Drugs affecting the Cardiovascular
System [CVS]
Hypertension
Hypertension: is sustained elevation of arterial B.P.  140/90 mm Hg.
Classification
I- According to etiology
1- Primary hypertension [idiopathic, essential]:
 It’s of unknown cause.
 It represents 90 % of cases of hypertension.
 Certain risk or predisposing factors may cause to this type of HTN E.g.:
Genetic factors (family history), obesity, stressful lifestyle, diabetes, smoking, alcohol, hypercholesterolemia and
high Na  intake.
.
2- Secondary hypertension:
 It presents 10% of the cases of HTN.
 Of known cause E.g.:
i. Chronic renal failure.
ii. Vascular disease (atherosclerosis).
iii. Endocrine disorders (phaeochromocytoma “↑ A & NA”, Cushing syndrome “↑ Gucocorticoids”)
iv. Drug induced (contraceptives, corticosteroids, … etc. )
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II- Classification of blood pressure, based on 7th report of the Joint National Committee on
Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7):
Complications:
◙ Most hypertensive patients are asymptomatic but in severe cases, headache occurs at the back of the head and
dizziness may also develop.
◙ Untreated HT may lead to Morbidity in:
 Heart ► Coronary artery disease (CAD), Left ventricular hypertrophy (LVH), Angina, Myocardial infarction (MI)
and Congestive heart failure (CHF).
 Brain ► Stroke, cerebral hemorrhage & thrombosis.
 Eye ► Retinal damage.
 Kidneys ► Renal failure.
Normal regulation of blood pressure
(BP):
Blood pressure (BP) = Total peripheral resistance (TPR) X Cardiac output (CO).
•TPR is determined by vascular smooth muscle (VSM) tone.
•CO = Heart rate (HR) & stroke volume (S.V).
Stroke volume [SV]: Is the volume of blood ejected by the heart per beat.
Peripheral resistance [PR]: Is the resistance exerted by blood vessels to blood flow.
Systolic BP [SBP]: Is the highest pressure during ventricular systole & depends on CO & PR.
Diastolic BP [DBP]: Is the lowest pressure occurring during ventricular diastole & depends on PR ONLY.
Aim of Treatment
Aim of treatment it to reduce mortality and morbidity.
Management of Hypertension
[I] Non-pharmacologic or non-drug therapy (Lifestyle modification):
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Reducing body weight by exercise together with dietary program.
Reduction of dietary salts, saturated fats and cholesterol.
Stopping smoking, caffeine and alcohol intake.
Performing regular aerobic physical exercise (e.g. walking, jogging, swimming and bicycling)
Avoidance of stressful conditions.
[II] Drug therapy.
1-Sympatholytics
2- Diuretics
3- Vasodilators.
4- Calcium Channel Blockers “CCBs”]
5- Antagonists of Renin Angiotensin System [RAS] including:
i. Angiotensin Converting Enzyme Inhibitors [ACEIs]
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Classes of Antihypertensive drugs
ii. Angiotensin II Receptor Blockers [ARBs]
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[I] Adrenoreceptor blockers:
Sympatholytics
Depressants
β-blockers
Non-selective: Propranolol, Timolol & Nadolol.
Cardioselective “β1”: Acebutolol, Atenolol & Metoprolol.
Mechanism of action:
i. ↓ β1 ► ↓ HR & Contractility ►↓ CO. ( the primary mechanism)
ii. ↓ β1 ► ↓ renin release ►↓AII ► VD ► ↓ PR AND ↓ Aldosterone ►↓Blood volume ►↓BP.
iii. Reducing sympathetic activity via a central mechanism.
Nebivolol is a selective blocker of β1 receptors, which also increases the production of nitric oxide, leading to
vasodilation.
Therapeutic uses:
1. Hypertension
2. Glaucoma
3. Migraine.
4. Hyperthyroidism
5. Angina pectoris [Not Variant Angina]
6. Myocardial infarction.
7. Arrhythmia.
◙ β-blockers are effective in white>black & effective in young>elderly.
◙ β-blockers cause NO postural hypotension [c.f. α-blockers].
Adverse effects:
1. Bronchoconstriction [C.I. in Bronchial asthma]
2. Rebound hypertension and arrhythmias: β-blockers must never be stopped quickly due to upregulation.
3. Disturbances in metabolism:
↑ LDL/HDL ratio ►↑ risk of atherosclerosis.
4. Aggravation of cardiac failure, bradycardia, heart block [C.I. in CHF]
5. Peripheral vasoconstriction, cold extremities [C.I. in PVD].
6. Fatigue and bad dreams.
7. Impotence and ↓ libido.
α-Blockers
Non-selective: Phenoxybenzamine & phentolamine [NOT USED IN HTN].
Selective “α1”: Prazosin, Terazosin & Doxazocin.
They block α1  Mixed vasodilation of:
 Arteries ► ↓PR ►↓Afterload ►↓BP.
 Veins ►↓ venous return [VR] ►↓preload ►↓CO ►↓BP.
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Mechanism of action:
Therapeutic uses:
In mild to moderate hypertension [ONLY selective α1 blockers].
Adverse effects:
1. Postural hypotension.
2. Reflex tachycardia [Severe with non-selective] “May be combined with β-blockers to ↓ tachycardia].
3. Na/Water retention [Used with diuretics].
α1 & β-Blockers
Labetalol & Carvedilol
Uses of labetolol:
1. Used in emergency hypertension.
2. Pregnancy-induced hypertension.
[II] Adrenergic neuron blockers [Antiadrenergics]:
Reserpine (↓ storage) & Guanethidine (↓ release).
[III] Ganglionic blockers: Trimetaphan.
[IV] Centrally acting drugs: α2 -stimulants (clonidine,& α-methyl dopa).
Clonidine [Catapress®]
Mechanism of action:
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↑α2 centrally ►↓ Sympathetic outflow.
α-methyldopa [Aldomet ®]
Mechanism of action:
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α-methyldopa is a competitive inhibitor of dopa decarboxylase enzyme ►↓NE synthesis.
α-methyldopa ► α-methyldopamine► α-methylnoradrenaline.
α-methylnoradrenaline is a potent α2 agonist [Act as clonidine] & act as a false transmitter.
Uses:
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Used in pregnancy induced hypertension.
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Diuretics
[I] Thiazides and thiazide-related compounds: Hydrochlorothiazide, chloro-thalidone, indapamide.
II] Loop diuretics: Frusemide (Lasix®), bumetanide.
Mechanism of action of thiazides & Loop diuretics:
•Initial effect (1st –6 weeks of treatment): Thiazides inhibits Na+/ Cl- reabsorption in the early distal tubule, while loop
diuretics inhibit Na  /K  /CI  co transport in the ascending limb of loop of Henle  diuresis  ↓ blood volume 
↓ venous return  ↓ CO  ↓ BP .
• Late effect (After several weeks of treatment): due to depletion of Na from vascular wall [i.e. due to natriuresis] 
secondary ↓ in Ca   content in VSM  ↓ in sensitivity of VSM to vasoconstrictor mediators (e.g. NA and A II) 
vasodilatation  ↓ TPR  ↓ BP.
N.B indapamide a non thiazide diuretic acts mainly through it’s natriuretic action and has a direct vasodilator effect.
N.B. Diuretics have no direct effect on vascular smooth muscle.
Side effects
1. Hypokalemia [Normal K=3.5-5mmol/l]: This may be corrected by oral KCl or Co-administration with K  -sparing
diuretic .
2. Effect on Ca:
Hypercalcemia with Thiazides & Hypocalcemia with loop diuretics
3. Hyperglycemia: Used with caution with diabetics.
4. Hyperuricemia [Normal uric acid = 2-7mg%]: So avoided in gouty patients or combined with uricosuric agent.
5. Hyperlipidaemia: ↑ VLDL, LDL & TG and ↓ HDL level. So avoided in atherosclerotic patients with risk of coronary
heart disease.
Clinical uses:
1. Used alone in mild to moderate HTN especially in black & elderly people [c.f β-blockers].
2. Used in CHF.
[III] k  - sparing diuretics: Spironolactone (Aldactone ) , triamtrene , amiloride.
Mechanism of action:
•Spironolactone is metabolized in liver to conrenone which is aldosterone antagonist  inhibit Na  reabsorption and
K  secretion in late distal & collecting tubule  natriuresis and hyperkalemia.
• Amiloride and triamtrene: they block Na  channels on the luminal side of the collecting tubule.
Uses: they are weak diuretics, used mainly in combination with [I] or [II] to correct hypokalemia and enhance their
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natriuretic effect.
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Vasodilators
Most vasodilators lead by various mechanisms to ↓ in VSM tone by decreasing the free
calcium [Ca   ]i  vasodilatation ,which may occur in :
(A) Resistance vessels [arterioles]  arteriodilatation  ↓ TPR.
(B) Capacitance vessels [venules]  venodilatation  ↓ venous return  ↓ CO.
(C) Both arterioles and venules  mixed dilation  ↓ TPR and CO.
• To know the role of Ca in SM contraction read the box below:
Ca   influx into the VSM membrane occurs through Ca   channels which are of two types:
i-Voltage-sensitive channels: open by depolarization and close by repolarization.
ii-Receptor-operated channels: open by activation of G-protein coupled receptor.

•Ca   influx through Ca
channels  ↑ Ca   release from intracellular storage sites (SR) 
formation of Ca   - calmodulin complex  ↑ MLCK  phosphorylation [activation of myosin] 
muscle contraction.
•Released Ca   is sequestered by the SR via ATP dependent Ca   pump .
[I] Direct vasodilators: They may be:
i] Arteriodilators: Hydralazine, minoxidil & diazoxide.
ii] Venodilators: Nitroglycerin (in high doses also arteriodilator).
iii]Mixed dilators (arteriovenodilators) : Sodium nitroprusside.
Mechanism of action:
•Hydralazine: ↓IP3-mediated intracellular Ca   release from SR & ↑ intracellular cGMP
leading to ↑ Ca   uptake by SR.
• Minoxidil & diazoxide: open ATP-dependent K  channels in VSM  hyperpolarization
 closure of Ca   channels  ↓ Ca   entry  vasodilatation.
[N.B. Minoxidil is first metabolized to minoxidil sulphate which is the active metabolite]
• Sodium nitroprusside: it reacts with tissue thiols and release NO “NO donor” 
guanylate cyclase  ↑ cGMP  ↑ Ca   uptake by SR.
[I] All members produce:
1- ↓TPR & ↓ BP  compensatory responses opposing their antihypertensive effect. These
responses mediated by:
(a) The CNS: Mediated by baroreceptors & sympathetic nerves  reflex tachycardia
(treated by β-blockers).
(b) The kidney: mediated by RAS  oedema (treated by diuretics).
• So the best combination is: vasodilator + β- blocker + diuretic. [β- blocker prevent
tachycardia ( β1 in heart ) & ↑ renin (β1 in kidney ) while diuretic prevent Na / H2O
retention].
2- Postural hypotension: occurs with veno and mixed dilators only.
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Side effects:
3-Headache, flushing and nasal congestion.
[II] Hydralazine: Lupus erythmatous-like syndrome (i.e. arthralgia, myalgia, skin rash &
fever).
[III] Diazoxide: hyperglycemia and hyperuricemia (like thiazides), thus used cautiously in
diabetic and gouty patients.
[IV] Minoxidil: Hirsutism (hypertrichosis), thus it is used topically as scalp lotion to promote
hair growth.
[V] Sodium nitroprusside: it is metabolized by RBCs into CN  which in further metabolized
in liver to SCN  which is excreted by the kidney.
On prolonged infusion  accumulation of CN  (metabolic acidosis and arrhythmia) or
SCN  (delirium and psychosis), thus it is avoided in patients with hepatic or renal
impairment. It also causes methaemogolbinaemia and hypoxia.
Clinical uses:
•Orally: hydralazine and minoxidil in sever HT. [N.B. Minoxidil is preferred when HT is
associated with renal failure].
•Parenterally: SNP [IV infusion] & diazoxide [IV injection] in HT emergencies.
[II] Ca   -Channel blockers:
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Diphenylalkylamines: Verapamil [Isoptin]
Benzothiazepines: Diltiazem.
Dihydropyridines [dipines]: Nifedipine (Adalat), Amlodipine (Norvasc), Felodipine,
Isradipine & Nicardipine.
Mechanism of action: They block voltage-sensitive [L-type] Ca   channels in the heart &
blood vessels  ↓ [Ca   ]i  ↓ arterial tone  ↓ TPR.
Pharmacological actions:
On heart: They cause bradycardia & ↓ contractility.
On blood vessels: They cause ONLY arteriodilatation  ↓ TPR.
Uses:
Used orally in mid to moderate HT. Nifedipine is used sublingually in severe HT . They also
have a cardioprotective effect against ischemic attacks (i.e. protect ischemic tissue
against Ca   overload).
1-No effect on blood glucose, uric acid, lipids or electrolytes.
2-No adverse effects on asthma or peripheral vascular disease (c.f. β-blockers).
3-Have beneficial effects on other diseases complicating HT e.g. diabetic nephropathy,
angina & CHF with diastolic [not systolic] dysfunction.
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Advantages over other antihypertensive:
Side effects: Reflex tachycardia, & headache, flushing, dizziness & peripheral (ankle)
edema especially on long standing.
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Antagonists of RAS
[I] Angiotensin converting enzyme (ACE) inhibitors [ -prils]:
Captopril (Capoten), Enalapril(Renitec), Prindopril(Coversyl), Fosinopril, Benazepril &
Lisinopril(Zestril).
Mechanism of action: they inhibit ACE (kininase II), thus they :
1- ↓ The formation of the potent vasoconstrictor peptide A II (The main effect in HT
associated with high PRA) & ↓ the degradation of the potent vasodilator peptide BK (this is
the main effect in HT associated with low PRA) all this result in dilatation of both arterioles
& venules  ↓ TPR & venous pressure [i.e. ↓ preload & afterload so useful in CHF].
2- ↓ aldosterone secretion  ↓ Na  & H2O retention  ↓ blood volume  ↓ CO.
3- ↓ Cardiac & endothelial RAS  ↓ CV remodeling.
Advantages in associated diseases:
1- Ischemic heart disease: they improve systolic contraction by ↓ the afterload.
2-Diabetes: they slow down development of diabetic nephropathy by improving
intrarenal haemodynamics  diminish proteinuria & stabilize renal functions.
3-CHF: they prevent & reverse myocardial remodeling.
Clinical uses:
1- HT especially with high PRA either as monotherapy in moderate cases or with diuretics
in severe cases.
2- HT associated with diabetes, asthma, and angina and heart failure.
3- CHF, myocardial infarction and necrosis.
Side effects: Hypotension following 1st dose (1stdose phenomenon), persistent cough (due
to accumulation of BK which stimulates cough sensors in bronchi), loss of sense of taste,
skin rash, blood dyscrasias, slight hyperkalemia, proteinurea and renal impairment.
Contraindications: Pregnancy, lactation and renal failure.
Drug interactions:
K  supplements & K  -sparing diuretics may lead to significant hyperkalemia.
Losartan (Cozaar), Valsartan (Targ, Diovan), Candisartan (Atacand).
Mechanism of action:
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[II] A II receptor blockers (- sartans OR At1 antagonists):
They preferentially block AT1 receptor (competitive antagonist) in VSM, adrenal cortex
and heart, thus reversing all actions mediated A II on these tissues:
•On blood vessels: vasodilatations  ↓ TPR. They also ↓ A ll–mediated VSM hypertrophy
and aldosterone induced collagen depositions  ↓ vascular remodeling.
•On adrenal cortex: ↓ aldosterone secretion  ↑ Na  & H2O excretion  ↓
volume.
•On heart: ↓ A ll mediated myocardial hypertrophy  ↓ myocardial remodeling.
Blood
Uses: used alone or in combination with diuretics.
Side effects: Hyperkalemia, renal insufficiency, but no cough.
Contraindications: pregnancy.
Stepwise drug therapy in
management of HT
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I] Start with monotherapy which may be:
•A thiazide diuretics or a Ca   -channel blocker: Preferred in elderly (> 65 year)
•A β-blocker: giving best results in Young, having good myocardium
•An ACE inhibitor: suitable for all patients.
II] If no control, shift to dual therapy:
Thiazide + β-blocker OR Ca   -channel blocker OR ACE ↓.
III] If no control, shift to triple therapy:
Add any of the above combinations with a vasodilator.
V] In HT emergencies “HT crisis”:
This is a life threatening situation in which diastolic BP is either:
i. >150 mmHg + Systolic >210 mmHg.
ii. >130 mmHg in individuals with preexisting complications.
This is treated by:
•IV infusion of sodium nitroprusside or trimetaphan.
•IV injection of diazoxide, labitalol, hydralazine or furosemide.
•Sublingual nifedipine.