Calcium-Channel Blockers

PHRM 306: Drugs affecting CVS

 Calcium-Channel Blockers (CCB)
• Calcium channels are
especially concentrated
in SA and AV  nodes.
• CCB can be used to
decrease impulse
conduction through the
AV node.
 Calcium-Channel Blockers (CCB)

• Calcium channels are

also present in
the smooth
muscle lining blood
vessels.
• By relaxing the tone of
this smooth muscle,
CCBs dilate the blood
vessels.
 Calcium-Channel Blockers (CCB)
• CCBs are recommended when the preferred
first-line agents are contraindicated or
ineffective.

• They are effective in treating hypertension in

patients with angina or diabetes.
 Calcium-Channel Blockers
• High doses of short-acting CCB should be
avoided because of
– increased risk of MI due to
• excessive vasodilatation and
• marked reflex cardiac stimulation.
Classification
 Different Classes of Calcium-Channel
Blockers
• Dihydropyridines (DHP)
– The most smooth muscle selective class of CCBs
• High vascular selectivity
• DHP is used to reduce
– systemic vascular resistance and
– arterial pressure
Drug Drug Interactions
• Amlodipine and nicardipine (ADP)
• Interaction with digoxin or warfarin
• Non-dihydropyridines
– Two currently used clinically.
• Verapamil (phenylalkylamine class)
•  Relatively selective for myocardium
• less effective as a systemic vasodilator. 
• Important role in treating angina by
– reducing myocardial oxygen demand and
– reversing coronary vasospasm &
– arrhythmias. 
• Is used to treat supraventricular
tachyarrhythmias (SVT), migraine headache.
• Diltiazem (Benzothiazepines)
• Diltiazem is a potent vasodilator (coronary and
peripheral vessels)
• It increases blood flow and decreases the HR via
strong depression of A-V node conduction.
• Diltiazem has negative 
– Inotropic (decrease in heart muscle contractility) 
– Chronotropic (lower HR by slowing SA node
conductivity)
– Dromotropic (slowing AV nodal conduction) effects.
 Therapeutic uses
• Calcium-channel blockers have an intrinsic
natriuretic effect and, therefore, do not
usually require the addition of a diuretic.
• These agents are useful in the treatment of
hypertensive patients who also have asthma,
diabetes, angina, and/or peripheral vascular
disease.
• Black hypertensives respond well to calcium-
channel blockers.
 Antianginal Drugs

PHRM 306: Drugs affecting CVS

 Overview
• Angina pectoris is a characteristic sudden,
severe, pressing chest pain radiating to the
neck, jaw, back, and arms.
 Overview
• It is caused by coronary blood flow that is
insufficient to meet the oxygen demands of
the myocardium, leading to ischemia.

Atherosclerotic
lesions
 Overview
The imbalance between oxygen delivery and
utilization may result –
i) exertion (physical activity),
ii) a spasm of the vascular smooth muscle, or
Obstruction of blood vessels caused by
atherosclerotic lesions.
 Overview
• These transient episodes (15 seconds to 15
minutes) of myocardial ischemia do not
cause cellular death, such as occurs in
myocardial infarction.
 Overview
• Drugs used in angina pectoris lower the
oxygen demand of the heart by affecting
blood pressure, venous return, heart rate,
and contractility.
• Lifestyle and risk factor modifications,
especially cessation of smoking, are also
important in the treatment of angina.
• Options other than medications for treating
angina include angioplasty and coronary
artery bypass surgery.
 Types of Angina
• Angina pectoris has three overlapping
patterns: 1) stable or typical angina, 2)
unstable angina, and 3) Prinzmetal's or
variant angina.
• They are caused by varying combinations of
increased myocardial demand and decreased
myocardial perfusion.
 Stable angina
• Stable angina is the most common form of
angina and, therefore, is called typical angina
pectoris.
• It is caused by the reduction of coronary
perfusion due to a fixed obstruction
produced by coronary atherosclerosis.
 Unstable angina
• Unstable angina lies between stable angina on
the one hand and myocardial infarction on the
other.
• In unstable angina, chest pains occur with
increased frequency.
• The symptoms are not relieved by rest or
nitroglycerin.
• Unstable angina requires hospital admission
and more aggressive therapy to prevent death
and progression to myocardial infarction.
 Prinzmetal's or variant or
vasospastic angina
• Prinzmetal's angina is an uncommon pattern
of episodic angina that occurs at rest and is
due to coronary artery spasm.
• Symptoms are caused by decreased blood
flow to the heart muscle due to spasm of the
coronary artery.
 Organic Nitrates
• Organic nitrates (and nitrites) are used in the
treatment of angina pectoris.
• These are simple nitric (HNO3) and nitrous
(HNO2) acid esters of glycerol.
 Organic Nitrates
• They differ in their volatility.
• For example, isosorbide dinitrate and
isosorbide mononitrate are solids at room
temperature, nitroglycerin is only moderately
volatile, and amyl nitrite is extremely volatile.

Isosorbide dinitrate Nitroglycerin Amyl nitrite

 Mechanism of action
• Nitrates decrease coronary vasoconstriction
or spasm and increase perfusion of the
myocardium by relaxing coronary arteries.
• In addition, they relax veins, decreasing
preload (venous return to the heart) and
myocardial oxygen consumption.
 Mechanism of action
• Organic nitrates, such as nitroglycerin, which
is also known as glyceryl trinitrate, are
thought to relax vascular smooth muscle by
their intracellular conversion to nitrite ions,
and then to nitric oxide, which in turn
activates guanylate cyclase and increases the
cells' cyclic guanosine monophosphate
(cGMP).
 Mechanism of action
• Elevated cGMP ultimately
leads to dephosphorylation
of the myosin light chain,
resulting in vascular
smooth muscle relaxation. +
Guanylate cyclase

Figure:
Effects of nitrates and nitrites on smooth
muscle.
 Effects on the CVS
• All these agents are effective, but they differ
in their onset of action and rate of
elimination.
• For prompt relief of an ongoing attack of
angina precipitated by exercise or emotional
stress, sublingual (or spray form)
nitroglycerin is the drug of choice.
 Effects on the CVS
• At therapeutic doses, nitroglycerin has two
major effects.
• First, it causes dilation of the large veins,
resulting in pooling of blood in the veins.
• This diminishes preload (venous return to the
heart) and reduces the work of the heart.
 Effects on the CVS
• Second, nitroglycerin dilates the coronary
vasculature (artery), providing an increased
blood supply to the heart muscle.
• Nitroglycerin decreases myocardial oxygen
consumption because of decreased cardiac
work.
 Pharmacokinetics
• The time to onset of action varies from 1
minute for nitroglycerin to more than 1 hour
for isosorbide mononitrate.
• Significant first-pass metabolism of
nitroglycerin occurs in the liver.
• Therefore, it is common to take the drug
either sublingually or via a transdermal
patch, thereby avoiding this route of
elimination.
 Pharmacokinetics
• Isosorbide mononitrate owes its improved
bioavailability and long duration of action to
its stability against hepatic breakdown.
• Oral isosorbide dinitrate undergoes
denitration to two mononitrates, both of
which possess antianginal activity.
 Adverse effects
• The most common adverse effect of
nitroglycerin, as well as of the other nitrates,
is headache.
• High doses of organic nitrates can also cause
postural hypotension, facial flushing, and
tachycardia.