Calcium antagonists

(calcium channel blockers)

They block calcium influx through voltagedependant calcium channels in the smooth muscles. They dilate coronaries and peripheral arteries and reduce heart afterload.

In the cell membranes their are three types of calcium channels: Voltage-dependent (L, N, O, P, Q, R, T) Receptor operating Stretch activated

Calcium antagonists block predominantly L-type calcium channels, localized in myocardium and myocytes Plateau phase of AP of blood vessels. L-type channels are connected to the plateau of the AP.

CCBS can relax other smooth muscles like bronchiolar muscle and GI muscles Response to CCBs is greatest in arteriolar smooth muscles than venous smooth muscles CCBs cant relax skeletal muscles why?

AP

Calcium antagonists
()
VDCC
ROCC

Ca2+
Cell wall

NA
Receptor

Ca2+
Sarcoplasmatic reticulum

AP action potential, NA noradrenaline VDCC voltage-dependent calcium channels ROCC receptor operating calcium channels

Regulation of intracelullular calcium

CCBs members
Short t1\2 Rapid onset
Long t1\2 Slow onset Verapamil Diltiazem Nifedipine

Dihyhdropyridines Arteries>>>>>heart
CCBs
Non dihydropyridines Arteries and heart

PO
Amlodipine

IV,PO

General characters
All of CCBS groups bind to L-type calcium channels Calcium antagonists reduce coronary and peripheral vascular resistance, decrease blood pressure and myocardial oxygen consumption They differ in their binding sites to the channel Rapid onset DHPs will trigger reflex tachycardia worsening of cardiac ischemia Slow onset DHPs dont trigger reflex tachycardia

General characters
Diltiazem and verapamil have negative chrontropic, inotropic and dromotropic effects on heart while the DHPs have less effect See the table next slide

Effects of CCBs
Drug Vasodilation Negative inotropic effect
1

Negative chronotropic effect

1

Depression of conduction
0

Nifedipine

Diltiazem
verapamil

3
4

2
4

5
5

4
5

 Dihydropyridines Norm frequent (with normal heart rate) and 24-hours long effect: Amlodipine, Felodipine Other dihydropyridines produce tachycardia (increase baroreflex sensibility): Isradipine, Lacidipine, Nicardipine, Nifedipine, Nimodipine, Nisoldipine, Nitrendipine Phenylalkylamines: Verapamil SR Benzotiazepines: Diltiazem SR Flunarizine type Cinnarizine, Flunarizine

 Arterial hypertension a) Dihydropyridines b) Verapamil SR and Diltiazem SR Coronary heart disease a) Dihydropyridines b) Verapamil SR and Diltiazem SR Ischemic cerebral stroke Cinnarizine, Flunarizine, Nimodipine SV tachyarrhythmias: Verapamil, Diltiazem (i.v.) Migraine (in remission periods) Flunarizine, Verapamil Beta-blockers + dihydropyridines: YES (OK) Beta-blockers + Verapamil or Diltiazem = NO

Main indications

Class IV antiarrhythmic drugs

Mainly verapamil (p. o./i. v.) and diltiazem (only i.v.) has specific action on SA and AV node (they shorten AP)

Indications: SV tachyarrhythmias

ARs: headache, ankle swelling,

bradycardia, AV block, negative inotropic effect (decreasing cardiac contractility)

Other uses
Verapamil :Decrease resistance to the chemotherapy in patients suffering from cancer DHPs :Raynauds disease

SEs of calcium antagonists

1. Arterial dilation: headache, flush, dizziness, ankle swelling (resistant to treatment with diuretics but not with ACE inhibitors). 2. Bradycardia and AV block (verapamil). Verapamil + beta-blockers: potentiate cardiodepression. 3. Tachycardia (nifedipine, nisoldipine). 4. Constipation (verapamil 8%; nifedipine 3%) 5. Haemorrhagic gingivitis

Stable angina managment

Acute attacks

Prophylactic

Non pharmacological treatment

Acute attack managment

Rest Sublingual nitrates
Remove after relief

Prophylactic
Beta blockers
We prefer B1 blokers The target is to achieve 50 beat \min at rest Dont stop them abruptly Make sure there isnt contraindication:
1. 2. 3. 4. Asthma DM Vasospastic angina Raynauds disease

Prophylactic
CCBs
Use slow onset DHPs or sustained released formulation from rapid onset ones Use NDHP if you make sure that there is no heart failure or another contraindication

Prophylactic
Nitrates
Use oral formulation from isosorbide mono or dinitrate,or patches
Make sure that there is time free intervals

Statins
Aggressive therapy if there is elevation in cholesterol levels
40-80 mg\day

Lower doses 10-20 mg \day

Aspirin 75-375 mg \day

Management
Aspirin and statins is a standard regimen Add either beta blockers or CCB or nitrates We prefer beta blockers if there isnt CI If there is CI use CCB or nitrates Combination is possible btw beta blocker and nitrates ,and CCB and nitrates, beta blocker and CCB use must be avoided