Calcium channel blockers (CCBs) work by blocking the movement of calcium through calcium channels. This disrupts the contraction of cardiac and smooth muscle. CCBs are used to treat hypertension, angina, and arrhythmias. The main types are verapamil, diltiazem, nifedipine, and amlodipine. They work by relaxing blood vessels and slowing heart rate to lower blood pressure. Side effects include hypotension, edema, and heart block. CCBs must be used cautiously in patients with heart failure or bradycardia.

1. Calcium Channel
Blockers
Prepared By:
Mr. Nadim Chhipa
Associate Professor,
ASP and BRI, Adalaj

2. It has been known since the late 1800s that transmembrane calcium
influx is necessary for the contraction of smooth and cardiac muscle.
The discovery of a calcium channel in cardiac muscle was followed
by the finding of several different types of calcium channels in
different tissues.
Calcium channel blockers (CCBs) also known as calcium
antagonists.
they are first line antihypertensive drugs.
They are also used to treat angina.
These medications disrupt the movement of calcium (Ca2+) through
calcium channels.
Introduction

3. Four types of Ca2+ channels (L, N, P, and T)
L-type are responsible for normal myocardial
contractility and for vascular smooth muscle
contractility.
N-type are restricted to neurons where they
function in neurotransmitter release.
P/Q-type signifies cerebellar Purkinje cells, it is
also one of high-voltage-gated calcium
channels
T-type calcium channels are not normally present
in the adult myocardium, but are prominent in
conducting – low voltage (R type)
Introduction

4. Classification

5. Classification

6. Mechanism of Action

7. Mechanism of Action

8. Mechanism of Action
• CCBs has four effects:
1)They act on vascular smooth muscle, reduce contraction of the arteries
and cause vasodilation .
2)They act on cardiac muscles (myocardium), they reduce the force of
contraction of the heart (Negative inotropic).
3) They slow down the conduction of electrical activity within the heart,
slow down the heartbeat (Negative chronotropic).
4)They block the calcium signal on adrenal cortex cells, they directly
reduce aldosterone production, which correlates to lower blood pressure.

9. Mechanism of Action

10. Mechanism of Action

11. Mechanism of Action

12. Mechanism of Action

13. Mechanism of Action

14. Mechanism of Action

15. Mechanism of Action

16. CCBs may improve cardiac function by:
A. Reducing cardiac afterload
B. Increasing O2 supply
C. Decreasing cardiac preload
D. Normalizing heart rate in patients with supraventricular
tachycardia

18. Verapamil
IUPAC Name: 5-[(3,4-dimethoxyphenethyl)methylamino]-2-
(3,4-dimethoxyphenyl)-2-isopropylvaleronitrile
• It was introduced in 1962 as a coronary vasodilator and is
the prototype of the Ca2 antagonists used in
cardiovascular diseases.
• It is used to treat hypertension, chest pain from cardiac ischemia and
supraventricular tachycardia.
Action:
• Verapamil inhibits entry of calcium ions into arterial smooth muscle as well as the
myocytes and conducting tissues.
• Verapamil reduces BP, relieves angina and slows AV conduction.

19. Verapamil
• It can be separated into its optically active isomers, of which the levorotatory
enantiomer is the most potent.
• The drug is metabolized quickly and, as a result, has low bioavailability.
• The liver is the main site of first-pass metabolism, forming several products.
• The preferential metabolic step involves N-dealkylation, followed by O-
demethylation, and subsequent conjugation of the product before elimination.
• The metabolites have no significant biological activity.
• Verapamil has an elimination half-life of approximately 5 hours.

20. Verapamil
INDICATIONS
Angina pectoris due to coronary artery spasm (Prinzmetal’s variant angina)
Effort-associated angina
Chronic stable angina
Unstable, crescendo, preinfarction angina
Essential hypertension
Parenteral: Treatment of supraventricular tachyarrhythmia.
Parenteral: Temporary control of rapid ventricular rate in atrial flutter or atrial
fibrillation

21. Verapamil
CONTRA-INDICATIONS
• Cardiogenic shock.
• severe bradycardia.
• severe left ventricular dysfunction.
• uncompensated heart failure.
• hypotension (systolic pressure <90 mm Hg),

22. Verapamil
SIDE EFFECTS
• Bradycardia.
• CHF.
• MI.
• AV block.
• Transient Asystole.
• hypotension.
• pulmonary and peripheral edema.
• nausea. Constipation.
• fatigue, hypotension, dizziness, headache.

23. Bepridil hydrochloride
IUPC Name: N-benzyl-N-[3-(2-methylpropoxy)-2-
pyrrolidin-1-ylpropyl]aniline;hydrochloride
• A long-acting, non selective, calcium channel blocker with significant anti-anginal activity.
The drug produces significant coronary vasodilation and modest peripheral effects. It has
antihypertensive and selective anti-arrhythmia activities and acts as a calmodulin
antagonist. It is no longer marketed in the United States, as it has been implicated in
causing ventricular arrhythmias.
• It is not related chemically to other calcium channel blockers such as diltiazem
hydrochloride, nifedipine and verapamil hydrochloride.

24. Bepridil hydrochloride
IUPC Name: N-benzyl-N-[3-(2-methylpropoxy)-2-
pyrrolidin-1-ylpropyl]aniline;hydrochloride
• INDICATIONS
• ChronicStable Angina (Classic Effort-Associated Angina)
• VASCOR (bepridil hydrochloride) is indicated for the treatment of chronic stable angina (classic
effort-associated angina). Because VASCOR (bepridil) has caused serious ventricular arrhythmias,
including torsades de pointes type ventricular tachycardia, and the occurrence of cases
of agranulocytosis associated with its use.
• it should be reserved for patients who have failed to respond optimally to, or are intolerant of, other
anti-anginal medication.
• VASCOR (bepridil) may be used alone or in combination with beta blockers and/or nitrates.
Controlled clinical studies have shown an added effect when VASCOR (bepridil) is administered to
patients already receiving propranolol.

25. Diltiazem hydrochloride
IUPC Name: (+)-cis-3-(acetoxy)-5-[2(dimethylamino)ethyl]-2,3-dihydro-
2-(4-methoxyphenyl)1,5-benzothiazepin-4(5H)one hydrochloride.
• Diltiazem, a benzothiazepine calcium-channel blocker.
• It is used alone or with an angiotensin-converting enzyme inhibitor.
Properties and uses:
• It is a white crystalline powder, freely soluble in water, in methanol,
and in methylene
• chloride, slightly soluble in ethanol.
• Diltiazem has two chiral centres (C2 and C3)
• It is used in the treatment of angina Pectoris and also used as
antiarrhythmic agent.

26. Diltiazem hydrochloride
• Diltiazem hydrochloride is metabolized extensively after oral dosing, by first-pass
metabolism. As a result, the bioavailability is about 40% of the administered dose.
• The drug undergoes several biotransformations, including deacetylation, oxidative O-
and N-demethylations, and conjugation of the phenolic metabolites.
• Of the various metabolites only the primary metabolite, deacetyldiltiazem, is
pharmacologically active. Deacetyldiltiazem has about 40% to 50% of the potency of the
parent compound.

27. Diltiazem hydrochloride
• The drug has electrophysiological properties similar to those of
verapamil and is used in clinically similar treatment conditions as an
antiarrhythmic agent, but it is less potent.
• The drug is absorbed rapidly and almost completely from the
digestive tract. It reaches peak plasma levels within 1 hour after
administration in gelatin capsules.
• Oral formulations on the market are sustained-release preparations
providing peak plasma levels 3 to 4 hours after administration.
Side Effects:
CNS: Headache, fatigue, dizziness, asthenia, drowsiness, nervousness, insomnia, confusion, tremor,
gait abnormality.
CV: Edema, arrhythmias, angina, second- or third-degree AV block, bradycardia.
CHF: flushing, hypotension, syncope, palpitations.
GI: Nausea, constipation, anorexia, vomiting, diarrhoea, impaired taste, weight increase. Skin: Rash.

28. Nifedipine
IUPAC Name: 1,4-dihydro-2, 6-dimethyl-4-(2- nitrophenyl)-3,5-
pyridinedicarboxylate dimethyl ester.
• It is a dihydropyridine derivative that bears no structural
resemblance to the other calcium antagonists.
• It is not a nitrate, but its nitro group is essential for its antianginal
effect.
• As a class, the dihydropyridines possess a central pyridine ring that is partially
saturated.
• To this, positions 2 and 6 are substituted with an alkyl group that may play a role in the
agent’s duration of action.
• In addition, positions 3 and 5 are carboxylic groups that must be protected with an ester
functional group. Depending on the type of ester used at these sites, the agent can be
distributed to various parts of the body. Finally, position 4 requires an aromatic
substitution possessing an electron-withdrawing group (i.e., Cl or NO2) in the ortho
and/or meta position.

29. Nifedipine
• Indications: Chronic stable angina, Prinzmetal’s angina.
• Contraindications: Acute MI, cardiogenic shock, acute unstable angina.
• Side effects: Peripheral edema, hypotension, palpitations, tachycardia, flushing,
dizziness, headache, nausea, increased micturition frequency, lethargy, eye pain, mental
depression, visual disturbances.

30. Amlodipine
IUPAC Name: 2-[(2-aminoethoxy)methyl]4-(2-chlorophenyl)-1,4-
dihydro-6-methyl-3,5-pyridinedicarboxylic acid 3-ethyl 5-methyl
ester
Trade name: Norvasc.
• It is a medication used for treatment of hypertension and
coronary artery disease.
• It is also used in Stable angina
• It is a second generation 1,4-dihyropyridine derivative of the prototypical molecule
nifedipine. Like most of the second-generation dihydropyridine derivatives, it has greater
selectivity for the vascular smooth muscle than myocardial tissue, a longer half-life (34
hours), and less negative inotropy than the prototypical nifedipine.
• It is a white or almost white powder, slightly soluble in water, freely soluble in methanol,
sparingly soluble in ethanol and 2-propanol.

31. Amlodipine
• Amlodipine was approved in September 2007 as a combination product with
olmesartan (Azor), an angiotensin II receptor antagonist for the treatment of
hypertension.
• Amlodipine is also marketed as a combination therapy with atorvastatin under the
tradename Norvasc for the management of high cholesterol and high blood
pressure.

32. Amlodipine
• Indications: Hypertension, Stable angina, Prinzmetal’s angina.
• Contraindications: Known hypersensitivity to dihydropyridine, Second or third
degree heart block, Lactation.
• Availability:It is available in Tablets—2.5, 5, 10 mg.

33. Felodipine
IUPAC Name: 4-(2,3-dichlorophenyl)-1,4-dihydro- 2,6-
dimethyl-3,5-pyridinedicarboxylic acid ethyl methyl ester
Trade name: Plendil.
• It is a second-generation dihydropyridine channel blocker of the nifedipine type.
• It is more selective for vascular smooth muscle than for myocardial tissue and serves as
an effective vasodilator. The drug is used in the treatment of angina and mild-to-
moderate essential hypertension.
• Felodipine, like most of the dihydropyridines, exhibits a high degree of protein binding
and has a half-life ranging from 10 to 18 hours.
• It is a white or light yellow, crystalline powder, practically insoluble in water, freely soluble
in acetone, ethanol, methanol, and in methylene chloride

34. Nicardipine
IUPAC Name: 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-
3,5 pyridinedicarboxylic acid methyl 2 [methyl
(phenylmethyl)amino]ethyl ester
Trade name: Cardene
• It is a more potent vasodilator of the systemic, coronary, cerebral, and renal
vasculature and has been used in the treatment of mild, moderate, and severe
hypertension.
• The drug is also used in the management of stable angina.

35. Nimodipine
IUPAC Name: 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl)-
3,5-pyridinedicarboxylic acid 2-methoxyethyl 1-methylethyl
ester
Trade name: Nimotop
• It is another dihydropyridine calcium channel blocker but differs in that it dilates
the cerebral blood vessels more effectively than do the other dihydropyridine
derivatives.
• This drug is indicated for treatment of subarachnoid hemorrhage-associated
neurological deficits.

37. Indication:
• Angina.
• Hypertension.
• Raynaud's phenomenon. (Nifedipine is the mainstay of medical treatment).
• Supraventricular tachycardias, including atrial fibrillation.
• Ischaemic neurological deficit after subarachnoid haemorrhage.
• Delay of preterm labour(prevent premature labour has been with nifedipine)
• Prophylaxis for cluster headache.

38. Side Effects:
• Verapamil and Diltiazem are used in arrhythmias because they have an
effect on the heart. They both are not great antihypertensive drugs
• because they have negative inotropic and chronotropic effects,
• however are used in patients who have palpitations/arrhythmias and suffer
from HTN since they can reduce heart rate and blood pressure
simultaneously.
• Dihydropyridines: depend on JNC-8, found in first line theraby espically
in black population have a high efficacy of 40 mmHg, regarding that the
highest reduction in blood pressure an orally taken anti-hypertensive drug
can cause is 40 mmHg.

39. Side Effects:
Common adverse effects
These can be predicted from the type of CCB and mode of action, as already
illustrated.
Examples include:
Myocardial effects
• Hypotension
• Heart failure
Conduction effects
• Heart block
• Arrhythmias

40. Side Effects:

41. CAUTIONS AND CONTRA-INDICATIONS:
• Again, these can be predicted from the type of CCB and mode of action.
Individual drug monographs need to be reviewed. Some examples include:
• Cardiovascular: shock, unstable angina, significant aortic stenosis,
bradycardia, heart failure, etc.
• Avoidance of grapefruit juice with felodipine, lacidipine, lercanidipine,
nicardipine, nifedipine, nimodipine and verapamil. This may affect
metabolism.
• Sudden withdrawal of CCBs may exacerbate angina.
• These are best considered under each individual drug.