibited by muscarinic antagonists and
possibly by adenosine antagonists.
Metylxanthines – structures
Metylxanthines – Pharmacological actions
• CNS:
– Stimulation: improves performance, sense of well being and allays fatigue
– thinking become clearer (150-200 mg)
– Higher doses – nervousness, insomnia and restlessness
– High doses – tremor, convulsion
• CVS:
– Stimulation of heart – increase in heart rate, cardiac output
Vagal stimulation – TOTAL VARIABLE EFFECTS (tachycardia+
bradycardia)
– Cardiac output and Cardiac workload – increase
– Higher doses – cardiac arrhythmia
– Dilatation of blood vessels including coronary – reduced peripheral
resistance
– But, constriction of cerebral vessels – migraine use
• BP: Direct cardiac action – increased BP
Vagal action & vasodilatation – decreased BP
Overall: Rise in SBP and decrease in DBP
• Kidney: mild diuretic (decrease in tubular reabsorption of Na and also
increase in renal blood flow)
• Stomach: increase in acid-pepsin secretion – even parenteral dose –
gastric irritant
• Smooth muscles: relaxed –
bronchodilatation, but no effect on
intestine and urinary tract
• Metabolic: Increase in Basal metabolic
rate (BMR) – plasma fatty acid level
raised – plasma fatty acid level raised
– release of endogenous
catecholamines
• Skeletal muscles:
– Caffeine increases contractile power
– High doses – direct release of Ca++ from
sercoplasmic reticulum
– Facilitates NM transmission by increasing Ach
release
– Decreased fatigue by CNS action – relieves
fatigue and increased muscular work
– Enhanced diaphragmatic contraction
Metylxanthines – MOA
• Blockade of adenosine receptors – no
contraction of smooth muscles
• Inhibition of Phosphodiesterase enzyme:
ATP/GTP cAMP/cGMP 5-AMP/5-GMP
(inhibit activity of PDE cAMP Ca2+ bronchial
relaxation)
• Higher doses – Release of Ca++ from
sarcoplasmic reticulum
Metylxanthines
• Kinetics:
– Absorbed orally, crosses placenta and secreted in milk
– Metabolized in liver by demethylation and oxidation
– T1/2 is 6-12 Hrs, but faster in children and slow
in elderly (prematures – slow)
– On prolonged and high dose – elimination is zero order from first
order
• ADRs:
– Low therapeutic index: Therapeutic range – 0.2 to 2 mg/100
ml, higher than 4 mg/100ml may cause arrhythmia,
convulsion and coma
• Insomnia, headache and nervousness Restlessness,
palpitation vomiting etc. Tachycardia, flushing,
hypotension Delirium, worsening of CVS status
convulsion and shock death
– Nausea and vomiting – common
Methylxanthines –
Preparation and Dosage
• Interindividual variation in plasma concentration
• Rapid IV injection: Precordial pain, syncope and
sudden death
• Theophylline: (Unicontin/Theolong)
– Poorly water soluble and cannot be injected
– Available as tablets 100/200 mg SR
• Aminophylline:
– Water soluble and can be injected IV
– Available as 100 mg tablets and 250 mg/ml injection
Signal transduction pathway for
Bronchodilatation
Glucocorticosteroids provide long-term
stabilization of the symptoms due to their anti-inflammatory
effects. Inhaled GCS, along with beta-2-agonists are the
first choice drugs for chronic asthma.
GCS inhibit the release of PGs and LTs and thus prevent
smooth muscle contraction, vascular permeability and
airway mucus secretion.
GCS produce eosinopenia which prevents cytotoxic effects
of the mediators released from eosinophils.
GCS enhance beta-2-adrenergic response by up-regulating
the beta-2-receptors in lung cells and leucocytes. Several
hours are required for DNA transcription and RNA
translation to occur after administering GCS.
The anti-inflammatory actions of GCS are mediated by
stimulation of synthesis of lipocortin, which inhibits
pathways for production of PGs, LTs and platelet activating
factor.
These mediators would normally contribute to increased
Vascular permeability and subsequent changes including
oedema, leucocyte migration, fibrin deposition.
The most used glucocorticoids
Hydrocortisone
Prednisolone
Nonfluorinated Fluorinated prednisolones

prednisolones Betamethasone, Dexamethasone
Methylprednisolone Fluticasone, Triamcinolone
Corticosteroids
2 types – Glucocorticoids and Mineralocorticoids
Glucocorticoids –
– In general: Suppress inflammatory responses to all noxious stimuli:
Pathogens, chemical, physical and immune mediated stimuli,
hypersensitivity
– Antiinflammatory action – reduction in mediators IL, TNF and PAF etc.
and reduction in exudate formation
Bronchial asthma is an inflammatory disease
– Not Bronchodilator but – Reduce bronchial hyperactivity, mucosal
oedema and suppress AG: AB reaction or other trigger stimuli
– Reduction in cardinal signs of inflammation
– Complete and sustained symptomatic relief than bronchodilators and
chromones – improves airflow, reduce exacerbations and may retard
airway remodeling and disease progression
Steroids act best in asthma than any other group of drugs – inhaled
But remember – Adverse Effects of Prolonged therapy
Systemic corticosteroid therapy
• Steroids are used as – inhaled,
systemic (oral/parenteral)
• Systemic steroid is useful in:
– Acute asthma (status asthmaticus) – not relieved
or worsening of obstruction in spite of
bronchodilatator and inhaled steroid –
hydrocortisone and prednisolone
– Chronic asthma – failure of previously
optimal regimen – frequent symptoms of
progressive severity
Corticosteroids
• Inhalation steroids – beclomethasone dipropionate,
budesonide, fluticasone propionate and triamcinolone
acetonide
• Inhalation: high topical and low systemic activity
– Due to poor absorption and marked 1stpass metabolism
– Can be step one for all asthma cases – inflammation starts even in
early cases
– However, not used for mild and episodic asthma
– Indicated when beta-2 agonists are required daily or disease not
only episodic
Low dose starting 100 to 200 mcg BD – 3-5 days with max 400 qid
Suppress inflammation and prevents episodes of asthma –
beta-2 agonist requirement lessens
No Role in acute attack
Peak effects starts after 4-7 days
Corticosteroids
• Inhalation steroids
To whom inhalation steroids can be given:
Fresh patients as well as to those who had already
required oral steroids
To be switched over from oral steroids – 1-2 weeks before
tapering (precipitation of asthma, muscular pain,
depression, hypotension)
• COPD: high doses are required
• Doses:
– Beclomethasone: available as 50, 100 and 1200 mcg/ml
metered-dose inhaler (MDI) – dose is 400 mcg/day
– Budesonide: available as 100, 200, 400 mcg/ml MDI – dose is
200 mcg BD
Corticosteroids
• Inhalation steroids
• Side effects: Hoarseness of voice, dysphonia,
sore throat, oropharyngeal candidiasis
– Minimized by using spacers, gargling after the
use
– Topical Nystatin and clotrimazole
• Systemic effects (primarily for systemic
glucocorticoids): Mood changes, osteoporosis,
growth retardation, bruisig, petechiae, pituitary –
adrenal – suppression etc.
Adverse
effects
of GCS
• Cushing’s syndrome
• Osteoporosis
• Tendency to hyperglycaemia
• Negative nitrogen balance
• Increased appetite
• Increased susceptibility
Cushing’s to infections
• Obesity etc.
syndrome
Leukotriene Modulators
Metabolism of arachidonic acid via 5-lipoxigenase
pathway leads to the cysteinyl LTs – C4, D4 and E4,
which activate cysteinyl leukotriene receptors to
cause bronchoconstriction, stimulate mucus
secretion and increase capillary permeability, leading
to pulmonary edema.
Zileuton inhibits the 5-lipoxigenase and blocks
synthesis of LTs.
Zafirlukast, Montelukast
block cysteinyl LT-receptors and used with
inhaled GCS in poorly respond asthmatic patients.
Leukotriene Antagonists
Montelucast and Zafirlucast:
• Cysteinyl leukotrienes LT-C4, LT-D4 and LTE4 are important mediators
of human asthma – Competitive antagonist of cysLT1
• Benefits – bronchodilatation, reduced eosinophil count, decreased
vascular permeability and suppression of inflammation and hyperactivity
• Used in mild to moderate asthma as alternative to inhaled
glucocorticoids
• Useful in children – reduces dose of steroids and beta agonists
Absorbed orally and highly plasma protein bound
• Half life: montelucast (3-6 hrs), zafirlucast (8-12 Hrs)
• Uses: Mild to moderate asthma as alternative to steroids – need of
steroid is reduced and rescue with beta-2 reduced
Not suitable for termination of attack – useful in NSAID induced asthma
• Safe drug, effective orally – only headache and rashes
Arachidonic acid
5-Lipoxigenase
Leukotrienes (LTs)
LTC4- LTD4- LTE4-

receptor receptor receptor
(–)
(–) (–)
Montelukast, Zafirlukast
Zileuton
5-LOX inhibitor, blocks LT-C4, LT-D4 and
LTB4 synthesis – prevents all LT induced
responses
– Efficacy is similar to montelucast
– Short duration of action and hepatotoxic
Mast cell stabilizers prevent transmembrane influx
of calcium ions, provoked by antigen-IgE antibody
reaction on the mast cell membrane. They prevent
degranulation and release of histamine and other
autacoids from mast cells. They also inhibit leukocyte
activation and chemotaxis.
Indications: prophylactic treatment of asthma.
Cromoglycate – per inh.

Ketotifen (p.o.)
Nedocromil – per inh.
Cromolyn sodium/
Sodium cromoglycate
• Synthetic compound and chemically benzopyrone
• Stabilizes mast cells – inhibits degranulation of mast cells and other
inflammatory cells
• Mediator release is restricted
• Also prevent chemotaxis of eosinophils and neutrophils – local inflammation is
prevented
• Basis of action may be due to delayed Cl-channel in the membranes
• Long term use prevents hyperactivity of bronchial tree
• No bronchodilatation or antagonism of constriction – no action on acute cases
• Not absorbed orally , given via inhaler – 1 mg/dose – 2 puffs 4 times daily
Uses: Prophylaxis of asthma, allergic rhinitis and allergic conjunctivitis (2%)
Ketotifen
H1 antihistaminic having Chromone like actions
– Inhibits mediator release (mast cells, macrophages,
eosinophils, lymphocytes and eosinophils)
– Not bronchodilator – only sedation
– 6-12 weeks therapy benefits 50% of patiens
– Low improvement of lung function
– Also used in atopic dermatitis, perennial rhinitis,
conjunctivitis, urticaria and food allergy etc. –
orally effective
Monoclonal Anti-IgE Antibody
Omalizumab is a recombinant humanized monoclonal
antibody.
(1) It inhibits the binding of IgE to mast cells and
basophils;
(2) it inhibits the activation of IgE already bound
to mast cells and prevents their degranulation;
(3) It down-regulates Fc epsilon receptor-1, present on
mast cells and basophils.
Omalizumab is indicated for asthmatic patients who are
not adequately controlled by inhaled GCS and who
demonstrate sensitivity to aero-allergens.
Anti-IgE antibody – omalizumab
•Humanized monoclonal antibody
•Administered IV or SC
•Neutralizes free IgE in circulation
•Expensive
•Reserved for resistant cases
Treatment – bronchial asthma
• Step I: When symptoms are less than once daily – occasional
inhalation of a short acting Beta-2 agonist – salbutamol, terbutaline.
If used more than once daily – step II (Mild episodic asthma)
• Step II: Regular inhalation of low-dose steroids. Alternatively,
cromoglycates. Beta-2 agonist as and whenever required (Mild
chronic asthma)
• Step III: Inhalation of high dose of steroids (800 mcg) + Beta-2
agonist. Sustained release theophylline may be added. LT inhibitors
may be tried instead of steroids (Moderate asthma with frequent
exacerbations) – spacers
• Step IV: Higher dose of steroid (800 to 200 mcg) + regular beta-2
agonist (long acting salmeterol)
Additional treatment with oral drugs – LT antagonist or SR
theophylline or oral beat-2 agonist (Severe asthma)
• Step V: Not controlled adequately – needing emergency care
frequently – Oral Steroid therapy
Treatment of Status Asthmaticus
It is a potentially life-threatening acute attack of severe

asthma needing immediate treatment. Most often
hospitalization is necessary.
(1) A high concentration (40-60%) of O2 is administered.

(2) High doses of inhaled short acting beta-2-agonist.
(3) High doses of systemic GCS (p.o./i.v.)
(4) Ipratropium through inhalation.
Aerosols
• Solid and liquid dispersed particles of 1 to 5 micron in size
suspended in gas
• Do not coalesce and do not sink
• Aim – to deliver to the alveoli without settling in bigger
tubes
– Particles > 10 micron are deposited primarily in the mouth &
oropharynx.
– Particles < 0.5 micron are inhaled to the alveoli and exhaled
without being deposited in the lungs.
• Aerosols are produced
– In solution: inhalers, nebulizers
– Dry powder: Rotahaler and spinhaler etc.
Devices – Definition
• A metered-dose inhaler (MDI) is a device that delivers a specific
amount of medication to the lungs, in the form of a short burst of
aerosolized medicine that is inhaled by the patient.
• A Rotahaler is a device used to deliver fine dry powered
medications that are measured out in Rotacap capsules
• An asthma Spacer is an add-on device used to increase the ease
of administering aerosolized medication from a "metered-dose
inhaler" (MDI)
II. Drug Therapy of Cough
The cough is a physiological useful protective reflex that

clears the respiratory pathway of the accumulated mucus
and foreign substances. Many times it occurs as a
symptom of an underlying disorder and needs treatment.
Stimulation of mechano or chemoreceptor – throat,
respiratory passages and stretch receptors in the lungs
Afferent fibres in vagus & sympathetic – impulses to
cough center – medulla.
The cough may be non-productive (dry) and
productive.
Nonproductive ones need suppression – cerebral hypoxia,
rupture of bullas and fracture ribs etc.
The productive cough is characterized by the presence of
excessive sputum and may be associated with chronic bronchitis
and bronchiectasis.
Productive – needs to clear airway
May be harmful if suppressed !
Most of the time, coughing is beneficial
• Removes excessive secretions
• Removes potentially harmful foreign substances
• In some situations, coughing can be harmful, such as after
hernia repair surgery
COUGH ETIOLOGY
• Upper/Lower Respiratory Tract Infection

• Postnasal drip due to sinusitis, rhinitis
• Smoking/Chronic Bronchitis
• Pulmonary Tuberculosis
• Asthmatic cough
• Gastrointestinal reflux
• Drugs – Captopril and Iodides
1. Antitussive Agents are used for the treatment
of non-productive cough which increases discomfort to
the patients.
Centrally Acting Antitussives
(supress the cough center that mediates the cough reflex)
• Codeine (methylmorphine)
Poppy
• Dihydrocodeine
• Dextrometorphan
• Glaucin (Glauvent®)
Perpheral Acting Antitussives

• Prenoxidiazine (Libexin® – tabl. 100 mg)
CODEINE
Opioid – opium alkaloid – methyl morphine
Partly converts to Morphine
Less potent than Morphine and degree of
analgesia is equivalent to Aspirin (60 mg)
But, more selective for cough centers and action
lasts for 6 Hours
Blocked by Naloxone
Low abuse liability
Drawbacks: constipation, respiratory depression
and drowsiness (Higher doses)
COUGH DRUGS –
NONOPIOIDS
Noscapine: Opium alakaloid
Depresses cough, but no analgesic, narcotic or dependence
liability
Equipotent with codeine – spasmodic cough
Histamine release – no in asthma
Dextromethorphan:
Synthetic – d-isomer (antitussive) and l-isomer (analgesic)
Effective as codeine but no addicting and constipating effect – No
impairment of mucocilliary function
But, dissociative effect – recreational drug?
In Combination – Paracetamol (acetaminophen)
2. Expectorants
These drugs increase the volume or/and decrease the
viscosity of the respiratory secretions and facilitate their
removal by ciliary action and coughing.
Mucokinetic Expectorants stimulate the flow of
respiratory tract secretions by stimulating the bronchial
secretory cells (to increase the volume) and the
ciliary movement (to facilitate their removal).
•Essential oils (oil anise, oil eucalyptus)
•Syrup of Ipecacauanha (in sub-emetic doses)
•Infusum of Radix Primulae
•Ammonium chloride, Sodium citrate
•Guaiacol and Guaifenasin (obtained from creosote wood)
DEMULCENTS AND
EXPECTORANTS
Demulcents
Soothing effect and symptomatic relief – reduce afferent
impulses – act by increasing flow of saliva
Expectorants (Mucokinetics)
Increase Bronchial Secretion – Na and K citrate
Irritation of Bronchial mucosa – Iodides
Enhance Bronchial secretions (and mucociliary
functions) – Guaiphenesin, Vasaka
Ammonium salts – nauseating, reflex stimulation of
bronchial secretion
Mucolytic Expectorants decrease the viscosity of mucus
by splitting the disulfide (–S–S–) bonds of mucoproteins.
This action is further facilitated by alkaline pH (7-9).
•Ambroxol
•Acetylcysteine
(used also for the treatment
of paracetamol intoxication)
•Bromhexine
•Dornase-alfa
•Mesna (used also for protection of cancerogenic activity
of cyclophosphamide and ifosphamide too)
MUCOLYTICS
Bromhexine: Derivative of Adhatoda vasica
(Vasaka) – increases bronchial secretion
Depolymerises mucopolysaccharides in bronchial secretions
– directly or by liberating lysosomal enzyme
Fibres of sputum breaks down
Useful in mucus plug
Ambroxol: Similar to Bromhexine
Acetylcysteine: Breaks sulfide bond in
mucopolysaccharides of bronchial secretions –
Respiratory tract administration
Carbocysteine: Similar to acetylcysteine –
administered orally
Drugs Affecting
GI Functions
Phases of gastric secretion
Phase Stimuli Pathway
Cephalic Sight, smell, taste 1) Vagus (M3 receptors)
(stimulate) or thought of food 2) Histamine (H2 receptor)
3) Gastrin
Gastric (stimulate) Food in the 1) Stretch: local reflex (M3
stomach receptors)
2) Chemical substances in
food (gastrin)
3) Increase pH: Inhibition of
somatostatin (GHIH)
release
Intestinal (inhibit) Chyme in the
duodenum
Physiology of Gastric Secretion
Food H2 – cAMP
M3, CCK2 – IP3-DAG
CNS
GC
Vagus
Peptic Ulcer
• A peptic ulcer disease or PUD is an ulcer (defined
as mucosal erosions equal to or greater than
0.5 cm) of an area of the gastrointestinal tract
exposed to the acid and pepsin secretion
• Gastritis is the precursor to PUD and it is
clinically difficult to differentiate the two
– Stomach (called gastric ulcer)
– Duodenum (called duodenal ulcer)
– Esophagus (called esophageal ulcer)
– Meckel's Diverticulum (called Meckel's Diverticulum
ulcer)
Duodenal Vs Gastric Ulcers
Duodenal Gastric
• Age: 25-75 years • Age: 55-65 years
• Gnawing or burning upper • Relieved by food but pain
abdomen pain relieved by food but may persist even after eating
reappears 1-3 hrs after meals • Anorexia, wt loss, vomiting
• Worsening pain when stomach Infrequent or absent remissions
empty Small % become cancerous
• Bleeding occurs with deep • Severe ulcers may erode
erosion through stomach wall
– Haematemesis
– Maelena
Gastroesophageal Reflux Disease
(GERD)
• Common and GI motility disorder
• Acidity of Gastric contents – most common factor
• Acid contents reflux back into esophagus
• Intense burning, sometimes belching
• Can lead to esophagitis, esophageal ulcers, and
strictures
– Barrett’s esophagus
• Commonly associated with obesity
• Improves with lifestyle management
Why Ulceration Occurs?
High pH (2 to 3) in the gastric lumen – Pepsin is
active
•
Require defense mechanisms to protect oesophagus
and stomach
•
Oesophagus – protected by lower esophageal
sphincter (LES)
–Stomach: a number of mechanisms
• Mucus secretion
• Prostaglandins: I2 and E2 (alcohol, aspirin, and other
drugs)
• Bicabonate ions
• High Blood Flow (nitric oxide mediated)
I. Treatment of Peptic Ulcer
Acid-peptic diseases include hyperacidity, GERD
(gastro-esophageal reflux disease), stress induced
mucosal erosions and peptic ulcers (gastric or duodenal).
A localized loss of gastric or duodenal mucosa leads to
the formation of peptic ulcer. Peptic ulcer arises when
the mucosal protective factors are impaired and aggressive
factors dominate. Ulcers occur five times more in the
duodenum (predominantly in the duodenal bulb and pyloric
channel). Benign gastric ulcers are located mainly in the
antrum.
What may contribute imbalance ?
• Helicobacter pylori
• NSAIDs
• Ethanol
• Tobacco
• Severe physiologic stress
(Burns, CNS trauma, Surgery,
Severe medical illness)
• Steroids
H. pylori
• Gram (-) rod with flagella
• H. pylori is most common cause of
PUD
• Transmission route fecal-oral
• Secretes urease → convert urea to
ammonia
• Produces alkaline environment
enabling survival in stomach
• Almost all duodenal and 2/3 gastric
ulcer it’s infected with HP
• Considered class 1 carcinogen →
gastric cancer
The Nobel Prize in Physiology or Medicine (2005) was awarded jointly
to Barry J. Marshall and J. Robin Warren "for their discovery of the
bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease"
J. Robin Warren (2005) Barry J. Marshall (2005)
NSAIDS
Damage to the cytoprotective role of PGs – PGE2 and PGI2
NSAIDs
Differentiating between H. pylori and
NSAID-induced ulcer
Ulcers associated with Ulcers associated with
H. pylori NSAIDs
• More often in • More often in stomach

duodenum • Often deep
• Often superficial • More severe GI bleeding
• Less severe GI • Sometimes
bleeding asymptomatic
A. Antacids (Drugs Neutralizing Gastric Acid)
Antacids are weak bases that neutralize

gastric hydrochloric acid. They raise the pH
of the stomach contents, decrease the acid
load delivered to the duodenum and reduce
the activity of pepsin. Antacids are given
between meal and at bed time when
symptoms of hyperacidity usually occur; the
presence of food in the stomach can
prolong their neutralizing capacity.
1. Systemic Antacids: Sodium bicarbonate
acts rapidly, has a brief effect and raises the pH of
gastric secretion to 7.4.
On neutralizing gastric acid (HCl), it forms carbon
dioxide (CO2) and sodium chloride (NaCl).
Formation of CO2 results in gastric distention and
belching that can be dangerous if ulcer is near
perforation. Unreacted alkali is absorbed and can raise
the pH of blood (systemic alkalosis) and the urine.
Absorption of NaCl may increase sodium load and this
may exacerbate fluid retention in patients with
hypertension and CHF. The sudden release
of CO2 can cause “rebound acidity”.
2. Non-systemic Antacids are poorly absorbed from GIT
a) Buffer Type Non-systemic Antacids
•Aluminium hydroxide
•Magnesium trisilicate
•Magaldrate
These drugs have slow onset but longer effect and raise the
gastric pH to 3.5-4.
The pepsin activity is inhibited around pH 4. “Rebound
acidity” is not a problem. Aluminium hydroxide and
Magnesium trisilicate neutralize gastric hydrochloric acid to
form aluminium chloride and magnesium chloride which
further react with intestinal bicarbonates to form aluminium
carbonate and magnesium carbonate.
Sodium chloride formed in these reactions gets
reabsorbed to compensate the loss of chlorides during
gastric acid neutralization. Buffer type non-systemic
antacids do not disturb the acid-based balance of the
body. Aluminium hydroxide can cause constipation as
they relax gastric smooth muscle and delay gastric
emptying) – also hypophosphatemia and osteomalacia.
In renal failure Al3+ antacid – Aluminium toxicity and
Encephalopathy.
Magnesium trisilicate – osmotic diarrhoea, as a side
effect.
Magaldrate is a hydrated complex of Aluminium and
Magnesium hydroxide sulfate. Aluminium antacids also
hypophosphatemia and osteomalcia.
b) Non-Buffer Type Antacids (Calcium carbonate and
Magnesium hydroxide) are powerful drugs with
fast onset of action, and raise gastric pH > 7.
Like Sodium bicarbonate Calcium carbonate
may cause belching due to liberation of carbon
dioxide.
It can cause constipation too, due to formation of
calcium stearate.
Magnesium hydroxide does not liberate carbon
dioxide but can cause diarrhoea.
Chemical reactions of antacids with
HCl in the stomach
c) Other Antacids
Simethicone (dimethyl polysiloxane) is a
silicone polymer and therefore has
water-repellent properties.
It acts as an antifoaming agents and reduces
gastric flatulence. It is not absorbed from GIT.
Decrease surface tension thereby reduce
bubble formation – added to prevent reflux.
Alginates: Form a layer of foam on top of
gastric contents and reduce reflux.
Oxethazaine: Surface anaesthetic.
• To avoid the formation of insoluble complexes
(chelation) of drugs with antacids that are not
absorbed: taking antacids 2 hrs before or after
ingestion of other drugs
• It is rational to combine aluminum hydroxide and
magnesium hydroxide in antacid preparations:
Combination provides a relatively fast and
sustained neutralizing capacity
– (Magnesium Hydroxide – Rapidly acting
– Aluminium Hydroxide – Slowly acting)
• Combination preserves normal bowel function
– (Aluminium Hydroxide – constipation
– Magnesium hydroxide – diarrhoea)
B. Drugs, Reducing Gastric Acid Secretion
1. Proton Pump Inhibitors (PPIs)
• Esomeprazole
• Lansoprazole
• Pantoprazole
•Omeprazole
•Rabeprazole
PPIs are the most widely

used drugs for peptic
ulcer and related
disorders, because of their
efficacy and safety.
PPIs are prodrugs. In the parietal cells they
undergo a molecular rearrangement to
sulfenamide cation (active metabolite).
This cation makes a covalent disulfide bond
with –SH group of gastric proton pump
H+/K+-ATPase. Thereby PPIs inactivate the
proton pump irreversibly and shut off the
acid secretion.
PPIs also inhibit gastric mucosal
carbonic anhydrase and reduce bicarbonate
secretion to mucus.
Omeprazole – MOA
• Substituted Benzimidazole derivative

• Its a Prodrug
• Diffuses into G. canaliculi = accumulation
pH < 5 (proton catalyzed ) = tetracyclic sulfenamide + sulphenic
acid
• Covalent binding with sulfhydryl cysteines of H⁺K⁺ ATPase
• Irreversible inactivation of the pump molecule
(The charged forms cannot diffuse back across the canaliculi)
• Acid suppressants regardless of stimulating factors
• Also inhibits gastric mucosal carbonic anhydrase
Pharmacokinetics – PPI
Oral forms are prepared as acid resistant formulations that
release the drug in the intestine (because they are degraded
in acid media)
After absorption, they are distributed by blood to parietal cell
canaliculi
They irreversibly inactivate the proton pump molecule – but
half life is very short and only 1-2 Hrs
Still action persists for 24 Hrs to 48 hrs after a single dose –
irreversible inhibition of PPI and new PP synthesis takes time
(24 to 48 hour suppression of acid secretion, despite the
much shorter plasma half-lives of the parent compounds)
Platue state is attained after 4-5 days of dosing
Action lasts for 4-5 days even after stoppage of the drug
Pharmacokinetics – PPI
Given on an empty stomach because food affects absorption
They should be given 30 minutes to 1 hour before food
intake because an acidic pH in the parietal cell acid
canaliculi is required for drug activation, and food stimulates
acid production
Concomitant use of other antisecretory drugs – H2 receptor
antagonists – reduces action
Highly protein bound and rapidly Metabolized by the liver by
CYP2C19 and CYP3A4 – dose reduction necessary in severe
hepatic failure
Excreted in Kidneys minimally (no dose reduction needed in
renal failure and elderly)
Adverse Effects
• The most common are GIT troubles in the form of
nausea, abdominal pain, constipation, flatulence, and
diarrhea, hypochlorhydria and risk of enteric infections
• Subacute myopathy, arthralgias, headaches, and skin
rashes
Prolonged use:
– Gynaecomastia, erectile dysfunction
– Leucopenia and hepatic dysfunction
– Vitamin B12 deficiency
– Hypergastrinemia which may predispose to rebound
hypersecretion of gastric acid upon discontinuation of therapy
and may promote the growth of gastrointestinal tumors (carcinoid
tumors)
PPI
• Drug Interaction:
– Inhibits metabolism
of Warfarin, Diazepam
• Therapeutic uses:
1. Gastroesophageal reflux disease (GERD)
2. Peptic Ulcer – Gastric and duodenal ulcers
3. Bleeding peptic Ulcer
4. Zollinger ellison Syndrome
5. Prevention of recurrence of NSAID – associated gastric
ulcers in patients who continue NSAID use.
6. Reducing the risk of duodenal ulcer recurrence
associated with H. pylori infections
PPI – Dosage schedule
• Omeprazole 20 mg o.d.
• Lansoprazole 30 mg o.d.
• Pantoprazole 40 mg o.d.
• Rabeprazole 20 mg o.d.
• Esomeprazole 20-40 mg o.d.
2. Antagonist of H2-receptors (H2-blockers)
– for treatment of peptic ulcer:
•Cimetidine
•Ranitidine
•Famotidine
•Nizatidine
•Roxatidine
3. Anticholinergics (M1-blockers)
•Pirenzepine and Telenzepine
4. Prostaglandin analogues
•Misoprostol (PGE1) and Enprostil (PGE2)
H2 Antagonists
Cimetidine, Ranitidine, Famotidine Nizatidine and Roxatidine
MOA:
– Reversible competitive inhibitors of H 2 receptor
– Highly selective, no action on H 1 or H3 receptors
– All phases of gastric acid secretion
– Very effective in inhibiting nocturnal acid secretion (as it
depends largely on Histamine )
– Modest impact on meal stimulated acid secretion (as it depends
on gastrin, acetylcholine and histamine)
– Volume of pepsin content and IF are also reduced
– Volume reduced by 60-70% – anti ulcerogenic effect
– No effect on motility
H2 antagonists
• Kinetics:
– All drugs are absorbed orally adequately
– Bioavailability upto 80 %
– Absorption is not interfered by presence of
food
– Can cross placental barrier and reaches milk
– Poor CNS penetration
– 2/3rd of the drugs are excreted unchanged in
bile and urine
• Preparations: available as tablets, injections
H2 antagonists – ADRs
• Extremely safe drugs and well
tolerated
• Main ADRs are related to Cimetidine:
– Antiandrogenic effects
– Increases prolactin secretion and inhibits degradation of estradiol by liver
– Cytochrome P450 inhibition – theophylline, metronidazole, phenytoin,
imipramine etc.
– Antacids
• Others:
– Headache, dizziness, bowel upset, dry mouth
– Bolus IV – release histamine – bradycardia, arrhythmia, cardiac arrest
– Elderly – precaution
Comparison of H2 antagonists
Cimetidine Ranitidine Famotidine Nizatidine

Bioavailability 80 50 40 >90
Relative Potency 1 5-10 32 5-10
Half life (hrs) 1.5-2.3 1.6-2.4 2.5-4 1.1-1.6
Duration of 6 8 12 8
action (hrs)
Inhibition of 1 0.1 0 0
CYP 450
Dose mg (bd) 400 150 20 150
Antiandrogenic effect, prolactin secretion and gynocomastia
H2 antagonists – Uses
Promote the healing of gastric and duodenal ulcers
• Duodenal ulcer – 70 to 90%
• Gastric ulcer – 50 to 75% (NSAID ulcers)
• Stress ulcer and gastritis
• GERD
• Zollinger-Ellison syndrome
Doses:
• 300 mg/40 mg/150 mg at bed time of
Ranitidine/Famotidine/Roxatidine respectively for healing
• Maintenance: 150/20/150 mg BD of
Ranitidine/Famotidine/Roxatidine
H2 blockers Tablets in Peptic ulcer
Cimetidine 800mg bedtime 400mg bedtime
/400mgBd
Ranitidine 300 mg 150 mg bedtime
bedtime/150mg BD
Famotidine 40 mg bedtime 20 mg bedtime
Roxatidine 150 mg bedtime 75 mg bedtime

Muscarinic antagonists
Atropine:
– Block the M1,3 class receptors
– Reduce acid production
– Abolish gastrointestinal spasm
Pirenzepine and Telenzepine
• Reduce meal stimulated HCl secretion by reversible blockade
of muscarinic (M1) receptors on the cell bodies of the
intramural cholinergic ganglia
(receptors on parietal cells are M3).
Unpopular as a first choice because of high incidence of
anticholinergic side effects (dry mouth and blurred vision)
Prostaglandin
analogues
• Inhibit gastric acid secretion

• Exhibit ‘cytoprotective’ activity
• Enhance local production of mucus or bicarbonate
• Promote local cell regeneration
• Help to maintain mucosal blood
Prostaglandin analogues – Misoprostol
Actions:
 Inhibit histamine-stimulated gastric acid secretion
 Stimulation of mucin and bicarbonate secretion
 Increase mucosal blood flow
(Reinforcing of mucous layer buffered by HCO3
secretion from epithelial cells)
Therapeutic uses:
Prevent ion of NSAID-induced mucosal injury
(rarely used because it needs frequent
administration – 4 times daily)
Misoprostol
• Doses: 200 mcg 4 times a day (Misoprost)
• ADRs:
– Diarrhoea and abdominal cramps
– Uterine bleeding
– Abortion
– Exacerbations of inflammatory bowel disease and
should be avoided in patients with this disorder
Contraindications:
1. Inflammatory bowel disease
2. Pregnancy (may cause abortion)
Drugs of Ulcer
treatment
Misoprostol Ranitidine
PGE2 Gastrin
Histamine
+ _ Proglumide
ACh
_
M3 _ H2
Adenyl
PGE cyclase
+ Gastrin
+ receptor + receptor
Ca++ ATP cAMP Ca++

+ + +
Protein Kinase
(Activated)
K+ + H+
K
Parietal cell
Proton pump
_ Lumen of stomach
Omeprazole _
Gastric acid Antacid
C. Mucosal Protective Drugs
•Sucralfate (aluminium salt of sulfated
sucrose)
in acidic environment (pH < 4) polymerizes
and forms a gel over ulcer crater which acts
as acid resistant physical barrier.
It also stimulates mucosal synthesis of PGE 2
and secretion of bicarbonates.
Sucralfate is administered orally.
Sucralfate – ulcer protective
Salt of sucrose complexed to sulfated aluminium
hydroxide (basic aluminium salt)
MOA:
• • In acidic pH polymerises to viscous gel that adheres to
ulcer crater – more on duodenal ulcer
• • Precipitates protein on surface proteins and acts as
physical barrier
• Dietary proteins get deposited on this layer forming
another coat
• Delays gastric emptying and causes gastric PG
synthesis – protective action
Sucralfate
Taken on empty stomach 1 hr. before meals
Concurrent
• antacids, H2 antagonist avoided (as it
needs
• acid for activation)
Uses:
•
• NSAID induced ulcers
• Patients with continued smoking
• ICU
• Topically – burn, bedsore ulcers, excoriated skins
•
Dose: 1 gm 1 Hr before meals
•
ADRs: Constipation, hypophosphatemia
C. Mucosal Protective Drugs
•Colloidal Bismuth Subcitrate in gastric acidic media
converts into bismuth oxychloride and bismuth
citrate which chelate glucoproteins and amino acids
at ulcer base to form an acid resistant coating.
It stimulates PGE, mucus and bicarbonate secretion.
It has also anti-H. pylori activity.
Bismuth subsalicylate
Pharmacological actions:
• Undergoes rapid dissolution in
the stomach into bismuth and salicylates
• Salicylates are absorbed
• Bismuth coats ulcers and erosions
protecting them from acid and pepsin and
increases prostaglandin and bicarbonate
production
Uses:
• Treatment of dyspepsia and acute
diarrhoea
D. Anti-Helicobacter Pylori Drugs
Peptic ulcer, although a multifactorial disease, also occurs

due to colonisation of mucosa by H. pylori: in 90% in cases
with duodenal ulcers, 60 to 70% – with gastric ulcers and
50% in patients with non-ulcer dyspepsia. H. pylori is
accepted as a cause of chronic atrophic gastritis too. It is a
risk factor for gastric adenocarcinoma and to some
extent for non-Hodgkin’s lymphoma affecting stomach.
H. pylori produces urease which hydrolyses urea into
ammonia. Ammonia neutralizes gastric acid to create a
neutral protective cloud over the bacteria.
H. pylori infection can be detected by a “urea breath test”,
but the test is not used after the treatment with PPIs.
Since H. pylori becomes less virulent in absence of acid,
a combination of an antibiotic with PPIs (or H2-blockers) is
more efficacious in eradicating this Gram (–) bacterium.
Anti-H. pylori Drugs: Amoxicillin, Clarithromycin,
metronidazole, tinidazole and tetracycline
Preferred anti-Helicobacter pylori Combinations
•Dual therapy (7-10 days).
Omeprazole (40 mg OD) + Amoxicillin (1000 mg BD)
•Triple therapy (14 days)
Omeparzole (or lanzoprazole), plus Clarithromycin,
plus Amoxicillin (resp. Metronidazole, or Tetracycline)
Triple Therapy
The BEST among all the Triple therapy regimen is:
Omeprazole / Lansoprazole - 20 / 30 mg bd
Clarithromycin - 500 mg bd
Amoxycillin / Metronidazole - 1gm / 500 mg bd
Given for 14 days followed by PPI for 4-6 weeks

Short regimens for 7-10 days not very effective
Triple Therapy
Some other Triple Therapy Regimens are
Bismuth subsalicylate - 2 tab qid

Metronidazole - 250 mg qid
Tetracycline - 500 mg qid
Ranitidine / Bismuth citrate - 400 mg bd

Tetracycline - 500 mg bd
Clarithromycin / Metronidazole - 500 mg bd
Additional
1. Drugs causing peptic ulcer:
•• Non Steroidal Anti Inflammatory Drugs (NSAIDs)
•• Glucocorticoids
•• Cytotoxic agents
2. Stress induced ulceration after head
trauma
3. Cushing’s ulcer
4. Stress induced ulceration after severe
burns – Curling’s ulcer
II. Antiemetic Drugs
Vomiting means expulsion of gastric contents
through mouth due to mass antiperistalsis. It is
often preceded by nausea. Vomiting can be life
saving, physiological response to the ingested
toxic substances. It also can be an adverse
reaction of radiation and antineoplastic agents.
Vomiting also occurs in early pregnancy, during
migraine attack, in motion sickness, etc.
Emetic Response: Relaxation of fundus, body of stomach
and also the oesophageal sphincter and oesophagus –
but contraction of pylorus and duodenum – then rythmic
contraction of diaphragm and abdominal muscles –
expulsion via mouth
Centre: Medulla Oblongata
Relay Centers: chemoreceptor trigger zone (CTZ) and
nucleus tractus solitarius (NTS)
The CTZ at the base of the 4th ventricle has numerous
receptors: D2-, 5-HT3-, M-, H1-, for SP etc. Stimulation of
different receptors are involved in different pathways
leading to emesis.
Afferent impulses: GIT, throat and other viscera
Triggering agents: Blood borne drugs, mediators, hormones
and toxins etc. – clinically cytotoxic drugs and radiation
Transmitter: 5-HT (enterochromaffin cells) – via 5HT3 receptor
of the enteric nervous system (ENS) – to vagal and spinal
visceral neurones – to CTZ and NTS
Spilling of 5-HT due to massive release – acts on CTZ
Other mediators: H1, D2, 5HT3, Muscarinic M and opioid µ etc.
– expressed in CTZ and NTS
Vestibular apparatus: generates impulses
Body equilibrium disturbed
Ototoxic drugs
Mainly relayed by cerebellum to vomiting centre – Muscarinic
and H1 receptors
Directly in higher centres: Bad smell, ghastly sight, pain, fear
Emetics
Drugs which induce vomiting
1.Acts on CTZ: Apomorphine
2.Acts reflexly and on CTZ: Ipecacuanha
Cephaelais ipecacuanha
Apomorphine: Morphine derivative – semisynthetic –
Dopaminergic agonist in CTZ
• 6 mg IM/SC – acts within 5 minutes
• Respiratory depression
• Orally – not recommended (large dose – slow
inconsistent)
• Parkinsonism
Ipecacuanha: Cephaelais ipecacuanha
◦ Syrup ipecac – 15 to 30 ml (10 to 15 in child)
◦ Action takes 15 minutes
◦ MOA: Irritation of Gastric mucosa and directly on CTZ
Household emetics
Salt water
•Warm water – mild emetic
•2 spoonful of common salt in 1 pint of warm water
Mustard seed
• 1 table spoonful ground mustard seeds in half-
pin of warm water
• Strong coffee is one of the best domestic
stimulants, especially after a narcotic poison
Main Antiemetic Drugs
(1) 5-HT3-receptor antagonists (setrons)
Dolasetron, Granisetron, Ondansetron
(Zofran – tab. 8 mg), Tropisetron
(2) Neurokinine-1 (NK1-, SP1-) receptor
antagonists: Aprepitant, Fosaprepitant (prodrug)
(3) D2-receptor antagonists
Neuroleptics: Chlorpromazine, Prochlorperzine, Haloperidol
Prokinetics: Domperidone, Metoclopramide
(4) H1-blockers: Diphenhydramine, Doxylamine, Promethazine
(5) M-cholinolytics: Scopolamine (Scopoderm TTS)
(6) Miscellaneous Antiemetic Agents
5-HT3-receptor antagonists block 5-HT3-
receptors both peripherally (on vagal nerve
terminals) and centrally (CTZ).
Granisetron is the most potent antiemetic
compared to ondansetron and dolasetron.
These drugs are most effective when given i.v.
30 min prior to anticancer chemotherapy
(granisetron – 10 mcg/kg). These doses may be
repeated every 24 h.
Ondansetron
Developed for Chemotherapy/radiotherapy induced vomiting – also
effective in others (Postoperative nausea and vomiting (PONV)
MOA: Acts peripherally as well as centrally – Blocks depolarizing action
of 5-HT3 receptors in vagus at GIT and CTZ/NTS
No action on Dopamine receptor – does not block Apomorphine
induced vomiting and mild gastrokinetic effect
Kinetics: 60-70% bioavailability – first pass metabolism.
Metabolized as glucoronide and sulfate. Eliminated in urine and faeces. T1/2 life 5-7 Hrs
Dose: 8 mg slow IV for 15 minutes ½ hr before chemotherapy. Followed
by 2 such doses 4 hours apart. Then 8 mg orally twice daily for 1 week.
For others 4-8 mg IV followed by every 8 hourly.
80% success – better/equal to Metoclopramide – no dystonia or
sedation. Adjuvant improve response.
ADRs: Headache and dizziness. Mild constipation and abdominal
discomfort. Hypotension, allergic reactions, chest pain and
bradycardia etc.
Neurokinine-1 (NK1-, SP1-) receptor antagonists
(Aprepitant etc.).
MOA: Emetogenic chemotherapy releases Substance P –
stimulates CTZ and NTS by acting on NK1 – blocking of NK1
receptors causes emesis blocking
•Little effect on 5-HT3 or D2 receptor
•GIT motility not affected
Uses: 125 mg + 80 mg + 80 mg for 3 days with IV
Ondansetron and Dexamethasone – for cisplatin
induced vomiting – useful in multiple cycle patients –
Orally 40 mg can be used for PONV
Kinetics: well absorbed orally, metabolized in liver,
excreted in faeces and urine. T1/2 10 – 13 Hrs
ADRs: Weakness, fatigue, flatulence etc.
D2-receptor antagonists (Neuroleptics)
Phenothiazines (prochlorperazine, thiethylperazine)
and butyrophenone group of antipsychotics (droperidol) can
be used to treat postoperative nausea and vomiting.
Uses:
•Useful in drug induced post anaesthetic nausea and vomiting
•Disease induced vomiting – Gastroenteritis, uraemia, liver disease
•Cancer chemotherapy
•Radiation sickness (less)
•Morning sickness
ADRs: Sedation, acute muscle dystonia – diagnose the cause first before
administering
Prochlorperazine (Stemetil) – D2 blocking agent – labyrinthine
suppressant – antivertigo and antiemetic action. Effective in Chemo-
Induced Nausea and Vomiting (CINV) with vertigo
• Extrapyramidal Symptoms and muscle dystonia
Emetogenic activity
Cisplatin
Carmustine
Cyclophosphamide
Mitomycin C
L-Asparginase
Fluorouracil Antiemetic activity
Methotrexate
5-HT3-blockers
Etoposide D2-blockers
Vincristine
Glucocorticoids
H1-blockers
Prokinetic antemetic
Metoclopramide is D2-receptor antagonists but in high doses
it also blocks 5-HT3-receptors. It crosses BBB. Its prokinetic
action (stimulation of GI motility) is connected with stimulation
of 5-HT4-receptors, present on excitatory interneurons, which
enhances ACh release from primary cholinergic neurons in
myenteric plexus. Metoclopramide is used as antiemetic and
as gastrokinetic agent to accelerate gastric empting prior to
giving emergency general anaesthesia in case the patient
has taken food less than 4 h before. This drug may also be
successful in stopping persistent hiccups. Being a central and
peripheral D2-blocker it produces sedation, muscle dystonia,
in high doses – extrapyramidal effects, galactorrhoea in
females and gynecomastia in males.
Sites of action of prokinetics Stimuli – cause 5-HT release
Stimulates extrinsic and intrinsic
pathway
Via peripheral 5-HT3 receptors
Extrinsic pathway – via vagus
and dorsal root ganglia – CNS –
vomiting stimulation – ondansetron
Intrinsic pathway – excitatory and
inhibitory interneurones coordinates
peristalsis
Contraction of proximal and relaxation of
distal gut muscles
Ach/Calcitonin gene-related peptide (CGRP)
and NANC (NO)
Prokinetics (metoclopramide – meto,
cisapride – cisa) – activates prejunctional 5-
HT4 – promote release of Ach/CGRP –
contractile activity
Also weak 5-HT3 blocking action (inhibitory
neurons)
Meto and cisa also inhibits D2
action normally D2 acts as releaser of Ach –
more contraction with Meto
Metoclopramide
Pharmacokinetics: Absorbed orally, crosses BBB and placenta and
secreted in milk. Conjugated in liver, t1/2 = 4-6 Hrs.
ADRs: Sedation, dizziness, loose stool and muscle dystonia
• Long use: Parkinsonism, galactorrhoea, gynaecomastia
• Safe in pregnancy but in lactating mother children may have loose
stool, dystonia etc. Drug interactions – abolishes levodopa action
Uses:
◦ Antiemetic: Postoperative, drug induced, disease associated,
radiation induced etc. but not effective in motion sickness. Still
preferred in vomiting due to anticancer drug – in combination with
Promethazine
◦ Gastrokinetic: To accelerate gastric emptying – Emergency
GA, gastroparesis (post vagotomy), duodenal intubation etc.
◦ Dyspepsia: stops hiccup
◦ GERD: Does not aid in healing, PPIs are preferred – used as adjuvant
Domperidone has a similar mechanism of action as metoclopramide, but
it is a peripheral D2-blocker. Its antiemetic efficacy is lower than
metoclopramide. It is also used to prevent the emetic side effect of
levodopa or bromocriptine without affecting their antiparkinsonian
effect. Chemically related to haloperidol but action like Metoclopramide
D2 antagonist – in upper GIT (not attenuated by atropine)
Rarely EP side effect – does not cross BBB, but hyperprolactinemia
occurs.
Acts mainly through CTZ – outside BBB. Does not abolish action of
levodopa.
Kinetics: absorbed orally but 15% bioavailability – high 1st pass
metabolism, completely metabolized and excreted in urine. T1/2
– 7-8 Hrs
ADRs: Less than Metoclopramide – dry mouth, loose stool, headache,
galactorrhoea etc. Arrhythmia on injection
Uses: Similar as Metoclopramide but milder spectrum of action –
not effective in chemotherapy
Other Prokinetics – Cisapride, mosapride, Itopride etc.
H1-blockers with anticholinergic properties (Cyclizine,
Diphenhydramine) are useful for prevention or
treatment of motion sickness and vertigo due to
labirinth dysfunction.
Doxylamine can be used in morning sickness
(vomiting during the first trimester of pregnancy, due
to the effect of increased oestrogen level on CTZ).
H1 Antihistaminics
Primarily used in motion sickness, morning sickness and some other
vomiting in lesser extent – also anticholinergic, antihistaminic and
antidopaminergic actions
Promethazine (Phenothiazine), diphenhydramine: 4-6 Hours protection
Combined with metoclopramide in CINV: additive effect plus counters extra
pyramidal effects
Promethazine theoclate (Avomine) – motion sickness
Doxylamine: Sedative H1 antihistaminic – marketed in combination
with Pyridoxine – specifically for morning sickness – duration of action
10 Hours (at bed time) – drowsiness, dry mouth, vertigo. Pyridoxine
serves as a cofactor for the glutamate decarboxylase and thus
increases the synthesis of GABA which acts as inhibitory
neurotransmitter at CTZ.
Meclizine: Long duration of action – sea sickness
Cinnarizine: anti vertigo action – inhibits Ca++ influx in endolymph
Motion sickness and morning
sickness
Motion Sickness: Anticholinergics are preferred
– followed by H1 Antihistaminics –
antidopaminergics do not work
Morning Sickness: Preferably drugs should be
avoided – reassurance and dietary modification
Dicyclomine, promethazine or metoclopramide

are preferred at low doses
Anticholinergic drugs: Hyoscine (Scopolamine)
is used in motion sickness as TTS.
Hyoscine: Motion Sickness (0.2 to 0.4 mg IM)
Used IM/SC, but short duration of action
MOA: Blocking of cholinergic link of vestibular
apparatus to the vomiting center – does not work in
vomiting due to other etiology
ADRs: Sedation, dry mouth and other
anticholinergic effects
Transdermal delivery system (1.5 mg)
Dicyclomine: Prophylaxis of motion sickness
and morning sickness
Miscellaneous Antiemetic Agents
•GCS: Dexamethasone, Methylprednisolone
•Canabinoides: Nabilone and Dronabinol stimulate CB1-
receptors present on neurons around the vomiting center
and are used in oncology. Their hallucinogenic activity
is weak.
•Benzodiazepines:
Alprazolam, Diazepam,
Lorazepam
•Others: Benzocaine,
Sodium citrate, T-ra Menthae
III. Laxative and Purgative Drugs
Laxatives provide elimination of soft semisolid stool
and Purgatives provide more watery evacuation.
Laxatives are used: to treat constipation; to avoid undue
straining at defecation in cases of hernia, haemorrhoids or
CVD; before or after surgery of any anorectal disease; in
bedridden patients.
Lactulose is an osmotic laxative drug. It is nonabsorble-
indigestible disaccharide (sugar), which increases fecal
bulk by hydrophilic and osmotic action. It is given in dose
of 10 g orally. Latency period is 1 to 3 days. Lactulose is
also used for treatment of hepatic encephalopathy.
Liquid paraffin is an inert mineral oil.
Liquid pararaffin is a fecal lubricant and stool softner
as it retards water absorption from the stool. It is given 15
to 30 ml per day at bed time. Latency period is 1 to 3 days.
Purgatives are used for complete colonic cleansing prior
to GI endoscopic procedures or before intestinal operation.
Purgatives may also be needed to flush out warms after the
use of anthelmintic drugs. In low doses purgatives can
be used as laxatives too.
Osmotic Purgatives include: Saline purgatives
(Magnesium sulfate) and Electrolyte purgatives
(PEG – PolyEthylene Glycol, which is a nonabsorbable
sugar). They act on small and on large intestine.
Saline purgatives are soluble
inorganic salts which increase the fecal bulk by retaining
water by osmotic effect, thus increasing peristalsis. These
agents also release CCK which further helps in increasing
intestinal secretion and peristalsis. Saline purgatives should
be ingested with enough water to protect vomiting. These
drugs can cause electrolyte disturbances and must be
avoided in patients with CVD as well as during pregnancy.
Irritant purgatives
•Antraquinone group: Senna, Cascara and Aloë
•Organic agents: Bisacodyl, Sodium picosulfate
•Oils: Castor oils
All irritant purgatives stimulate peristalsis by irritant action of intestinal mucosa.
They also stimulate colonic electrolyte and fluid secretion by altering the
absorptive and secretory activity of the mucosal cells.
Senna, Cascara and Aloë occur naturally in plants.
Senna is more commonly used. These plant agents contain anthraquinone
glycosides with purgative action.
The organic irritants are prodrugs. The primary site of
action of their active metabolites is in the colon. Bisacodyl
is activated in the intestine by deacetylation. In the colon
Sodium picosulfate is converted to the active metabolite.
Castor oil is hydrolyzed in the intestine by pancreatic lipase
to ricinolic acid which increases the intestinal motility.
Aloë vera
IV. Antidiarrhoeal Agents
Diarrhoea is an abnormal increase in the frequency and the liquidity of stool.
Increased motility of GIT and the decreased ability of intestine to absorb water
from the stool are the major factors, causing diarrhoea.
Osmotic diarrhoea may cause by ingestion of some type of meal, use of some
osmotic substances, lactulose or magnesium containing antacids, lactase enzyme deficiency.
Secretory diarrhoea occurs when the intestinal wall loses its functional integrity or gets
damaged resulting in an increased secretion of electrolyte in the intestinal tract.
This may be due to some bacterial infection (Schigella, Salmonella), bacterial endotoxins
(from E. coli, V. cholerae, S. aureus), viral infections (rotavirus etc.), protozoal infections
(Lamblia intestinalis, E. histolytica), underlying pathology (inflammatory bowel disease)
or due to side effects of drugs (antibiotics, anticancer agents, colchicine,
prostaglandins, orlistat, acarbose). Excess of bile also causes diarrhoea.
Motility disorder diarrhoea. Increased motility reduces the contact time of the stool with the
intestinal wall, so that lesser amount of water is absorbed back from the faces. Motility disorders
include IBS, scleroderma, diabetic neuropathy, vagotomy etc. Some drugs can increase
intestinal motility: prokinetic antiemetics, bethanechol, digitalis, quinidine, ampicillin
(causes disbiosis); neurosis, etc.
Treatment of infective diarrhoeas needs proper diagnosis
and suitable antibiotic and/or antiprotozoal drug. For
symptomatic relief of non-specific diarrhoes are used:
(1) Antimotility and Antisecretory Agents
a) Opioid agonists which does not cross BBB
• Loperamide (Imodium®) and Racecadotril (Hidrasec®)
These drugs stimulate mu- and delta-receptors, present in the small and large
intestines. Activation of mu-receptors decreases peristaltic movements.
Activation of delta-receptors contributes to their antisecretory effects.
Although all opioids such as morphine and codeine have antidiarrhoeal effects,
their CNS effects and dependence liability limit their usefulness.
Loperamide directly stimulates mu- and delta-receptors.
Racecadotril blocks enzyme encephalinase and increases local concentration
of enkephalins in intestinal mucosa which then stimulate
mu- and delta-receptors. This drug can be used orally from
children under 5 years old (including babies), but
Loperamide is contraindicated in children < 5 years old.
b) Miscellaneous Agents
•Carbo activatus (absorbent drug)
•Bismuth subsalicylate reduces stool frequency and
liquidity in acute diarrhoea due to inhibition of
PG synthesis. Bismuth has some antimicrobial and
mucosal protective effect too.
(2) Fluid and Electrolyte Replacement

During diarrhoea, a glucose-coupled transport continues
in the intestines which causes water and electrolyte losses
through the stools.
V. Treatment of Inflammatory Bowel Disease
Ulcerative colitis and Crohn’s disease are two important

inflammatory bowel diseases. The pathogenesis of these
diseases involves autoimmune mechanism and imbalance
between proinflammatory and anti-inflammatory cytokines.
The main drugs, used in the treatment of these diseases are
aminosalicylates, GCS and some immunosuppressants.
Antidiarrhoeal agents must be avoided in active and
severe ulcerative colitis as they can lead to dilatation of
the colon and its perforation.
Aminosalicylates (sulfasalazine, olsalazine) contain a
5-aminosalicylic acid (5-ASA) moiety bound by an azo
(N=N) bond to an inert moiety or by another 5-ASA
molecule. 5-ASA inhibits the synthesis of PGs by inhibiting
COX, like salicylates, as well as inhibiting the production of
cytokines. 5-ASA also inhibits the activity of nuclear
factor-kB, which is an important transcription factor for
pro-inflammatory cytokines. It suppresses the generation
of superoxide free radicals. Aminosalicylates induce and
maintain remission in patients with ulcerative colitis.
GCS (Prednisone, Prednisolone) have been the mainstay of the treatment for
acute/severe exacerbations of irritable bowel disease. Moderately severe
attacks of ulcerative colitis should be treated orally with systemic GCS.
Immunosuppressive Agents
•Cyclosporine may induce remissions in case of severe ulcerative colitis
unresponsive to GCS.
•Azathioprine, mercaptopurine
•Methotrexate is useful in controlling relapse of Crohn’s diseases
unresponsive to GCS or azathioprine
•Infliximab is a chimeric (25% mouse and 75% human) anti-TNF-alpha-
monoclonal antibody, which inhibits T-cells and macrophage functions.
Consequently, the release of other proinflammatory cytokines (IL-1, 2, 8; collagenase and
metaloproteinases) is prevented. It is administered by i.v. infusion. A single dose of infliximab
(5 to 10 mg/kg) induces remission in approximately 40% of patients with Crohn’s disease. An
additional dose after 8 weeks produces long-lasting remission.
•Adalimumab is a recombinant human anti-TNF-alpha-monoclonal antibody. It
is given s.c. and has a longer plasma half life. It has lesser side effects
compared to infliximab.
VI. Drugs used in Pancreatic Insufficiency
Pancreatic enzyme agents contain a mixture of amylase,
lipase and proteases. They are the mainstay of the treatment
of the pancreatic enzyme insufficiency which is most
commonly caused by cystic fibrosis, chronic pancreatitis or
pancreatic resection. Exocrine pancreatic enzyme insufficiency
leads to fat and protein indigestion
which in turn causes steatorrhoea,
azotorrhoea, vitamin deficiency and
weight loss.
•Festal, Kreon,
•Mezym forte, Panzytrat
VII. Hepatoprotectors
Drugs which stimulate regenerative processes
•Acidum oroticum, Essentiale, Silymarin
Drugs which stimulate fat infiltration
•Thioctic acid (Acidum aphfa-lipoicum)
Derivatives of Methionine: Ademethionine
Interferons (in viral hepatitis)
•Interferon alfa-2a
•Peginterferon alfa-2a
•Interferon alfa-2b
Antiviral vaccines: Hepatitis A and B vaccine,
•Hepatitis A vaccine, Hepatitis B vaccine
VIII. Drugs Acting on Biliary tract
Choleretic Drugs: Cholagol, Cholamin, Febichol
Cholekinetic Drugs: Oleum olivarum, Rowachol
Drugs which improve the solubility
of cholesterol gallstones: Ursodeoxycholic acid
IX. Probiotics – regulators of intestinal

or other bacterial flora
BioGaia, Linex, Lactoflor, Lactagyn® (vaginal flora),
Normoflor, Probien®

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Diuretic drugs

Diuretics exert their effect directly on the

• Carbonic anhydrase inhibitors

Acetazolamide inhibits carbonic

Acetazolamide blocks not only renal CA, but

• Potassium wasting resulting into the hypokalaemia

• Liver failure with impaired consciousness

Furosemide enhances the action of antihypertensive drugs and non-

Thiazides Thiazide analogues

Vasodilators with antihypertensive effect

• Impaired glucose tolerance

• Dyslipidemia – increased total cholesterol and LDL,

• They reduce plasma volume in pregnant women and

Often they are used

Competitive Blockers of the

• Spironolactone and eplerenone

Infusions (1:10) made from madder facilitate dilution

It is an important ingredient of many phytoproducts

A disorder of unknown origin affecting the

Stress Na+ Intake Obesity Smoking

> 140 mmHg > 90 mmHg

Systolic Blood Diastolic Blood

•Increased: peripheral vessel resistance,

Na+ & water

ACE (kininase II)

• It’s a prodrug – converted to enalaprilate

Losartan Irbesartan Valsartan

Oral: in a once daily dosing regimen.

• They do not interfere with degradation of kinins

AP – action potential, NA – noradrenaline

Dihydropyridines (nifedipine, amlodipine,

• Orally not used any more

• Topically as 2-5% lotion/gel and takes months to get effects

MOA of hair growth:

• A commonly used non-invasive index of

• Vasospastic angina (uncommon form) is also known as:

They can be given to relieve rapidly the

cGMP-dependent protein kinase

Activation of PKG results in phosphorylation

Celullar action of nitrates

Property GTN ISDN 5-ISMN

It can be avoided by a “nitrate-low”

Atenolol Propranolol Carvedilol

AP – action potential, NA – noradrenaline

• ADRs and contraindications:

• Negative Inotropic, Chronotropic and Dromotropic

Coronary Suppression Suppression Suppression

Verapamil ++++ ++++ +++++ +++++

Beta-Blockers or Nitrates Plus

Undesireable effects are shown in italics

Blocking beta-oxidation, reducing Trimetazidine

delays pulse rate with

Associated with hyperuricemia.

 Relieve acute gouty attacks

 Prevent recurrent gouty episodes

 Given orally, rapidly absorbed

 Partially metabolized and

 Selective for an acute attack of