Antihypertensive Agents

ISAAC TABIRI HENNEH (PhD, MPhil, BPharm, MPSGh

Department of Pharmacotherapeutics and Pharmacy Practice

School of Pharmacy and Pharmaceutical Sciences
University of Cape Coast
Email: isaac.henneh@ucc.edu.gh
Tel: 0245790062
 HYPERTENSION
• HPT is a persistently high arterial blood pressure that is above
"normal B.P”
• i.e. Systolic - >140 mmHg and/or Diastolic - >90 mm Hg

• HPT is usually asymptomatic but progressive

• If not effectively managed or controlled

• hypertension could lead to complications such as heart failure,
myocardial ischaemia, stroke, kidney failure

• The higher the B.P., the greater the risk of cardiovascular and
other complications
• The two main determinants of B.P. are
• cardiac output (CO) and
• total peripheral resistance (TPR).
• Total peripheral resistance refers to the amount of force
affecting resistance to blood flow throughout the circulatory
system.
 Types and Causes of Hypertension
1. Primary Hyperension:
• In about 90% of the hypertensive cases, no specific underlying cause can be identified
• Increasing age, family history, excess body weight, lack of physical activity and
excessive alcohol intake may be predisposing factors.

2. Seconday Hypertension:
In about 10% of cases, the cause of HPT may be secondary to some definite
abnormality such as
• Kidney related
• Chronic kidney disease,
• Polycystic kidney disease
• Endocrine
• Phaechromocytoma
• hyperaldosteronism (Conn’s disease)
• Hypercortism (Cushing’s disease)
• hyperthyroidism
• Acromegaly
• Vascular
• Renal artery stenosis
• Coarction of the artery
 Classes of drugs for Management
of hypertension
Any of the first five classes can be used as 1st Line
• Diuretics (mainly thiazide diuretics)
• Calcium channel blockers
• Angiotensin Converting Enzyme inhibitors (ACEIs)
• Angiotensin II receptor Blockers (ARBs)
• β- blockers

• Others
• - receptor antagonists
• Centrally acting agents
Diuretics
• The three main classes of diuretics
include
• Thiazides & Thiazide-like Diuretics
• Loop diuretics
• Potassium(K+) Sparing Diuretics
 Thiazides & Thiazide-like Diuretics

Common examples of drugs in this class are

• Thiazides: Bendrofluazide,
hydrochlorthiazides, cyclopenthiazide,
chlorthiazide etc

• Thiazide-like Drugs:- Chlorthalidone,

indapamide, xipamide etc
Thiazide Diuretics Continued
Mechanism of Action:
• They lower blood pressure initially, by increasing
sodium and water excretion via interaction with Na-
Cl cotransporter in kidney.
• This causes a decrease in extracellular volume,
resulting in a decrease in cardiac output and renal
blood flow.
• With long-term treatment, plasma volume approaches
a normal value, but a hypotensive effect persists that
is related to a decrease in peripheral resistance.
• They possibly cause a fall in smooth muscle Na+ which causes a
secondary reduction in intracellular Ca 2+ so that the muscle
becomes less responsive to endogenous vasoconstrictors.
 Thiazide Diuretics Continued
• The antihypertensive effect of the thiazides occur at
relatively low doses.
• No additional B.P reduction benefit is achieved with high
dose of thiazides but more side effects
• This may cause electrolyte disturbances

• The antihypertensive effect is long-lasting and may persist

for 24 hours.
• Drugs must be administered once daily in the
management of hypertension

• Compared to the loop diuretics, the thiazides are relatively less potent as
diuretics but have more pronounced antihypertensive effects.
• Thiazides are well absorbed after oral administration and widely
distributed in the body
 Thiazide Diuretics Continued

• Thiazide diuretics may be used

• in combination therapy with other classes of antihypertensive
agents for adequate/optimal control of B.P.

• Where the hypertension is complicated by renal failure,

• it may be necessary to use a more potent diuretic like loop
diuretic or metolazone (thiazide-like diuretic)

• To avoid cardiac rhythm disturbances with diuretic-

induced hypokalaemia,
• It may be necessary to add a K+ sparing diuretic such as
amiloride or triamterene or a potassium supplement to thiazides
or loop diuretics
 Thiazide Diuretics - Adverse Effects
• Thiazides should be used cautiously in the presence of severe renal
and hepatic disease, since azotemia and coma may result
• Hyponatraemia is potentially serious, especially in the elderly

• The most important toxic effect associated with this class of

diuretics is hypokalemia

• Other dose-related problems include hyperuricaemia precipitating

gout and hyperglycaemia

• The commonest unwanted effect not obviously related to the main

renal actions of the thiazides is erectile dysfunction
Loop Diuretics
Examples include:
• Frusemide, Torasemide, Piretanide, bumetanide, ethacrynic acid

Mechanism of Action
• They act by blocking sodium and chloride reabsorption in the kidneys,
even in patients with poor renal function or those who have not
responded to thiazide diuretics.

• They are more potent than thiazide diuretics & increase both K+ & Ca2+
loss

• When used for HPT, the potent diuretic effect of the loops may
provoke reflex stimulation of the R-A-A-S. that may counter any fall in
Blood pressure.
• The main side effects are hypokalemia, metabolic alkalosis &
hypovolemia.
• Both Thiazides & the loop diuretics are potassium depleting diuretics
Loop Diuretics
• Clinically the loop & other potent diuretics are used in
patients with conditions leading to salt and water
overload such as:
• Pulmonary oedema
• Congestive heart failure
• Nephrotic syndrome
• Renal failure
• Hepatic cirrhosis complicated by ascites
• In hypertensive patients with renal or heart failure the loop
diuretics may be preferred over thiazides
 Potassium (K+) Sparing Diuretics
• These are weak diuretics
Mechanism of Action
• They are inhibitors of epithelial sodium transport at the late
distal and collecting ducts.

• Amiloride & Triamterene are sodium channel blockers, controlled

by aldosterone’s protein mediator
• Spironolactone and eplerenone are aldosterone antagonist

• All of these agents reduce potassium loss in the urine.

• They are sometimes used in combination with loop diuretics
and thiazides to reduce the amount of potassium loss induced by
these diuretics.
 Potassium (K+) Sparing Diuretics Continued

• Other conditions in which spironolactone may be used

include:
• Resistant oedema associated with excess aldosterone
including nephritic syndrome, cirrhosis and heart
failure.

• Side effects include:

• Nausea
• Gynaecomastia in men
• Menstrual irregularities in women.
 Calcium (Ca2+) Channel Blockers
• Examples of drugs in this class include Verapamil, Diltiazem & the
Dihydropyridines such as nifedipine, amlodipine, felodipine etc

• All the different groups of the CCB’s may be used as

antihypertensive agents but the dihydropyridines are the most
effective because of their peripheral vasodilating properties.
• The longer acting dihydropyridines such as amlodipine and
felodipine are also preferred over nifedipine since they are suitable
for once daily administration.
• Nimodipine is selective for cerebral vessels and may be used
clinically to prevent cerebral vasospasm following subarachnoid
haemorrhage

• If a CCB is needed for managing hypertension with angina,

verapamil or diltiazem may be preferred.
Calcium (Ca2+) Channel Blockers

• Mechanism of Action:
• They bind to the L-type channels and, by
blocking the entry of Ca 2+ into the cell, cause
relaxation of the arteriolar smooth muscle.
• This reduces the peripheral resistance and results
in a fall in blood pressure.
Calcium (Ca2+) Channel Blockers
Adverse reactions
• Arterial dilation: headache, flushing and dizziness, ankle
edema (resistant to diuretics)
• Bradycardia (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).
• Gingival hyperplasia
 Renin-Angiotensen Mechanism &
Regulation of B.P.
• Inadequate blood flow to the kidneys leads to the release of
renin via sympathetic activity
• Renin acts on angiotensinogen, converts it to angiotensen I,
which is then converted to Angiotensen II by Angiotensen
Converting Enzymes (A.C.E).
• Angiotensen II is a potent vasoconstrictor which causes an
increase in B.P by increasing TPR.
• It also raises the levels of aldosterone and stimulates thirst.
• The net effect is an increase in fluid and salt retention,
leading to a rise in the B.P
Angiotensinogen Kininogen

Renin
Kallikrein
Angiotensin I

ACE (kininase II)

Bradykinin

Angiotensin II Causes
Vasodilation
Dry Cough

Aldosterone Degradation
release products
Angiotensin Converting Enzymes Inhibitors

• Angiotensen II stimulates the release of aldosterone

which causes Na+ and H2O retention as well as K+ loss
from the kidney
• BV and BP would increase as a result of the salt & water
retention plus the vasoconstriction caused by AGII
• Reducing the circulating levels of Angiotensen II in the
body also
• reduces increased sympathetic outflow facilitated by
Angiotensen II both centrally and peripherally.
ACEIs
• ACE is also responsible for the breakdown
of bradykinin, a peptide that increases the
production of nitric oxide and prostacyclin
by the blood vessels.
• Both nitric oxide and prostacyclin are potent
vasodilators.
• Vasodilation of both arterioles and veins
occurs as a result of
• decreased vasoconstriction (from diminished
levels of angiotensin II) and
• enhanced vasodilation (from increased
bradykinin)
ACEIs
• Unlike other vasodilators, ACEIs do not provoke
reflex tachycardia & are thus safe in patients with
ischemic heart events

• The dose-response relationship for B.P. reduction is

linear initially but a plateau could be reached within
the therapeutic dosage range,
• where further increases in doses do not increase the
antihypertensive effect.

• ACEIs combine well with thiazides or Ca2+ channel

blockers for management of hypertension.
ACEIs
• K+ supplements and K+ sparing diuretics should be used
with caution with A.C.E. Inhibitors because of the risk of
hyperkalaemia, especially in patients with pre-existing
renal impairment.

• The use of NSAIDS could compromise the

antihypertensive effect of ACEI

• ACEIs are contra-indicated absolutely in 2nd and 3rd

trimester of pregnancy due to
• Fetal hypotension
• Fetal renal failure
• Fetal malformation/death
 ACEIs
• Caucasian populations have HIGH renin activity and
thus respond well to beta blockers and A.C.E.Is

• Black populations usually have LOW renin activity

and thus respond poorly to beta blockers and the
A.C.E.Is

• Common examples include

• Captopril, Enalapril, Lisinopril, Fosinopril, Quinapril
and Ramipril.
Side effects of ACEIs
• ACEIs cause profound hypotension, which is much
higher in patients with Na+ or water depletion.
• There is the need for dosage adjustment when used together
with diuretics.

• Others side effects include:

• Skin rashes (hypersentivity reaction)
• Neutropenia .
• Reversible renal failure precipitated in patients with
renovascular disease.
• Dry non-productive & irritant cough (mediated by the build
up of bradykinins)
• Angioedema
Angiotensin II receptor Blockers (ARBs)

• They block AG II receptors and thus all

the effects associated with raised plasma
levels of AgII in the body
• It has no effect on bradykinin metabolism
• Like ACEI, the ARBs are also
contraindicated in pregnancy.
• Common examples include: Losartan,
Valsaltan and Candesartan, Irbesartan
Angiotensin II receptor Blockers (ARBs)
AT1-antagonists (ARBs) 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.
 β-adrenoceptor Antagonists

• Mechanism of Action:
• β-adrenergic stimulation in the heart, the kidneys and
the nervous system could lead to
• Increase in CO via β1 stimulation of heart.
• Increased aldosterone mediated Na+ and water retention
(RAAS) via stimulation β1 adrenoceptors on the kidneys.
• All of the above effects could be antagonized with the
use of β-blockers to cause a reduction in B.P.

• Block of β1-receptors in renal juxtaglomerular granule cells

that secrete renin may be involved and such a mechanism
could explain why β-blockers are less effective in older
patients who may have low renin levels.
Variations among beta blockers
• β-blockers vary in the way in which they are eliminated from
the body.

• Lipid soluble β blockers such as propranolol depend on liver

metabolism and clearance from the body
• Water soluble derivatives like atenolol and bisoprolol are eliminated
through the kidneys.
• Propranolol has a short t1/2 & is extensively metabolized in the liver
• Atenolol has a longer t1/2 and may be administered once daily.

• Pindolol and sotalol have intrinsic sympathomimetic or

partial agonist activities
• Some beta blockers have both α1 & β adrenergic blocking
properties e.g. Labetalol & Carvedilol
 β-blockers

• For the management of hypertension and other

cardiovascular diseases,

• the selective β1 blockers (E.g. Atenolol,

Bisoprolol) may be preferred as they are
administered once daily & also have less central
adverse effects .

• Β-blockers with additional α1 adrenoceptor

blocking effects such as labetalol and
carvedilol may also preferred over non-
selective β blockers for HPT .
Indications and contra-indications
• The primary therapeutic benefits of β-blockers are
seen in hypertensive patients with concomitant heart
disease, such as
• supraventricular tachyarrhythmia (for example, atrial
fibrillation),
• previous myocardial infarction, stable ischemic heart
disease, and
• chronic heart failure.

• Conditions that discourage the use of β-blockers

include reversible bronchospastic disease such as
asthma, second- and third-degree heart block, and severe
peripheral vascular disease
 Side effects of β-blockers
• The β-blockers may decrease libido and cause
erectile dysfunction, which can severely reduce patient
compliance.

• Antagonism of β-adrenergic effects in the CNS is

associated with
• reduced sympathetic outflow which may cause a sense of
malaise, vivid dreams, nightmares, hallucinations & sedation.
• These central side effects are common with the lipid soluble
β-blockers such as propranolol.
• Bradycardia
 Side effects of β-blockers

• Bronchospasm (β2-mediated), not recommended for

asthmatics
• Tiredness and fatigue.
• NB: β2-stimulation of skeletal muscle is associated with increased muscle activity
so blockade will lead to tiredness and fatigue especially during exercise
• β-blockers could mask the signs of hypoglycaemia and
must be used with caution in diabetics.
• Non-cardioselective β-blockers may disturb lipid
metabolism, decreasing high-density lipoprotein
cholesterol and increasing triglycerides.
• Beta blockers could cause AV Block & complicate
peripheral Vascular Diseases.
α1 Adrenoceptor antagonists & other vasodilators

• These have dilatation effects on vascular smooth muscles.

• Common examples include: Prazosin, Indoramin, Terazosin,
doxazosin and tamsulosin.
• Terazosin and Doxazosin are longer acting and well tolerated.
• They are used once daily for hypertension.
• They are used with other antihypertensives in cases of resistant
hypertension.
Mechanism:
• They cause vasodilatation by selectively blocking vascular α1-
adrenoceptors.
• Unlike non-selective α-blockers, these drugs are not likely to cause
tachycardia, but they may cause postural hypotension.
Centrally Acting Antihypertensives

Drugs acting on presynaptic α2 receptors in the brain

stem reduces sympathetic out flow and eventually,
reduces B.P.

These drugs are associated with central side effects.

Examples are Clonidine and Methydopa.
Clonidine
• It acts centrally as an α2 agonist to produce inhibition
of sympathetic vasomotor centers,
• decreasing sympathetic outflow to the periphery.
• This leads to reduced total peripheral resistance and
decreased blood pressure.
• It is used primarily for the treatment of hypertension
that has not responded adequately to treatment with
two or more drugs.
• Its adverse effects are sedation, drowsiness, dry mouth
and interference with sexual performance in men.
• Abrupt cessation with the use of clonidine will lead to a
rise a rebound hypertensive effect.
α-Methyldopa
• It is an α2 agonist that is converted to
methylnorepinephrine centrally to diminish adrenergic
outflow from the CNS.
• Its side effect of sedation and drowsiness coupled with
multiple administration, limit their use as
antihypertensive agents in recent times.
• However, methyldopa is very safe in the management of
hypertension in pregnancy.
• Apart from the side effects listed for clonidine,
methyldopa is associated with immunological effects
leading to hepatitis and pyrexia.
• M-DOPA could also cause haemolytic anaemia
Hydralazine
• It is a product that is metabolized to release nitric
oxide
• It decreases total peripheral resistance via
arteriolar dilation
• It is used in moderate to severe hypertension
• It can be used in pregnancy
• Side effects include edema and reflex tachycardia
Nitroprusside
It is an inorganic nitro-vasodilator which acts by releasing
nitric oxide, an unstable compound which causes
vasodilation.
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.

ADRs: Confusion, psychosis, metabolic acidosis.

Another vasodilator is minoxidil
Reserpine
• Reserpine is an alkaloid obtained from Rawoulfia
spps.
• It was originally used in psychiatry
• Reserpine acts by inhibiting the transport of dopamine
and noradrenaline into the storage granule/vessicles
• Thus reserpine causes the depletion of neuronal stores
of the catecholamines both centrally and peripherally.
• The major central side effect is depression/impotence
• Currently reserpine is not indicated for use as
antihypertensive in Ghana
HEART FAILURE
 Heart Failure

• The inability of the heart to

maintain C.O. sufficient to meet the
metabolic needs of the body during
excercise and ultimately at rest
whilst maintaining a normal filling
pressure
• Heart failure is a progressive complex clinical
syndrome usually with high mortality rate
• It is characterised by the presence of a
significant heart disease, usually with
dyspnoea, fatigue and fluid retention.
• In HF, there is a decrease in C.O & Increased
sympathetic activity
• Congestive heart failure (CHF) is a condition in
which the heart's function as a pump is
inadequate to meet the body's needs.
 Determinants of Cardiac
output
1) Heart Rate:- (Chronotropy)
2) Myocardial Contractility:-(Inotropy)
3) Venous Return:-(Preload)
4) Peripheral Resistance:-
( Afterload)
• The preload is the volume of blood in the ventricles
at the end of a diastole.

• Afterload represents the Ventricular wall tension

developed during ejection (i.e Peripheral resistance)

• The force of myocardial contraction is determined by

the strength and integrity of the muscle cells.

• The force of contraction is decreased in conditions like

IHD, Hypertension, dilated cardiac myopathy, Vulvular
heart disease etc

• Another factor/mechanism that influences cardiac

performance is Neuroendocrine activation.
• The plasma levels of renin, angiotensen II,
aldosterone, noradrenaline & ADH increase in
heart failure.
• Increased sympathetic activity in HF also leads to
sympathetically mediated increase in renin
secretion and increase in angiotensen II and
aldosterone levels.
• Neuroendocrine activation is believed to be
responsible for many of the characteristic
features of heart failure
Sequence of abnormal pathological events
that occurs in patients with heart failure

Heart failure

Inadequate Cardiac Output

Systemic Vasoconstriction

SAS (NE) RAAS (Ag-II)

Decrease blood flow to the

skin, GIT, the kidneys etc
 HEART FAILURE

Strength of
Contraction

Contractility

Baroreceptors
Sympathetic
CO BP
activity

Renal Blood flow

HR
Renin
Venous
Preload Pressure Vasoconstriction
Angiotensin II

Pulmonary Capillary Aldosterone

Congestion Filtration
Blood
Na+ and Water Retention Afterload
Volume

Dilated hypertrophy Edema Concentric hypertrophy

Cardiotoxic effects of substances released following
neuroendocrine activation (NEA) in heart failure

Angiotensen II
• Is a potent vasoconstrictor,
• It causes progressive ventricular
dilatation(remodelling), leading to destruction of the
cardiac myocytes .
• It also stimulates the secretion of Aldosterone leading
to Na+ retention & K+ loss.
Cardiotoxic effects of substances released following
neuroendocrine activation (NEA) in heart failure

Increased sympathetic activation

• Vasoconstriction, tachyarrhythmias,
sympathetically mediated renin release (Na+
retention, etc)
• Initially there appears to be improvement in
CO, but ventricular remodelling occurs &
Cardiac fxn worsens if no intervention is
administered to control the NEA
Desirable effects of drugs used in Heart failure
• Improve cardiac performance

• Improve exercise capacity

• Reduce arrhythmias (both ventricular and

supraventricular),

• Maintain adequate renal function and prevent

electrolyte imbalance
 Classes of drugs used in Heart failure
1) Diuretics⇒ Mainly Loop diuretics and thiazides

2) Neuro endocrine antagonists:- A.C.E.Inhibitors,

Ag II antagonist, Aldosterone antagonists, β-
Adrenoceptor antagonist.

3) Positive ionotropic agents : Cardiac glycosides,

1-adrenoceptor agonists,Phosphodiesterase
inhibitors.

4) Vasodilators: Organic nitrates, hydrallazine,

sodium nitroprusside and α-adrenoceptor
antagonists
 DIURETICS
• The potent diuretics such as the loop & thiazide
diuretics act by decreasing peripheral and pulmonary
oedema associated with heart failure.

• The mechanism is by decreasing preload and thus

reducing circulating blood volume.

• Both loop and thiazide diuretics are well absorbed after

oral administration but in heart failure absorption may
be erratic so the loop diuretics are administered by i.v
administration.
• Both the loop & thiazide diuretics are
eliminated by renal excretion.
• Loop diuretics have rapid onset of action
and short duration of action.
• Depending on the Patients condition, the
loop diuretics may be administered once
daily or 2 or 3 times daily to reduce the
plasma volume .
 Drug Interactions
• Loop diuretics increase the nephrotoxic
effect of Gentamicin and cephalosporins.
• Decreased plasma concentration of K+ is
associated with the potent diuretics which
enhances the risk of digoxin toxicity.
• Concurrent use with NSAIDS may impair
diuresis, provoke hyperkalaemia and renal
failure.
• Loop Diuretics:
• They act by inhibiting Na+/K+/Cl_-transporter in the thick
ascending segment of the loop of Henle. Examples include
Frusemide, Torasemide, Piretanide, Bumethanide &
Ethacrynic acid

• The Thiazides:- They act by inhibiting Na+/Cl- co-

transporter in the distal convuluted tuble. E.g. Include
Bendrofluazide, hydrochlorthiazides, cyclopenthiazide

• Thiazide-like diuretics (mechanism of action & biological

effects are similar):

• E.g. Chlorthalidone, indapamide, xipamide & metolazone

Adverse/toxic Effects
• Dehydration ( due to Salt and water depletion –
effect is dose dependent)

• Acid-Base & Electrolyte imbalance including:

• Hyponatraemia
• Hypokalaemia & Hypomagnesaemia

• Rapid iv administration of the loop diuretics may

cause deafness
Potassium Sparing Diuretics
oThese include :
a) Amiloride and triamterene, which act by blocking
Na+ channels controlled by aldosterone’s protein
mediator in the collecting tubules .

b) Aldosterone receptor antagonists (e.g

Spironolactone)

oThe K+ sparing diuretics are less effective alone in

decreasing end diastolic volume & pressure
(Preload)
• Spironolactone in particular has been shown
to have beneficial clinical effects in reducing
mortality in patients with heart failure

• For maintenance of K+ balance ,thiazides or

loop diuretics could be used in combination
with K+ sparing diuretics .

• (i.e. Combined diuretic effects with less

electrolyte imbalance)
β-Blockers
• β-Blockers that have been found useful in
heart falure include: Bisoprolol,
Metoprolol & Carvedilol.

• Bisoprolol and metoprolol are selective for

β1 receptors

• Carvedilol is α1, β non-selective & also has

antioxidant properties and thus protects
against recurrent MI .
• The ß1: effect of carvedilol is significantly
greater than labetalol

• In addition, the duration of ß1 effects of

carvedilol is much longer than that of Labetalol

• Labetalol has no known antioxidant effects

• Beta blockers reduce both cardiac preload
and afterload
• Slow the heart rate & thus improve
coronary circulation
• Slow the development of myocardial
hypertrophy in the ventricles
• Decrease progression of the disease
• Carvedilol may be combined with diuretics
& A.C.E. Inhibitors for maximum
therapeutic benefit in patients with chronic
heart failure.
Side effects include:
• Postural hypotension

• Dizziness

• Bradycardia

• Headache

• & some allergic reactions manifesting as

facial swelling and/or difficulty breathing
• Diltiazem or verapamil could worsen the cardiac
adverse effects.
• Carvedilol is contra indicated in Asthmatics or
patients with bronchospastic disorders
• Must be avoided or given with caution in
individuals with kidney disease or liver disease
• The effects of carvedilol may be increased
because of slower elimination from the body
• Contraindicated in patients with peripheral
vascular diseases.
A.C.E. INHIBITORS
• Improve pump function of the heart

• Reduces arteriolar and venous constriction

• Reduce sympathetic stimulation

• Reduce diuretic induced renin secretion

• Increase renal and skeletal muscle blood
flow.

• They do not only improve symptoms, but

reduces mortality in patients with heart
failure
• A.C.E.Inhibitors block the breakdown of bradykinins.

• Bradykinins stimulate the production of vasodilator

prostaglandins and NO.

• Thus impact both on preload & afterlaoad, Improve blood

supply & reduces vascular hypertrophy

• A.C.E. Inhibitors also block the Angiotensen II mediated

effects such as:

• potent vasoconstriction, Aldosterone and anti-diuretic

hormone release that leads to salt and water retention as
well as enhanced sympathetic activity
• Common examples: Captopril, Enalapril, Lisinopril,
Ramapril & Fosinopril

• Captopril is short acting ( i.e. t1/2 of about 2hrs)

• Drug elimination is through the kidneys & is reduced in
renal failure leading to accumulation & enhanced adverse
effects.

• Enalapril is a pro drug. It is coverted to enalaprilaat, the

active metabolite after oral administration. Which has a
much longer t1/2 than captopril

• Fosinopril and Lisinopril have the longest t1/2 & hence used
once daily.

• Ramapril has a relatively shorter t1/2 & may be used 2x

daily
 Side Effects
• Profound hypotension especially after the first
dose & in dehydrated patients or patients on
diuretics ( postural hypotension )

• Hyperkalaemia

• Skin rashes and neutropenia [Allergy]

• Dry & irritating cough-which is bradykinin

mediated
 ANGIOTENSEN II RECEPTOR BLOCKERS
• The effects on symptoms and
haemodynamics in patients with heart
failure is similar to that of A.C.E. Inhibitors.
• It has the advantage of being free of cough
with A.C.E.Inhibitors. & thus may be used
as an alternative to A.C.E. Inhibitors in
those who cannot tolerate the cough side
effect
• Examples include Losartan, Valsartan,
Candesartan
 Vasodilators
• Arteriolar dilators reduces aortic impedance,
decrease after load and enhance cardiac output.
E.g.  adrenergic blockers –Prazosin, Terazosin etc

• The Venodilators reduces left ventricular end

diastolic pressure and volume(preload) & hence
could affect pulmonary congestion and symptoms
of breathlessness observed in acute heart failure.
• Most of the vasodilators have both arteriolar
dilatating and venodilation effects.
• E.g. Hydrallazine, Isosorbide dinitrate, Sodium
Nitroprusside etc
 Molecular mechanism of action of the
organic nitrates
• The nitrates causes the release of NO after interaction
of with –SH groups in the vascular endothelium

• NO activates guanylate cyclase, leading to increased

cellular levels of cGMP.

• cGMP → activates protein kinases which antagonizes

the influx or accummulation of intracellular Ca2+,
responsible for constriction of the vessels.

• cGMP activation of the protein kinases may also affect

the contractile proteins in the vessels directly, causing
vasodilation
Ischaemic heart diseases
 Ischaemic heart diseases
ANGINA occurs when there is an IMBALANCE
between O2 requirements of the heart cells
(myocardial O2 demand) and O2 available to it
(myocardial O2 supply).

i.e In angina,Coronary blood supply is insufficient

to meet the myocardial energy requirements

Three types: Stable, Unstable & Variant Angina

• STABLE ANGINA
• Attacks are provoked by exertion or excitement.
• The attack ceases when the increased energy
demand is withdrawn.
• The underlying pathology is usually chronic
coronary artery disease.
• Treatment could be directed at increasing
myocardial O2 supply through vasodilation
• or reducing myocardial O2 consumption through
reduced heart rate, decreased myocardial
contractility, decreased preload and decreased
afterload
Variant angina/Atypical angina

• It occurs when the increase in myocardial O2

demand is due to spasms of the coronary
arteries as in coronary artery stenosis

Unstable angina
• It occurs with lesser exertion or at rest

• It is unpredictable, unlike stable angina

• The underlying pathology for unstable
angina is usually rapture of an
atheromatous plaque with thrombus
formation in a coronary artery.

• Coronary spasms may be an additional

mechanism.

• Unstable angina may lead to myocardial

infarction and/or sudden death.
Drugs that are used for treating or
preventing attacks of angina include:

• Organic nitrates

• Ca2+ channel antagonists

•  adrenoceptor antagonist

• K+ channel activators
In Unstable angina, other useful
pharmacological agents include:
• Low dose aspirin and other
antiplateletes such as Clopidogrel,
Ticlopidine and dipyridamole
• Antithrombotic agents or anticoagulants
such as heparin, warfarin and heparin
derivatives (e.g Enoxaprin)
• Lipid lowering drugs e.g the statins
The Organic nitrates include Glyceryl trinitrate, Amyl
nitrate, ISD, ISM
• The nitrates relieve coronary arterial spasms in variant
angina and any vascular spasms that may occur in stable
or unstable angina
• They cause improvement in blood flow through the
coronary vessels and hence improvement of perfusion
to ischaemic areas
GTNT is a short acting smooth muscle relaxant
with widespread vasodilator activity
• It is extensively metabolized in the liver and has
almost 0% bioavailability when administered
orally.
• It is either administered sublingually or
transdermally as a patch or paste
• It is also rapidly eliminated from the body with
elimination t1/2 of about 2mins
• The side effects are dose related.& It
include headache, flushing, postural
dizziness, postural hypotension, syncope
etc.
• The symptoms of the adverse effects can
be terminated by swallowing the tablet or
spitting it out.
• With a patch or paste, the effect could be
terminated by removing the patch
• Read about the pharmacology of
Isosorbide mononitrate & dinitrate, &
note the differences between these agent
Beta blockers in Angina
• -blockers reduce myocardial O2 consumption
by:

• Reducing an increase in heart rate associated

with exercise and anxiety.

• Reducing the force of myocardial contraction.

• They also improve myocardial perfusion by

increasing the duration of diastole and the
time available for coronary circulation
• The -blockers reduce the rate of mortality in
patients with myocardial infarction.

• It also reduces re-infarction following a previous

myocardial infarction

• The preferred beta blockers are those selective for

beta -1 receptors or those with vasodilating
propertites (i.e α1,  antagonists effects- Atenolol,
Bisoprolol, Metoprolol, Labetalol & Carvidelol
• Ca2+ channel blockers- Verapamil & Diltiazem for
both stable & Unstable angina
• Dihydropyridine for variant angina. Short acting
Nifedipine may increase the risk of sudden death in
unstable angina, via reflex tachycardia
 Myocardial Infarction
• Infarction is death of part of the myocardium from
deprivation of blood & oxygen
• MI occurs for e.g when a coronary vessels becomes
blocked as a result of thrombosis
• It is the commonest cause of sudden deaths (Heart
attack) in many parts of the world
• Nb The heart cells rely on aerobic metabolism and
hence if the supply of oxygen via coronary circulation is
poor, sequence of events leading to cell death by
necrosis ensues.
• Prevention of ischaemic damage following coronary
thrombosis is an important therapeutic aim in the
management of Ischaemic heart diseases
Pharmacological agents that are used
in the management of MI include:
• Thrombolytics- Dissolves clots and decreases risk of
sudden deaths
• Antithrombotic agents-Reduces risk of thrombus &
embolus formation
• Antiplatelets – Prevents blood clots formation
• Opioids- Relieves pain and improve circulation
• Beta-blockers - reduces mortality and re-infarction
• & A.C.E. Inhibitors- reduces ventricular remodeling and
risk of CCF
• Lipid lowering drugs –Reduces atheroma & risk of
thrombotic events