Calcium Channel Blockers

Drugs include
 Phenylalkylamine: Verapamil
 Benzothiazepin: Diltiazem
 Dihydropyridines: Nifedipine, Felodipine, Amlodipine,
Nimodipine, Isradipine, Nicardipine,
Nisoldipine, Nitrendipine,Lacidipine
Mechanism of antihypertensive action
Vasodilatation /  PVR:
 These drugs block L- type voltage sensitive Ca++ channels in vascular
smooth muscle cell membrane and block influx of Ca++ into cells. Thus
they markedly relax the smooth muscle by reducing intracellular
availability of Ca++ .They mainly produce arteriolar vasodilatation and
have mild effect on veins.
 Dihydropyridines additionally stimulate release of NO from vascular
endothelium.
Negative inotropic & chrontropic effect /  CO
 During phase 2 of the actionpotential in myocardial fibers, Ca++ influx
stimulates release of more Ca++ from sarcoplsmic reticulum allowing
myocardial contraction. Calcium channel blockers thus produce negative
inotropic effect.
 Depolarization of phase 0 in SA and AV node is mainly due to Ca++
current. Thus the automaticiy and conductivity of thse cells is also

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 dependent on Ca++ current. Thus Ca++ channel blockers exert negative
inotropic effect.
 Negative inotropic & chronotropic effects result in decreased CO

Dihydropyridines Vs Non-Dihydropyridines
 Dihydropyridines have more selective action on smooth muscle than on
the heart. They do not produce –ve inotropic and –ve chronotropic effect.
Their antihypertensive use is usually accompanied by a reflex increase in
heart rate and sympathetic activation. Cardiodepressant effect requires
much larger doses.
 Non- dihydropyridines have more pronounced cardiodepressant effect
and reduce CO. They are less potent vasodilators effect and may decrease
PVR. In contrast to the dihydropyridines, there tends to be no reflex rise
in heart rate with these drugs.
 All Ca++ channel blockers are equally effective antihypertensives.
Place in therapy
 Calcium channel blockers are effective as a monotheapy and are
generally considered as second line agents.
 They are especially effective in African-American unlike beta blockers
and ACE inhibitors.
 They are indicated for treating hypertension associated ischemic heart
disease.
 No adverse feotal affects unlike thiazides, beta blocker and ACEi’s and
can be used during pregnancy.
 Non- dihydropyridines have been shown to reduce proteinurea and may
be used as second line agents in diabetic hypertensive patients with
proteinurea.

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Adverse Effects
 Side-effects associated with the dihydropyridine class of calcium-
channel blockers include flushing, headaches, postural dizziness,
palpitations and tachycardia and ankle oedema. Rash and gingival
hypertrophy may also occur.
 The non-dihydropyridines especially, can worsen heart failure, and
precipitate heart block in some patients. Constipation is also more
common. Nausea, head ache, dizziness, edema, gingival hyperplasia may
occur.

Contraindication
 Non- dihydropyridines should be avoided in patients with
atrioventricular node dysfunction and left ventricular dysfunction.
 Combination Non-dihydropyridines with beta blockers should be
avoided.
 Short acting dihydropyridiens preparations (eg. Nifedipine, nicardipine,
nimodipine) should not be used because of marked fluctuation in BP.
Worsening of angina and congestive heart failure has also been noted.
These have not been observed with long acting preparations (eg.
Amlodipine and Felodipine).

Central a 2 receptor agonists

 Drugs include: - Methyldopa, Clonidine, guanabenz and
guanfacine
MOA:- alpha central sympathetic outflow

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Place in Therapy
 These drugs should be reserved for third line therapy because of
their side effect profile.
 Methyldopa is recommended for use during pregnancy.

Side effects include

 Sedation, dry mouth, bradycardia, heart block, and rebound
hypertension are common with clonidine, guanabenz and
guanfacine
 Methyldopa in addition produces hemolytic anemia (<1% of
patients), colitis, hepatitis. But rebound hypertension is less
common.
Drugs interactions
 Tricyclic antidepressants abolish their antihypertensive effect.
 Chlorpromazine abolishes antihypertensive effect of clonidine.

Vasodilators
 Drugs include: Hydralazine, Minoxidil, Sodium Nirtopruside,
Diazoxide
Mechanism of actions
 The mechanism of action of hydralazine is unknown. But it is a
known arteriolar dilator and has a minimal effect on dilation of
capacitance vessels.
 Hydralazine-induced vasodilatation is associated with powerful
stimulation of the sympathetic nervous system. These effects
counteract its antihypertensive effect.

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 Minoxidil and diazoxide are extremely potent vasodilators and
work by activating potassium channels in vascular smooth muscle.
 Minoxidil is a prodrug converted by sulfate conjugation into the
active metabolite (minoxidil sulfate). Minoxidil sulfate activates the
ATP-modulated potassium channel. By opening potassium
channels in smooth muscle and thereby permitting potassium
efflux, it causes hyperpolarization and relaxation of smooth
muscle.
 Diazoxide also hyperpolarizes arterial smooth muscle cells by
activating ATP-sensitive K+ channels.
 Sodium Nitorpruside act as a vasodilator by releasing NO which
activates guanylate cyclase, leading to the formation of cyclic GMP
and vasodilatation.
Side effects
 Tachycardia, fluid retention, headache, flushing, dizziness
 Minoxidil causes hypertrichosis. Because of the tachycardia
and severe fluid retention patients on minoxidil frequently need
treatment with β-blockade and large doses of a potent diuretic
(furosemide); doses of furosemide (as high as 200 mg a day)
may be necessary to prevent the massive fluid accumulation
that may occur.
 Treatment with hydralazine especially at high doses may cause
a lupus-like syndrome. Symptoms include fever, rash and/or
arthralgia. Dermatitis, hepatitis, peripheral neuropathy may also
occur.

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  Diazoxide is diabetogenic owing to its chemical similarity to
thiazide diuretics. Patients on chronic high doses may require
therapy with oral hypoglycaemic agents.
Contraindication
 Monotherapy with such agents would be contraindicated in
patients with anginaHowever, in normal clinical practice it is
nearly always necessary to co-administer a â-blocker with
direct-acting vasodilator.
Place in therapy
 Reserved for third or fourth line of therapy for refractory cases.

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