Lecture 7:

Cardiovascular system (CVS)

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I. Diuretic Drugs:
*Normal regulation of fluids & electrolytes by the kidney:
20% of blood plasma entering the kidney is filtered from Glomerular
capillaries→ Filtrate free from proteins & blood cells
contain glucose, NaHCO3, Amino acid, Na+, K+ & Cl-.

Glomerular filtration (GF)= Creatinine Clearance= 75-120

ml/min= 180 L/day.

**Kidney Function disease:

A. Edematous: B. Non Edematous states:

oedema ‫فيه‬ oedema ‫ليس فيه‬
1) HF → Loop diuretics 1) HTN → ↓ Blood volume & dilates
arterioles.
2) Hepatic ascites :
a) ↑ portal B.P:→ This is due to portal system 2) Hypercalcaemia: → Loop diuretics
obstruction due to cirrhosis +↓ osmotic pressure due Ca2+ excretion) → hypovolemia (↑Ca2+) → 
to ↓ protein (plasma) by liver. normal saline is used to maintain blood
 blood escape to abdomen. volume.
ry
b) 2 hyperaldosteronism: inability of liver to
inactivate Aldosterone. 3) Diabetes Insipidus: → Thiazides ↓
plasma volume→ ↓ G.F.R→ promote
3) Nephrotic syndrome → leads to plasma reabsorption of Na+ & H2O.
protein loss→ ↓ osmotic pressure & plasma
volume→ secretion of Aldosterone→ Na+ & H2O
retention.

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 4) Premenstrual edema → estrogen imbalance
loss of fluid in extracellular space.


Na+ ion ‫** الحكاية حكاية‬Diuretic Drugs:

1. 2. Loop 3. K+ sparing Osmotic Carbonic Anhydras

Thiazides: diuretics: diuretics: diuretics: inhibitors:
*HCTZ *Furosemide *Spironolactone *Mannitol *Acetazolamide
*Chlorthalidone *Bumetanide * Amiloride *Urea
*Chlorothiazide *Torsemide * Eplerenone
*Indapamide *Ethacrynic à *Triametrene
*Metolazone
1. Proximal Convoluted tubules:
* All glucose, amino à & bicarbonate are reabsorbed.
*2/3 Na+ is reabsorbed by Na+/K+ ATPase (>50%).
*H2O follows passively to maintain osmotic quality.
*Carbonic anhydrase is found in the lumen & cells of PCT.

A. Carbonic Anhydrase Inhibitors: → Acetazolamide

*M.O.A : Acetazolamide inhibits Carbonic anhydrase :

(a) ↓ H+→↓ Na+/H+ exchange→ mild diuresis.
(b) HCO3- is retained in lumen ↑ urinary pH "alkaline urine"
(Urinary excretion) Loss of HCO3- Cause: Hyperchloremic
metabolic acidosis & decreased diuretic efficacy
following several drugs of therapy.

* Therapeutic Uses:
1) ttt of Glaucoma: (open angle) by blocking carbonic anhydrase in the ciliary
body of the eye→ ↓ production of aqueous humor.
N.B. Topical carbonic anhydrase inhibitors e.g. Dorzolamide &
Brinzolamide have the advantage of not causing any systemic effect.
2) Mountain Sickness: Acetazolamide given at night for 5 days before ascending.

*S.E: 1) Metabolic acidosis. 2) K+ depletion

3) Renal stone formation 4) Alkaline urine.

*C.I: Patients with hepatic cirrhosis due to ↓ NH4- excretion (liver can't convert

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NH3→ Urea→ so accumulation of NH3 leading to hepatic coma.)

2. Descending Loop Of Henle:

*Remaining filtrate is concentrated due to H2O reabsorption→ 3 folds increase
in salt conc.
3. Ascending Loop Of Henle:
*It is the major site for salt reabsorption (25-30% of tubular NaCl returns to
blood) → HOW ?→ By Active reabsorption of Na +, K+ & Cl- which is mediated
by Na+/K+/2Cl- co-transporter.

B. Loop or High ceiling Diuretics:→

Furosemide , Bumetanide ,
Ethacrynic à & Torsemide
* M.O.A : They inhibit Na+/K+/2Cl- co-transporter system.
*They are most effective diuretics → why?

* Therapeutic Uses : 1) D.O.C in emergency ttt of acute pulmonary edema

(direct pulmonary V.D.)
2) Useful in ttt of Hypercalcaemia→ by stimulating tubular
2+
Ca excretion.
3) Used in ttt of Hyperkalemia.

*S.E: 1) Ototoxicity→ mainly Ethacrynic à

***Aminoglycoside ABs→ ↑ risk of Ototoxicity.
2) Acute Hypovolemia→ Hypotension & shock.
3) K+ depletion (Hypokalemia).
4) Hypomagnesaemia (chronic use of loop diuretics +↓ Mg intake) → occurs
mainly in elderly.
5) In patients with normal Ca2+ Conc., Hypocalcaemia doesn't result→ why?
because Ca2+ is reabsorbed in DCTs

*D.I: NSAIDs reduce the diuretic effect of loop diuretics.

** Important notes from previous Exams:

*I.V administration of furosemide results in diuresis:
-Onset: 2-10 minutes - peak: 30 minutes
-duration: 120 minutes.

*Furosemide: causes metabolic alkalosis & also Thiazide diuretics.

*When giving Furosemide dose, check renal function because t1/2 depends on
renal clearance but doesn't depend on dose.

*Loop diuretics: no change in Urinary pH.

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4. Distal Convoluted tubule:
10 % of filtered NaCl is reabsorbed via Na+/ Cl- transporter.

C. Thiazides & related agents:

(most commonly used diuretics/ they are sulfonamide derivatives).
1) Chlorothiazide & Hydrochlorothiazide:
*M.O.A: 1) They inhibit Na+/Cl- transporter system.
2) They inhibit carbonic anhydrase (Chlorothiazide>Hydrochlorothiazide)
N.B. Hydrochlorothiazide is more potent than Chlorothiazide.

*S.E : 1) Volume depletion.

2) Hypo: kalemia
natremia (due to hypovolemia→↑ ADH)
magnesemia (especially in elderly).
3) Hyper: Calcemia (↑ bone density, ↓ hip fracture by 1/3)
Glycemia (impaired insulin release & tissue glucose uptake).
Lipidemia (5-15% ↑ serum cholesterol→ return to normal é therapy)
Sensitivity (sulfa→ bone marrow suppression, dermatitis& nephritis)

*Therapeutic Uses:
1. HTN (take 1-3 weeks to produce stable reduction)
a) They relax arteriolar smooth muscle→ ↓ P.R.
b) ↓ blood volume→ with continued use volume recovery occurs
**Controlling of HTN is mainly due to (a) not (b)
2. Heart failure.
3. Hypercalciurea "Ca Oxalate stones in urinary tract".
4. Diabetes Insipidus→ how? They can substitute ADH. They reduce plasma
volume→ ↓ GFR→ ↑ reabsorption of Na+ & H2O→ Urine volume drops from
11 L/day to 3 L/day.
* D.I: NSAIDs diminish their effects.
*Thiazides + Digoxin→ due to Hypokalemia.
*Thiazides + Lithium→ due to Na+ excretion so ↑ plasma Li→ toxicity.

2) Thiazide-like analogs:

Chlorthalidone: Metolazone: Indapamide "natrilix SR"

*very long duration of *More potent than Thiazides *Long duration of action.
action→ so used once/day *Unlike Thiazides causes Na+ *Low doses→ antihypertensive action
in ttt of HTN excretion in advanced renal with minimal diuretic effect.
*t1/2 40-65 hrs failure. *Metabolized & excreted by GIT &
kidney → less likely to accumulate in
patients with renal failure.
**Important Notes from past exams:
*Thiazide Diuretics:
1) Best taken in morning to avoid being awakened during night because of an
urge to void.
2) Patients should also be advised to maintain adequate hydration & to take drug
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with food or milk.
5. Collecting duct:

D. K+ Sparing Diuretics: acts mainly on late distal tubule.

1. Spironolactone: it is converted 2. Triamterene &

to Canrenone (active metabolite)
which is responsible for its activity.
a. M.O.A: Spironolactone+ aldosterone R→ inactive
complex→ failure of synthesis of mediator
proteins necessary to Na+ retention & K+
excretion.
b. ttt of It isn't useful for ttt of Addison's disease→
Addison's because no significant circulating levels of
Aldosterone.
disease:
c. Uses: 1) Diuretic (in combination with Thiazides or
loop diuretics/not alone).
2) 2ry hyper aldosteronism
3) D.O.C in patients with Hepatic cirrhosis.
4) Heart failure: prevent cardiac remodeling
d. S.E: 1. It chemically resembles some of sex
steroids→ gynecomastia in males & menstrual
irregularities of females.
2. Gastric upset & peptic ulcer.
3. Hyperkalemia.
e. D.I: ACEIs→ ↑ risk of hyperkalemia.
Amiloride
Block Na+ channel→ ↓ Na+/ K+
exchange.
Useful for individuals with Addiso
disease because their action doesn'
depend on Aldosterone.
Both & spironolactone aren't
effective diuretics & usually used i
combination with loop or thiazide
diuretics to restore K+ balance.
1) Leg cramps.
2) ↑ blood urea nitrogen (uric acid
3. Hyperkalemia

E. Osmotic Diuretics: ( Mannitol , Urea )

*At the kidney→ they are filtered with no reabsorption→ they carry H2O with
them with no effect on Na+
* Uses: 1) patients with ↑ intracranial pressure.
2) After ingestion of toxic substances which can cause renal failure.
3) Patients with acute renal failure→ maintain urine flow→ save them from
dialysis.
* S.E: 1) Extracellular H2O expansion due to presence of mannitol in
extracellular fluid→ extract H2O from cells.
2) Dehydration if H2O not replaced. 3) Hypernatremia.

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 **Important Notes:

1. Hyperuricemia is seen with Thiazide & loop diuretics→ why?

Acid/base secretory system

(is located in proximal tubule)
It secretes variety of organic acids such as
uric acid.

Most diuretics are delivered to tubular fluid

via this system.

Organic acid secretory system is saturable

so diuretic drugs compete with uric à.

Hyperuricemia
N.B: Probencid: drug used for ttt of gout can interfere in the excretion of
Thiazides & ↑ serum uric acid level.

2. Thiazides/ loop diuretics/ spironolactone→ their effect depends on

renal prostaglandin synthesis→ so NSAIDs diminish their effect.

3. With decreased renal function Thiazide diuretics lose efficacy.

Loop diuretics maintain efficacy till
clearance= 5ml/min.

4. ttt of Hypokalemia associated with loop or thiazide diuretics:

a) Diet supplement of K+ (Citrus fruit, bananas & prunes).
b) Use K+ sparing diuretics.

5. Thiazides & Loop diuretics→ Hypokalemia→ digitalis toxicity

(arrhythmia).

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II. Anti- Hypertensive Drugs:
Diuretics: B-blockers: ACEIs: ARBs Renin-
inhibitors:
Amiloride Atenolol Benzapril Azilsartan Medoxomil Aliskiren
Bumetanide Carvedilol Captopril Candesartan
Chlorthalidone Labetalol Enalapril Eprosartan
Eplerenone Metoprolol Fosinopril Irbesartan
Furosemide Nadolol Lisinopril Losartan
HCTZ Nebivolol Moexipril Olmesartan
Metolazone Propranolol Quinapril Telmisartan
Spironolactone Timolol Ramipril Valsartan.
Triametrene Labetalol
Others: −blockers: Calcium channel blockers (CCBs):
Clonidine Doxazosin Amlodipine Nicardipine
Diazoxide Prazosin Diltiazem Nifedipine
Hydralazine Terazosin Felodipine Nislodipine
−methyl dopa Isradipine Verapamil
Minoxidil
Sodium nitroprusside

*Type of Anti-hypertensive drug used in case of concomitant disease:

Concomitant Type of Anti-Hypertensive drug:

disease: Diuretic B- ACEIs ARBs CCBs Aldosterone
blocker (R) blocker
Angina: ✓ ✓ ✓  ✓ 
Diabetes: ✓ ✓ ✓ ✓ ✓ 
Recurrent Stroke: ✓  ✓   
HF: ✓ ✓ ✓ ✓ C.I ✓
Post MI:  ✓ ✓   ✓
Chronic renal   ✓ ✓  
disease:
*Black patients respond to diuretics & CCBs> ACEIs & B - blockers.
*Elderly respond to CCBs, Diuretics & ACEIs > B -blockers & −blockers.

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A. Diuretics: 1st line therapy for ttt of HTN.
A. Thiazides: *For mild or moderate HTN.
*M.O.A: Thiazides : ↓ water & Na+ retention→ ↓ bl. volume → ↓C.O.P ↓ B.P
↓ P.R
*Lose efficacy if patient creatinine clearance is < 50 ml/min
 use loop diuretics which maintain efficacy till creatinine clearance < 5ml/ m
B. Loop E.g. Furosemide.
diuretics: *Used in patients with renal insufficiency (rate 30- 40 ml/min) & cardiac failu
C. K - Sparing Discussed before.
+

diuretics:

B. -blockers:
*M.O.A:
 −blockers: ↓ activation of   receptor on heart→ ↓ C.O→↓ P.R
↓ Renin→ ↓ Ag II→ ↓ Aldosterone→ ↓ H2O retention→ ↓ bl. vol.
 ↓ P
*Precautions & Monitoring:
1) ECG: should be monitored why?
Because they cause bradycardia & ↓ electrical conduction within heart.
2) Use with Caution in patients with:

Diabetes : Because they mask hypoglycemic symptoms such as Tachycardia

Asthma: No available - blocker is totally safe in patients with asthma
Neurological disorders: Because they enter CNS→ fatigue, lethargy & mental depression.
Raynaud's or peripheral Because vasoconstriction can occur.
vascular disease (PVD):
Acute Heart failure: Because ↓ contractility → compensatory mechanism→ H.F
3) S.E: ↑ LDL, ↓HDL, ↑ TGs
Impotence & ↓ Libido →↓ patient compliance.
4) Avoid sudden drug withdrawal→ upregulation of  - receptors→ HTN &
Arrhythmia.
**Special Agents:

1) Non • Propranolol 1st  - blocker with extensive & highly variable liver metabolism
Selective • Nadolol Once daily dose
 - blockers: • Timolol 1st  - blocker shown to be effective after MI to prevent sudden
•⬧Metipranolol death
2) Relative • Metoprolol ⬧: Once daily dosing
Cardio- • ⬧Atenolol * Esmolol: Ultra short acting
selective • Esmolol *Betaxolol: ttt of chronic open angle glaucoma.
 - blockers: •⬧Betaxolol
•⬧Bisoprolol
3)  - blockers •Pindolol ⬧: Once daily dosing
with intrinsic •⬧Acebutolol *Carteolol: low lipid solubility→ doesn't penetrate CNS.
sympatho- •⬧Carteolol *Acebutolol: is cardioselective.
mimetic •⬧Penbutolol
activity:
)   • Labetalol *Labetalol: also used for Hypertensive crisis.
blockers: • Carvedilol

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C. ACE inhibitors:→ Pril
1st line alternatives to Thiazides or B- blockers
*M.O.A:

*S.E: 1. Postural hypotension.

2. Reduced renal function.
3. Hyperkalemia.
4. Angiodema & persistent dry cough due to ↑ level of bradykinin.

*D.I: 1. Antihypertensive effect may be diminished by NSAIDs.

2. with k+ sparing diuretic→ hyperkalemia.

*Specific agents:

*Captopril: Original ACE inhibitor/ 3 doses *Taken on empty stomach coz food
*Enalapril: Prodrug→ enalapril (active delays absorption.
metabolite) → used for *All are renally excreted except
hypertensive emergency. Fosinopril.
*Lisinopril: Long acting analog of Enalapril *All are prodrugs except Captopril.
Benzapril, Fosinopril, Once daily dosing.
Moexipril, Perindopril,
Quinapril, Ramipril,
Trandolopril.

D. Angiotensin II receptor blockers (ARBs) → Sartans

*Acts on AT1 receptor subtype.
*Doesn't  bradykinin level→  no dry cough.
* Nephrotoxicity in Diabetes→ used in Diabetic HTN.

E. Renin Inhibitors: Aliskiren "Orally"

*Inhibits enzyme activity of Renin→ Ang I, Ang II & Aldosterone.
*Dry cough & Angiodema < ACEIs.

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E. Calcium Channel Blockers:

*M.O.A: They block calcium channels (L-type) in the heart & smooth muscle of
coronary & peripheral vasculature → Ca2+ doesn't enter→ block Ca2+release
from sarcoplasmic reticulum & mitochondria → relaxation & dilatation of
smooth muscles.

*Classes:
1. Diphenalkylamines: *mainly affects the heart >>> vascular smooth muscle.
e.g. Verapamil *Used for Angina, supraventricular tachyarrhythmia &
migraine headaches.
2. Benzothiazepines *Intermediate in action (both cardiac & vascular).
e.g. Diltiazem
3. Dihydropyridines: *Greater affinity for vascular calcium channels than for
1st generation: Nifedipine calcium channel in the heart→ for HTN.
nd
2 generation: Amlodipine,
Felodipine, Isradipine,
Nicardipine, Nislodipine.
*Uses: They are considered alternatives to B- blockers for:
a) Patients with asthma
b) Patients with Peripheral Vascular disease.

N.B: CCBs have intrinsic natriuretic effect→ so usually don't require addition of
Diuretics.

*Most of CCBs have short t1/2 (3-8 hrs) so ttt:

•3 times / day.
• Use S.R preparations.
*S.E: Constipation in 10 % of patients.

F. − Adrenergic- blockers:
*M.O.A : Prazocin, Doxazosin & Terazocin→ competitive block of →
vasodilation of both arteries & veins.

*Minimal effect on C.O, Renal flow & G.F.R.

*S.E: 1) First dose syncope (fainting).

2) Reflex tachycardia ( used with B- blocker).
3) Na+, H2O retention
*C.I in patients with heart failure.

G.    blockers:
•Carvedilol & Labetalol→ H.F

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H. Centrally Acting:
M.O.A: They act primarily on  CNS → Central sympathetic outflow→ P.R

1. Clonidine: 2. - methyl dopa: converted to Methyl

N.E (False neurotransmitter)→  P.R

•They don't  renal blood flow or GFR→ So they are useful in ttt of HTN complicated with renal
disease.
•They cause Na+, H2O retention→ Use with diuretic e.g. HCTZ.
•Sudden withdrawal→ rebound HTN so withdraw slowly.
•Most common S.E: Sedation & dry mouth.
• It has a tendency to cause or worsen •Fever & other flu like symptoms may occur du
depression. to hepatic dysfunction
• It heightens the depressant effect of alcohol→ • +ve Coombs test: if chronic ttt (> 12
so not used to treat Hypertensive alcoholic pts. hrs)→ Hemolytic anemia.
3. Guanabenz & Guanafacine:→ no advantages over Clonidine so rarely used.
Notes:
• Methyl dopa is considered to be the safest antihypertensive agent in pregnancy.
•Alternatives: 1. Hydralazine
2. Labetalol
**Put (✓) or ():
•Clonidine Major S.E is nasal stiffness ().
• Methyl dopa passes BBB (✓).

I. Vasodilators:
• Direct relaxation of vascular smooth muscle→  P.R
• General S.E: 1. Reflex tachycardia → C.I Angina, M.I & H.F
2.  Plasma renin conc. → Na+, H2O retention.
•To overcome this S.Es they are used with Diuretics &  −blockers.

Hydralazine: Minoxidil: Na Nitroprusside: Diazoxide:

**Should be protected
from light.
Act primarily on Arteries Arteries & Veins Arteries
Arteries→ Afterload.
S.E: S.E: S.E: S.E: 1. Transient
Lupus- like syndrome Hypertrichosis Nitroprusside metabolism hyperglycemia.
but it is reversible upon (Growth of body Cyanide ion so long term 2. Related to Thiazide
discontinuation of drug. hair) high dose administration chemically→ pts with
→ Cyanide toxicity. thiazide sensitivity→
ttt: infusion of Na cross react to
thiosulfate→ Thiocyanate. Diazoxide.
Uses: • used as Uses: Orally & Uses: Hypertensive Uses: Hypertensive
monotherapy in Topically to emergency. emergency (IV Bolus)
pregnancy induced HTN. treat male Onset: instantaneous. • Oral form→ ttt of
•Hypertensive emergency baldness. Duration: 1-2 min so Hypoglycemia.
2% & 5 % taken by infusion slowly.

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Emergency HTN:→ SBP> 210 mmHg DBP> 150 mmHg.

1. Nitroprusside:
• By slow IV infusion.
2. Fenoldopam:
•Peripheral D (R) agonist.
•By IV infusion.
3. Labetalol:
• IV Bolus & infusion.
• doesn't cause reflex tachycardia (   blocker).
4. Nicardipine:
• IV infusion 5mg/h (initial dose)→ 15mg/h (maximum dose).
•t1/2→ long (8 hrs).

III. Anti- Arrhythmic Drug

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Class I: Na+ Class II: Class III: K+ Class IV: Ca2+
channel blockers −blockers channel blockers channel blockers.
IA :→Quinidine (Q) Propranolol Amiodarone Verapamil
Procainamide (P) Metoprolol Dofetilide Diltiazem
 Disopyramide (D) Esmolol Bretylium Nifedipine
Ibutilide Nicardipine
IB:→ Mexiletine (M) Others: Sotalol Isradipine
 Lidocaine (L) Adenosine Bepridil
Tocainide (T) Digoxin Nimodipine
Felodipine
IC :→ Propafenone Amlodipine
 Flecainide.

Type of Arrhythmia: Class I: Class II: Class III: Class IV: Others:
1. Atrial a. Atrial Propranolol Verapamil Digoxin
arrhythmia flutter:
b. Atrial Quinidine Propranolol Amiodarone Diltiazem Anticoag.
fibrillation: (Dofetilide) (prevent
stroke)
2. Supra- a. A.V node Propranolol Verapamil Digoxin
ventricular reentry:
T.C b. Acute Verapamil Adenosine
supra-
ventricular
T.C:
3. a. Acute Lidocaine Amiodarone
Ventricular ventricular
T.C: T.C:
b. Ventricular Lidocaine Amiodarone Epinephrin
Fibrillation:

**Action Potential:
1. Phase 0: Depolarization→Na+ inward as Na+ channel opens.
2. Phase 1: Partial Repolarization→
Na+ channel closes & K+ channels (outwards) & Cl- inwards.
3. Phase 2: Plateau→
K+ channels opens & K+ outside & Ca2+ channels opens (Inward).
4. Phase 3: Repolarization→ Ca2+ channel closes & outward of K+
5. Phase 4: Resting potential→ Na+/K+ ATpase.

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15
•IA : Slows phase 0 Depolarization in ventricular muscle fibers.
•IB : Shortens phase 3 Repolarization in ventricular muscle fibres.
•IC : Markedly slows phase 0 Depolarization.
•II : Inhibits phase 4 Depolarization in SA & AV.
•III : Prolongs phase 3 Repolarization in Ventricular muscle fibres.
•IV : Inhibits action potential in SA & AV.

I) Class I: Na+ channel blockers:

•Use dependant→ blocks only open or inactivated channels.
•IA: Intermediate binding
•IB: Rapid binding
•IC: Slow binding.
•M.O.A: Prolongs refractory period & slows conduction (decrease rate of
rise of phase 0 & decreases slope of phase I).

N.B. Class III prolongs QT interval which may cause ventricular

tachyarrhythmias (Torsades de pointes).

A. Quinidine: •Mild & Adrenergic blocking action.

• May cause Torsades de pointes→ Class III activity.
•Used to maintain Sinus rhythm after direct cardioversion of artrial flutter or
fibrillation & to prevent frequent Vent. T.C
 D.O.C for Atrial premature contraction & ventricular premature contractio
(VPC).
N.B. Should not be used without prior digitalization because it may cause  in
frequency of impulse transmission (If Cardiac toxicity occur→ reversed by Na
lactate IV).
•S.E: 1) Symptoms of Cinchonism (blurred vision, psychosis, Tinnutis,
disorientation & headache).
2)  Digoxin effect (in HF).
B. •Acetylated in liver to NAPA (N-Acetyl procainamide).
Procainamide: •Has activity of Class III.
•Used for VPC or ventricular T.C
•C.I in CHF→ S.E: Lupus erythematous (in 30% of pts).
C. •Has Class III activity.
Disopyramide: •Greater inotropic effect than Quinidine.
•Causes Peripheral V.C.
•Used for VPC.
•S.E: Anticholinergic S.E (Dry mouth, blurred vision, constipation & urinary r
 Not used with glaucoma, Myasthenia gravis or urinary retention.
D. Lidocaine: •Used for Ventricular Arrhythmia
Similar in action •D.O.C in emergency ttt of Cardiac Arrhythmia.
to Phenytoin.

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 •D.O.C in emergency cases e.g. Open heart surgery, Digitalis Intoxication & M
•S.E: CNS effects (Parathesia, Drowsiness, slurred speech & Confusion).
E. Mexiletine & •Ventricular Arrythmia
Tocainide: •Tocainide→ Pulmonary Toxicity.
F. Flecainide & •Slowly dissociates from channels
Propafenone: •Used for Refractory Atrial flutter/ fibrillation & supravent. T.C & For Vent.
Tachyarrhythmia.
•S.E: Dizziness, blurred vision, Life threatening vent T.C
•C.I: CHF due to –ve Inotropic effect.

II. Class II -Blockers:→  Phase 4 depolarization.

A. Propranolol: •Post M.I
(Inderal®) •Atrial flutter/ fibrillation & AV re-entry.
B. Metoprolol: •Most common B-blocker used.
• risk of bronchospasm.
C. Esmolol: •IV→ Short t1/2
•Acute arrythmia during emergency.

III. Class III K+channel blocker→Prolongs Phase 3

repolarizatn.
 For Ventricular Fibrillation.
A. Amiodarone: •Action of Class I, II, III & IV.
•Has antianginal activity.
• Used in Refractory Vent. & Supravent. Tachycardia.
• t1/2 (45-50 days)→ several weeks.
•S.E: 1) Photosensetivity 2) Blue discoloration (I2 accumulation).
3) GIT disturbances 4) Hyper/ Hypo-Thyroidism.
B. Sotalol: •Post M.I (due to −blocking activity).
• More effective than Propafenone, Procainamide & Mexilitine in
preventing Recurrence of Arrhythmia.
•Causes Torsades de pointes as Class III.
C. Dofetilide: •Used in Atrial fibrillation (inpatients only or by special doctors).
•Used in HF & CAD with impaired LVF

IV. Class IV Ca2+ channel blockers→ shortens action

potential so  Refractory period.
⬧Verapamil & Diltiazem:
•Verapamil has higher action on heart > vascular smooth muscle.
•Nifedipine is vice versa.
•Diltiazem is intermediate.
•Use dependant as they bind to open depolarized channels only.
•Used in Atrial flutter & A.V reentry.

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•S.E: 1) –ve Inotropic effect →  C.I in pts with depressed Cardiac
function as in HF.
2)  P.R

V. Others:
A. Digoxin: • Refractory period→ Conduction in AV node.
•Used in Atrial flutter/ fibrillation
•Toxic doses→ Vent. arrythmia (use Lidocaine & Phenytoin).
B. Adenosine: • Refractory period→ Conduction in AV node.
t1/2→ 15 seconds. • IV→ D.O.C in supravent. Tachyarrhythmias
•S.E: Chest pain, Flushing &  in B.P
IV. Antianginal
Drugs:
Nitrates: −blockers: Calcium Channel blockers (CCB)
Isosorbide mononitrate Acebutolol Verapamil
Isosorbide dinitrate Atenolol Diltiazem
Nitroglycerin Propranolol Amlodipine
Metoprolol Nifedipine
Nicardipine
⬧Types of Angina:
1. Stable angina "Relieved by Nitroglycerin"
(Typical angina): •Pain arise due to physical activity or emotional excitement.
2. Unstable •Pain arise not due to activity.
angina: •Not treated by nitroglycerin→reuires hospitalization to prevent M.I.
3. Prinzmetal's •Occurs due to Coronary artery spasm.
or Vasospastic •Symptoms don't need physical activity to happen.
angina: •ttt By CCBs & Nitrates.
4. Mixed: •Pain during Rest & Effort.
• Due to fixed obstruction associated with endothelial dysfunction.

I. Nitrates:
*M.O.A:
Nitrates→ NO→ cGMP→ Dephosphorylation of Myosin light chain →
relaxation of vascular smooth muscle→ Dilatation of Coronary artries
 preload→ Dilatation of veins
  O2 demand & O2 Supply.

• S.E:
1) 30-60% of patients receiving therapy with long acting agents→
Throbbing headache.
2) Postural hypotension & Reflex tachycardia.

•D.I: Sildenafil potentiates the action of Nitrates→ Hypotension

So at least 6 hours between the ingestion of 2 drugs is recommended.

18
•Tolerance to Nitrates rapidly develop: The blood vessels become
desensitized to the vasodilation →How to overcome?
•Provide daily Nitrate free interval to restore sensetivity to the drug.
•This interval 10-20 hours & usually at night because demand on the
heart is decreased at that time.
•Nitroglycerin patches worn for 12 hours then removed for 12 hours.

N.B. Variant angina: Worsen early in the morning so in these patients

Nitrate free interval should occur in late afternoon.

N.B Glycerol trinitrate: is preferred taken in sitting position to

avoid 1st hypotension effect "Postural hypotension".

Drug: Dosage Form: Onset: Duration of Action:

Nitroglycerin Sublingual tablet or Spray: 2 min 25 min
(Glyceryl Oral sustained release: 35 min 4-8 hrs.
trinitrate): Transdermal: 30 min 8-14 hrs.
Isosorbide Sublingul: 5 min 1 hr
dinitrate: Oral S.R 30 min 8 hr.
Isosorbide Oral S.R 30 min 12 h.
mononitrate:
N.B: At room temperature:→ Isosorbide mononitrate & Isosorbide dinitrate (solids).
 Nitroglycerin (moderately volatile)
Amyl nitrate (extremely volatile)→ So administration by inhalation
•Isosorbide dinitrate→denitration→2 mononitrates (both of which posses antianginal
activity).

II. - blockers:
•They  O2 demand of Myocardium by lowering both Rate & Force of
Contraction
•Used in pts with M.I→  Survival.
•C.I in Asthma, Diabetes, PVD & COPD.
•Avoid abrupt stoppage→ Rebound Angina or HTN.

III. Calcium channel blockers:

•C.I in HF→ -ve Inotropic effect.
•Variant Angina→ Nitrates or CCBs (B-blockers is C.I)

**ttt of Angina in patients with concomitant disease:

Long Acting Nitrates: −blockers: Ca2+channel blockers:
Recent M.I: ✓ ✓
Asthma, COPD: ✓ ✓
Hypotension: ✓ ✓ ✓
Diabetes: ✓ ✓

19
Chronic renal disease: ✓ ✓ ✓

V. Heart Failure:
RAAS Is: -blockers: Diuretics: Vasodilators: Inotropic
Agents:
Captopril Atenolol Furosemide Hydralazine Amlirinone
Lisinopril Carvidolol Bumetanide Na+ nitroprusside Milrinone
Enalapril Metoprolol HCTZ Isosorbide dinitrate Digoxin
Enalapril ACEIs Metolazone Digitoxin
Quinapril Spironolactone Dobutamine
Fosinopril
Ramipril

Valsartan
Losartan
ARBs
Candisartan
Telmisartan
*Forms of Heart Failure:

Low Output Failure: High Output Failure:

Metabolic demands are within normal limits Metabolic demands  e.g. Hyperthyroidism or
but the heart is unable to meet them anemia & the heart is unable to meet them.

Left Sided Failure (Most Common): Right Sided Failure:

Blood can't be adequately pumped from Left Blood can't be pumped from Right ventricle to
ventricle to Peripheral circulation & it Lung & accumulates within right ventricle→
accumulates within left ventricle→ Left ventricle Right ventricle isn't able to accept blood from
isn't able to accept blood from Left atrium & right atrium→ The fluid portion of blood block
Lung→ fluid portion of blood back up into up throughout the body→ Systemic edema.
Pulmonary alveoli → Pulmonary edema .
Overtime, Left sided Failure causes Right sided failure & vice versa.
Signs & Symptoms: Signs & Symptoms:
1) Dyspnea: due to pulmonary edema (Both 1
Paroxysmal nocturnal dyspnea & Orthopnea)
2) Dry cough, wheezing & fatigue.
3) Nocturia 4) Rales

20
**Compensatory Responses in HF:
1. Sympathetic activity:  C.O→ B.P→(+) Baroreceptors→  -
receptors in heart→  H.R & F.O.C→   receptors →  V.C→  Preload.
2. RAS system:  B.P to kidney→ release of Renin & Aldosterone→
AgII→  P.R→Preload→  Na+ & H2O retention→  Blood volume→ 
Preload→ Pulmonary & Peripheral edema.
3. Myocardial Hypertrophy: Heart in size & chambers dilate.

Systolic HF: (more common). Diastolic HF: (less common).

Ventricles unable to pump Ventricles unable to relax & fill with blood
**Symptoms: 1) Dyspnea 2) Oedema 3) Fatigue.

*Goals of ttt: 1)  Symptoms

2)  Progression of disease.
3) Improves survival.
1. Renin- Angiotensin System Inhibitors:
*Renin System is activated by: 1) Perfusion.
2) Sympathetic activation of Juxtoglomerular cells ( )

A. ACEIs:→1st line therapy.

•  Ag II &  Bradykinin→ P.R→ Preload→ H2O retention.
•Should be taken on empty stomache.

•S.E: 1) Dry cough 2) Hyperkalemia.

3) Renal insufficiency 4) Angioedema.

B. ARBs: Their use in HF is as a substitute for ACEIs in patients with severe

cough or Angioedema.
• Losartan→ 1st pass metabolism.
•Candisartan→ have  Vd (not bound to plasma proteins).
•S.E: As ACEIs except No Dry Cough.

2. - Blockers (BB):
•Prevent effects of NE on Cardiac muscle fibers &  remodelling.
•The 2  -blockers approved for use in HF are→ Carvedilol (  blockers).
 Metoprolol ( 1-blocker).
•Should not be used in Acute HF.

3. Diuretics:
• Pulmonary edema & Peripheral edema.
• Blood volume→  preload & afterload.
•Relieves Paroxysmal Nocturnal dyspnea.
•Thiazides are not used in renal insufficiency (CrCl< 50 ml/min)→Loop diuretics

21
are used.

4. Direct Vasodilators:
1. Dilatation of Venous blood vessels→ preload. "Isosorbide dinitrate".
2. Dilatation of Arterial blood vessels→ afterload "Hydralazine".
•If the patient is intolerant to ACEIs or -blockers, the combination of
Hydralazine & Isosorbide dinitrate is most commonly used.

5. Spironolactone (direct antagonist of Aldosterone):

•Last choice for pts (Reserved for most advanced cases of HF).
•S.E: K+ retension, Peptic Ulcer, Gynecomastia & decreased Libido.

6. Inotropic drugs: (V. Imp)

*Enhances Cardiac contractility→  Ca2+ Conc.→ Cardiac output pressure.

A. Digitalis: *M.O.A: Inhibits Na+/K+ ATpase→  Na+/ Ca2+ exchange→  intracellular

Ca2+→  Contraction→ C.O.P
*Binding of Digitalis to the pump is inhibited by K +.
Hyperkalemia→ effect & Hypokalemia→ effect.
*Uses:
1) pts with severe Systolic HF.
2) Not used with Diastolic or Right sided HF.
(Diuretic then ACEIs then Digoxin).
*Adverse Effects:
1) Cardiac→ Arrythmia (due to  K+)
2) GIT→ Nausea, vomiting.
3) CNS→ fatigue, confussion, blurred vision & halos of dark objects.
N.B Elderly develop hazy vision not halos.
*Toxicity Of Digitalis:
*Toxicity occurs due to:
 Digitalis conc. which occurs  K+ Conc. which
due to: occurs due to:
Amiodarone Thiazides
**Quinidine Loop Diuretics
**Verapamil Corticosteroids
Tetracycline drugs which metabolism
Erythromycin
*Also  Mg2+ &Ca2+ can  toxicity.
*** Antibody→ Digoxin immune Fab.

B. e.g. Dobutamine
 −Agonists: *I.V infusion in acute HF in a hospital setting.

22
 C. Phospho- e.g. Amrinone & Milrinone.
diesterase cAMP→(-)→AMP→  Intracellular Ca2+ &  F.O.C
*Used in short term use & in Refractory HF→ Only Parentral.
Inhibitors:
**Order of Therapy:

1) Diretics

2) ACEIs or ARBs

3) B-blockers

4) Digoxin
N.B Tenectaplase: is used primarily to reduce mortality associated with
Myocardial Infarction.

VI. Blood Drugs:

Platelet Agreggation Anticoagulants: Thrombolytic Agent: ttt of bleeding:
Inhibitors:
Clopidogrel C Heparin H Alteplase Tranexamic acid
Aspirin A Enoxiparin E Streptokinase Aminocaproic acid
Dipyridamole D Dalteparin D Urokinase Protamine sulfate
Eptifabtide E Reteplase Vitamin K
Warfarin W Aprotinin
Ticlopidine T Argatroban A ttt of Anemia: ttt of Sickle Cell
Abciximab A Lepirudin L Anemia:
Tirofiban T Fondaparin F Iron Hydroxyurea
Anagrelide A Folic acid Pentoxifylline
Erythropoiten
Cyanocobalamine (B12)
**Important Definitions: •
⬧Thrombus:→ The Clot adheres to the vessel wall.
⬧Embolus:→ detached clot (Clot floats in blood)
⬧ Arterial Thrombosis:→ Platelet rich clot.
⬧ Venous Thrombosis:→ Fibrin rich clot→ due to improper activation
of the coagulation cascade.

**Platelet response to Vascular Injury:

A) Resting platelets:
1. Chemical mediators synthesized by endothelial cells to inhibit platelet
aggregation→ Prostacycline (prostaglandin I2) + Nitrous oxide→ bind to
platelet membrane receptors→  Synthesis of cAMP→  intracellular
Ca2+→ inhibit platelet aggregation.

23
B) If Endothelium is injured:
1. Platelets adhere to sub endothelial collagen → Platelets are activated by
Collagen→ Activated platelets release chemical mediators such as (ADP,
Thromboxane A2, Serotonin, Platelet Activation factor &
Thrombin)→ These chemical mediators bind to outer membrane of
Resting Platelets that are circulating nearby.

2) Resting platelets become activated & start to Aggregate→ How?

 levels of Ca2+ &  cAMP within platelets.

 Ca2+→ Release of platelet granules containing chemical mediators such as

ADP, Serotonin that activate other platelets.
Activation of Thromboxane A2 Synthesis.
 Activation of Gp IIb/ IIIa receptors.

**Gp IIb/ IIIa receptors :bind Fibrinogen→ Platelet crosslinking.

Fibrinogen Thrombin coagulation factors→ Fibrin Clot.
N.B. Plasminogen Tissue activator → Plasmin + degradation of Fibrin clot .

A. Antiplatelets (Platelet Aggregation Inhibitors)→ for Arterial Thrombosis.

CADE TATA.
1. Thromboxane A2 *M.O.A: Arachidonic acid Cox 1 Prostaglandin A2→ Promote clumbin
Inhibitors → effect.
*Uses: 1) Prophylaxis to cerebral Ischemia.
Aspirin: 2)  Mortality in pre & post M.I
3)  Incidence of Recurrent M.I
(Irreversible
*Dose: 81-325 mg
acetylation)
*S.E: 1) Cerebral heamorrhage.
2) GIT Bleeding.
*Interactions: Ibuprofen (as it blocks aspirin from inhibition of COX 1)
so Aspirin is given 30 mins before or 8 hrs after Ibuprofen.
2. ADP *M.O.A: They inhibit ADP mediated platelet Aggregation.
Antagonists→ ADP→ binds to its (R) → activation of GpIIa/ IIIb.
Ticlopidine: Clopidogrel:
Ticlopidine *Uses:1. prevent ischemic attacks *Uses:1. Prevent Atherosclerotic
& stroke. events after stroke or M.I
& 2. Combination with Aspirin to  2. Unstable Angina
stent thrombosis. 3. Stent or intervension
Clopidogrel *S.E: *S.E:
1. Thrombotic Cytopenia (TTP) 1. May cause TTP (thrombocytic
2. Agranulocytosis (neutropenia). thrombocytopenia purpura)
3. Aplastic anemia
*D.I: They inhibit Cyt p450→  wrfarin, phenytoin & Fluvastatin.
*Dose: Ticlopidine 250 mg twice daily→ maximum effect 3-11 days.
3. Glycoprotein Gp *Abciximab: antibody against Gp II b/ IIIa receptor.
II b/III a receptor *Eptifibatide & Tirofiban: they are Gp II b/ III a receptor blockers.
antagonists→ *Taken IV Infusion with heparin or Aspirin

24
 *Oral forms are toxic.
Abciximab,
Eptifibatide
& Tirofiban:
4.Phosphodiesterase *CAMP→  Ca2+→ potentiate action of prostacyclin
Inhibitors→ Phosphodiesterase
Inactive
CAMP→
 (−) phosphodiestrase →  CAMP→  Ca2+→ Coronary V.D
Dipyridamole & Dipyridamole: *Not used alone
Cilostazol: *In combination with Aspirin or Warfarin →
embolism of prosthetic heart valve.
Cilostazol: *Metabolized in liver→ 2 active metabolites.
*Uses: 1) ↓ symptoms of intermittent Claudication.
2) ttt of Buerger disease & vascular sclerosis
*S.E: 1) Alters lipid profile 2) GIT S.E
C.I: CHF
ttt of Polythethemia vera=  in viscosity of blood due to  in RBCs no
5. Anagrelide:
N.B. Oprelvekin → Thrombopoietic growth factor.
 formation of platelets→ttt f Thrombocytopenia.
B. Anticoagulants:
Venous Thrombosis→ ttt by Anticoagulants→ Injectable
 Oral

*Extrinsic pathway: in Vivo→ initiated by clotting factor VII.

*Intrinsic pathway: in Vitro→ initiated following contact with glass or
charged surface. highly
*Formation of Fibrin:
Proenzymes→ enzymes→ factor Xa→ Prothrombin→ Thrombin.
(+)
Fibrinogen→ Fibrin.
*Coagulation takes place at a Cell surface where a complex is formed.

25
 Complex: 1) Membrane surface provided by ph. 1→ Platelet.
Endoth. cells.
2) Enzymes.
3) Substrate.
4) Co-factor (Ca2+).
N.B. There are endogenous anticoagulants as Antithrombin III, Protein C or S.

N.B. Hypoprothrombinemia:  ability of blood to clot.

*For Rapid ttt: fresh blood or plasma (source of Prothrombin).
*Vitamin K derivatives: used if the situation isn't urgent.

*Venous Thromboembolic disease (VTED):

*Classical triad of risk factors predisposing to VTED:
1. Vascular injury 2. Venous stasis 3. Hypercoagulation state.
*It may lead to deep venous thrombosis and/or Pulmonary embolism.
ttt 1. Non pharmacological prevention: by using compression stockings.
2 . Pharmacological prevention : by use of anticoagulants

Anti-coagulants may be : 1) Injectable.

2) Oral.

A. Injectable Anticoagulants:
I. Unfractionated Heparin II. Low molecular weight Heparin
(Heparin):*** (LMWH)*****
(Enoxaprine, Deltaparin & Tinzaparin
Origin & *Extracted from Procaine intestine *Produced by enzymatic depolymerizatio
Structure: & bovine lung. unfractionated heparin.
*Mix of straight chain anionic
glycosaminglycan with wide range
of molecular weigts.
M.O.A: 1. They interact with Antithrombin III → acceleration of its interaction with:
Thrombin & factor Xa factor Xa >>> Thrombin
N.B. Antithrombin III: factor that inactivates Thrombin & Factor Xa slowly bu
presence of Heparin or LMWHs→ rapid inactivation.
2.  Conversion of Fibrinogen to Fibrin

Route of *I.V. →Anticoagulant effect within *S.C→ anticogulant effect within 4 hrs.
Administration: minutes "I.V infusion".
*Deep S.C→ Anticoagulant effect
within 2 hours.
* I.M: is contraindicated because of hematoma formation.
Dose: *Loading dose: I.V bolous either *Enoxaparin: 1mg/ kg/dose every 12 hrs.
5000 unit or 70-100 unit/kg. *Enoxaparin 1.5 mg/kg/dose every 24 hrs
*Maintanence dose: I.V Infusion *Tinzaparin 175 IU/ Kg/ dose every 24 hr
15-25 unit/kg/hr.
**t1/2 is 1.5 hrs **t1/2 of LMWH> 2.4 folds (3-7 hrs).

26
Monitoring of Anticoagulant response to Heparin AAnticoagulant response is predictable so
dose: is variable so it needs monitoring: need for dose monitoring except in cases o
1. Heparin assay. abnormal renal function or pregnancy.
2. Activated partial Thromboplastin
time (apTT)→ dose titrated so that
apTT is 1.5-2.5 of control.
Uses: 1. ttt of deep vein vein Thrombosis (D.V.T) & pulmonary embolism.
2. Prophylactically to prevent postoperative venous thrombosis for e.g. Hip
replacement & those in acute phase of M.I.
3. Used in dialysis machine to prevent Thrombosis.
4.D.O.C for treating pregnant woman with prothetic heart valve or venous
thromboembolism because they don't cross placenta.
Side effects: 1. Bleeding: stop administration or add protamine sulphate (antidote for hepa
(1mg for 100 units)
because Heparin sulfate is a weak anticoagulant → the case may worsen
2. Hypersensitivity:because heparin prep. are obtained from animal source.
(anaphylactic shock, urticaria, chills & fever).
3. Thrombosis: chronic Heparin administration can lead to reduction () of
Antithrombin III activity→  inactivation of coagulation factors→ Thrombosis
4. Thrombocytopenia: A condition in which circulating blood contains an
abnormally small number of platelets.
→ Type I: occurs in 1st 5 days of ttt (mild)
 Type II: occurs from day 5-14 (severe).
III. Other Thrombin inhibitors→for Heparin induced Thrombocytopenia (HIT).

1. Lepirudin: *Direct Thrombin antagonist.

*I.V→ Used in ttt of Heparin induced Thrombocytopenia (HIT) &
Other thromboembolic disorders.
2. Argatroban: *Thrombin antagonist.
*Prophylaxis for ttt of HIT.
*Used during percutaneous intervention.

IV. Factor Xa inhibitor:

Fondaparinux: *Selectively accelerate binding of Antithrombin III to factor Xa.

*Used to prevent DVT & pulmonary embolism in surgery
(hip fracture & replacement).
*Used in HIT.

B. Oral Anticoagulants:→ Vitamin K antagonists.

e.g. Warfarin & Dicumarol.
(--)
*M.O.A: Coagulation factors require Vit. K for activation.
*Uses:
1. Prevention & ttt of VTED. 2. Pulmonary embolism & DVT.
3. M.I.
4. Surgery (Orthopedic & gynecology) to prevent thromboembolism.
*Adverse effects: 1) Purple toe syndrome.
2) Bleeding:→If Minor→ ttt with oral Vit. K

27
  If severe→ I.V (Blood frozen plasma).
3) Teratogenic.
*Interactions:

 Effect (Toxicity)  Effect

 Bleeding. Warfarin  Thrombosis
( PT/INR) ( PT/INR)
1. Inhibition of metabolism:*Phenylbutazone *Chronic alcohol intake.
*Co-trimoxazole *Metronidazole *Barbiturates.
*Acute alcohol intoxication.*Cimetidine *Gluthethimide
*Grisefulvin
2. Sulfa/ Trimethoprim: they eliminate *Rifampin.
bacterial flora so produce Vit K deficiency.

3. Disease state: Hepatic disease &

Hypermetabolic state→  Vit K.

4. Displace from protein binding:

(SMZ-TMP-Tolbutamide-phenylbutazone).
N.B: Monitoring of Warfarin therapy: (V.Imp)
1. Prothrombin time (PT): It is the measure of the time it takes for Fibrin to
gel in plasma after addition of Calcium & Thromboplastin.
2. INR (International normalization ratio): Therapeutic goal→2.5-3.5
INR= Patient (PT)
International sensitivity index (ISI).
C. Thrombolytic Drugs:→ Fibrinolytics:

*M.O.A: Fibrin Plasmin Fibrin degradation.

Plasminogen (+)
**Local Thrombi may  after dissolving clots.
Aspirin & Heparin may be used in combination.

1. Alteplase & Reteplase:(I.V) 2. Streptokinase (IV)

M.O.A: *It activates plasminogen that is bound to *Acts on free plasminogen
Fibrin in a thrombus or hemostatic plug. streptokinase+ plasminogen→ streptokina
Plasminogen Alteplase Plasmin plasminogen complex:
Fibrin degradation 1. Converts plasminogen to plasmin which
**High Fibrin specificity. degrades Fibrin.
2. Degradation of Fibrinogen.
3. Degradation of Clotting factor (V) &(V
**Low fibrin specificity.
Uses: 1. ttt of deep vein thrombosis & pulmonary embolism.
2. ttt of Acute M.I.
3. are helpful for unclotting catheters & stunts.
Half life 5 minutes < 30 minutes.
Monitor: By measurement of Thromboplastin time (maintained at 2-5 of control).
S.E: 1. They don't differentiate between the Fibrin of unwanted Thrombus & fibrin of a
beneficial hemostatic plug→ Hemorrhage for e.g. previously unsuspected lesion such
peptic ulcer.

28
 2. low Antigenicity:as prepared by DNA. 2. High Antigenicity:because it is prepare
3. Both: as clot dissolve→ local thrombi from B- Hemolytic streptococci.
→ enhanced platelet aggregation→ 3. Most individuals have strept. infection
Thrombosis so to prevent this administer sometime in their lives→ antibodies→
antiplatelet as aspirin or antithrombotic against streptokinase so sufficient
as heparin streptokinase must be taken.
C.I: In patients with healing wounds, pregnancy, metastatic cancer & history of
cerebrovascular accident.
3. Anistreplase: *It is a Complex of Streptokinase + Plasminogen
*Streptokinase is released & Plasminogen→ plasmin.
4. Urokinase: For pulmonary embolism.
S.E: Bleeding

D. Drugs Used to treat Bleeding: = Antifibrinolytics.

=Antidote for Fibrinolytics.
1. Plasminogen Activation Inhibitors:
Aminocaproic & Tranexamic à:
2. Heparin Antagonist:
Protamine Sulphate (basic)
3. Warfarin antagonist:
Vitamin K
4. Plasmin Inhibitor:
Aprotinin
*Inhibits activation of plasminogen→ Plasmin.
*May cause thrombi.
*Antagonize Heparin→ How?
+vely charged protamine (+) –vely charged Heparin→
stable complex.
S.E: Hypersensetivity as well as flushing and hypotension
when injected rapidly.
*Inhibit action of oral anticoagulant (warfarin) depending
on Vit K.
*Action after 24 hours.
*If immediate hemostasis is required→ frozen plasma
should be infused.
*Inhibit Plasmin. *Can inhibit streptokinase.
*Shouldn't be given to patients who received the ttt 12
months ago due to anaphylactic reaction.

1.

29
E. Anemia & Agents used to treat it:

*Types of Anemia:
1. Deficiency Anemia:
A. Iron deficiency: due to nutrition deficiency.
-Hypochromic→ Low Hb content.
-Microcytic→ Low RBCs' size.
B. Prenecious Anemia: due to deficiency of intrinsic factor which is essential for
Vit B12 absorption.

2. Aplastic anemia: due to depression of bone marrow.

May be: A) Idiopathic.
B) Secondary: due to exposure to X-ray or Chloramphenicol or
Felbamate , Carbamazepine & Phenytoin.

3. Heamolytic: due to excessive destruction of RBCs

e.g. due to: 1. Toxic factors.
2. Congenital abnormalities.

Nutritional Anemia= Deficient Erythropoiesis:

due to deficiency of:
1) Iron. 2) Cupper. 3) Cobalt.
4) Protein (intrinsic factor). 5) Vitamin C 6) Folic acid.

1. Iron:
*Stored as ferritin & Haemosidtin & 5-10 & of iron in diet is absorbed.
Fe3+ by reduction Fe2+ easily absorbed from GIT Bone marrow.
30
 Vit C + HCl by transferitin
*Disturbances in Iron:
1. Increase in Fe 3+
a) Haemo-chromatosis: Increase storage of iron in body which may lead to:
tissue damage + Nausea+ Vomiting.
b) Chronic haemo-chromatosis: excessive deposition of iron in tissues→ bronzy
skin, hepatic cirrhosis & D.M.
Acute Iron Toxicity:
Abdominal Pain-Nausea-Vomiting- Constipation-CVS collapse- Coma then death
within 6-24 hrs.
*ttt by 1. Gastric lavage. 2. IV inj. of iron binding chelates (desferoxamine).
2. Decrease in Iron→Microcytic Hypochromic anemia.
ttt 1)Oral Iron preparations→ before meals.
1. Fe2SO4 (Standard)→ 30% (GIT S.E)
2. Fe Ca Citrate (best for pregnant).
3. Fe gluconate→ 12 %
4. Fe fumarate (in multivitamin preparation)  amount of elementary iron 33%.

2) Parentral preparation: Used in emergencies if oral ttt failed.

1. Iron Dextran: Ferron + Fe (OH)3+ dextran→ I.M Injection.
2. Dextriferron: Fe (OH)3 + dextrin→ I.V injection.

N.B. We add Vit C to Iron preparation to increase Fe3+absorption because Vit C

is a reducing agent & also HCl is very important in iron absorption.
So its absorption is hindered in case of achlorohydria or antacid consumption.

2. Cupper (Cu):
*Essential for human metabolism & in some patients of deficiency anaemia.
*Disturbance in Cu metabolism ( Cu)→Wilson's disease→ ttt Penicillamine.

3. Vitamin B12 Cyanocobalamine:→ Cobalt (CO)

*Improves haematocrite & Hb & Erythrocytic values.
Where Haematocrite=

*Deficiency is due to 1)  intake

2)  Absorption (pernicious anemia)

4. Folic acid:
*Deficiency maybe due to:
1)  demand (pregnancy & lactation) 2)  Absorption.
3) Alcoholism 4) Drugs (Methotrexate or Trimethoprim).
*Deficiency may cause Megaloblastic anemia→ ttt with Folinic acid + Vit. B12

5. Erythropoietin & Darbepoietin:

*Made by kidney to regulate RBCs proliferation.
*Used to treat Anemia in ESRD & HIV patients.
*Minimum effective dose that don't exceed 12g/dl (Hemoglobin level).

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 F. Sickle-Cell disease:→ sickle shape of RBCs→ accelerated haemolysis.

1. Hydroxyurea:
S.E: Bone marrow suppression & Cutaneous Vasculitis.

2. Pentoxifyllin: Rheologic modifier.

VII. Antihyperlipidemic Drugs:

1.HMG- Co A 2. Fibrates: 3. Bile acid 4. Cholesterol

reductase inhibitor sequestrants: absorption Inhibitors:
(Statins):
Atrovastatin Fenofibrate Cholestyramine Ezetimibe
Fluvastatin Gemfibrozil Cholestipol
Simvastatin 5. Omega-3 fatty Colsevelam 6. Niacin
Rosuvastatin acids:
Lovastatin Docosahexaenoic à
Pravastatin Eicosapentaenoic à

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 *Types of Hyperlipidemia:
1. Type I (Hyperchylomicronemia):
* TG & Chylomicron.
Cause:→ Lpoprotein lipase.
ttt: Low diet (fat), No therapy.

2. Type II A (Hypercholesterolemia):
LDL,  Cholesterol, VLDL & TG are normal.
Caused by: synthesis or processing of LDL

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 receptors.
ttt: Cholestyramine, Niacin, Statins.
3. Type II B (Familial Mixed
Hyperlipidemia):
 LDL  VLDL  TG  Cholesterol.
Cause: Overproduction of VLDL by the liver.
ttt: As Type II A
4. Type III (Familial
Dysbetalipoprotenemia):
 IDL→  TG &  Cholesterol
*Overproduction of IDL or underutilization
ttt: Niacin, Fenofibrates & Statins.
5. Type IV (Familial hypertriglyceridemia):
 VLDL,  TG,  LDL,  Cholesterol
Cause: overproduction of VLDL or  removal
ttt: Niacin, Fenofibrates.

6. Type V (Familial Mixed

hypertriglyceridemia):
 VLDL,  TG,  Chylomicron,  Cholesterol.
Cause: Overproduction of VLDL or  removal.
ttt: Niacin, Fenofibrate, Statins.

*Drugs that lower the serum Lipoprotein concentration:

1. HMG-Co A *M.O.A: Compete with HMG-Co A reductase which is the rate limiting step.
reductase *Reduction in plasma cholesterol→  LDL receptors→ Net result is a further
inhibitors: reduction in plasma LDL.
(Statins) *They  HDL as Cholestyramine.(Simvastatin produces highest %in HDL)
*Atrovastatin & Rosuvastatin are the most potent members.
*t1/2 of Atrovastatin: 14 hrs, Rosuvastatin: 19 hrs & Others: 1-2 hrs.
*Only Simvastatin & Lovastatin penetrate CNS.
*Adverse Effects:1) Abnormal Liver function.
2) Myopathy & Rhabdomyolysis 3) May  Warfarin levels.
4) C.I in Pregnancy & lactation (Category X).

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 N.B All Statins are administered in the evening except of long acting Statins
Atrovastatin & Rosuvastatin since most Cholesterol synthesis occurs at night.
2. Lipolysis *M.O.A:
inhibitor: 1) Adipose tissue (-) Lipolysis→ free fatty à→TG→VLDL→LDL.
Niacin   TG, VLDL, LDL.
(Nicotinic acid): 2) The most effective in  HDL (good cholesterol carrier).
3)  Secretion of tissue plasminogen activator &  Fibrinogen.
  Endothelial dysfunction which may cause Thrombosis.
*Adverse Effects: 1) Nausea & abdominal pain.
2) Cutaneous flush & pruritis (Aspirin may  these symptoms).
3)  Uric secretion→ gout
4) Hepatotoxicity & Impaired glucose tolerance.
3. Lipoprotein *Fenofibrates> Gemfibrozil in  LDL & TG
Lipase: *Fenofibrate (prodrug) → Fenofibric acid (active form).
Fibrates: *M.O.A:  Lipoprotein lipase→ TG
Apo C II conc.→ TG &  HDL (Apo A1)
*Uses: 1) Type III (Dysbetalipoprotenemia)→ TG, VLDL,  LDL).
2) Type IV (Familial hypertriglyceridemia)→ VLDL,  TG.
3) Type V (Familial mixed hypertriglyceridemia)→ VLDL,  TG,  CM.
*Adverse Effects: 1)  Gall stones 2) Rhabdomyolysis & Myopathy.
3) GIT disturbances. 4)  Warfarin levels
*C.I: in patients with renal insufficiency, hepatic dysfunction & gall bladder
disease
4. Bile à binding *M.O.A: Cholestyramine, Cholestipol & Colsevelam bind with (-ve) charged
resins: bile à→ Complex→ excreted with feaces→ bile à don't return to liver→Liver
converts Cholesterol to bile à→ hepatic uptake of Cholesterol containing LDL
by  LDL receptors →  in plasma LDL.
*Uses: 1) D.O.C in Type IIA & IIB
2) Can  pruritis caused by bile à accumulation due to biliary Obstruction.
*Adverse Effects: 1) GIT disturbances.
2) Impair absorption of Fat soluble vitamins (K,E,D,A) except Colsevelam.
3) Drugs should be taken 2 hrs before or 4-6 hrs after the bile à binding resins.
5. Cholesterol *M.O.A: Selectively inhibit the absorption of intestinal cholesterol (dietary &
absorption biliary)  in delivery of Cholesterol to liver→ in Cholesterol stores & its
Inhibitors: clearance.
Ezetimibe: *Combination of Simvastatin & Ezetimibe→ LDL more > than Statins alone
*N.B: In Type II (Niacin & Cholestyramine are commonly used).

II. Cholesterol gallstones:

ttt by Chenodiol (Orally).

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- It is the bile acid Chenodeoxycholic acid which is a naturally occurring normal
hepatic metabolite of Cholesterol.

Course of ttt: 2 years.

Precautions: 1. Periodic liver function due to risk of hepatotoxicity.

2. Cholecystogram or ultrasonogram to monitor stone dissolution.
3. Serum total cholesterol & LDL every 6 months because they may
 by 10 %.

*S.E: Diarrhea (common S.E).

N.B: Portagen: it is a dietary product used to treat pts with Steatorrhea.

Lofenalac: it is a dietary product used to treat pts with Phenylketonuria.

**Important Extra Notes:

1. Gaucher disease: genetic disorder in which Fatty acids accumulates in cells &
Certain organs ttt by Miglustat.

2. Simple Lipids are esters of Fatty acids with Low M.WT Alcohols.

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