Antianginal Drugs

Prepared for

Mr. Apurba Sarker Apu

Senior Lecturer

Dept. of Pharmacy

East West University

Prepared by

Md. Shahariar Sadat 2006-3-70-014

Md. Regouanur Rahman 2007-3-70-016

Rahat Shams 2007-3-70-058

Md. Shaidur Rahman Chowdhury 2007-3-70-075

Quazi Tanzeem-Ul-Haque 2007-3-70-060

An antianginal drug is any agent which are used in the treatment of angina pectoris.

Angina Pectoris

Angina pectoris is a clinical syndrome characterized by episodes of chest pain.

It occurs when there is a deficit in myocardial oxygen supply in relation to myocardial oxygen demand.

Caused by atherosclerotic plaque in the coronary arteries but may also be caused by coronary vasospasm.

Angina Pectoris

Located substernally but sometimes perceived in the neck, shoulder or epigastrium

Primarily caused by imbalance between the oxygen requirement of the heart and oxygen supplied to it by the coronary vessels

Types of Angina

1.Classic Angina

2.Variant Angina

3.Unstable Angina

Pathophysiology of AnginaTherapeutic strategies

The defect that causes anginal pain is inadequate O2 delivery relative to myocardial oxygen requirement

Can be corrected in 3 ways

1. Increasing O2 delivery

2. Reducing O2 requirement

3. Efficiency of O2 utilization

Pathophysiology of Angina

Newer investigational approachShifting the energy substrate

reference of the heart from fatty acid to glucose

Partial fatty acid oxidation inhibitors (e.g., Ranolazine, Trimetazidine)

Treatment of Angina

NITRATES

CALCIUM CHANNEL BLOCKERS

BETA BLOCKERS

NITRATES

NITROGLYCERINE (NTG) Active ingredient in dynamite Most important of the nitrates Available forms

Sublingual (10-20 min) Transferal (8-10 h)

Effect of sublingual NTG results from unchanged drug because it avoids first-pass effect

NITRATES

Rapidly denitrated in the liver and smooth muscle

Nitroglycerin (Glyceryl) Dinitrate Mononitrate

First-pass effect is 90% (because of high enzyme activity in the liver)

Efficacy of oral (swallowed) NTG results from high levels of glyceryl dinitrate (which have a significant vasodilating effect)

NITRATES

Mechanism of Action

Denitration causes release of nitric oxide (NO) within smooth muscle cells which stimulates guanyl cyclase and causes an increase in cGMP leading to smooth muscle relaxation

NITRATES

Isosorbide DinitrateAnother commonly used nitrateAvailable in sublingual and oral formRapidly denitrated in the liver and smooth muscle

to isosorbide mononitrate which is also active

NITRATES

Isosorbide Mononitrate

Available as a separate drug

Oral form

Amyl Nitrite

•Volatile and rapidly acting vasodilator• Inhalational route•Rarely prescribed

NITRATESOrgan System Effects

1. Cardiovascular System

Smooth muscle relaxation

peripheral venodilation

reduced cardiac size and CO through reduced preload

Reduced afterload because of arteriolar dilation

increase in ejection and further decrease in cardiac size

Sensitivity veins >> arteries > arterioles

NITRATES

Venodilation decreased diastolic heart size and fiber tension

Arteriolar dilation reduced peripheral resistance and BP

Overall reduction in myocardial fiber tension, O2 consumption and double product

No direct effects on the cardiac muscle Can cause reflex tachycardia and increased

force of contraction when reducing BP

NITRATES

2. Other smooth muscle effect Relaxation of the smooth muscle of the bronchi, GIT,

GUT Effects are too small to be clinically significant

3. Action on platelets Decrease platelet aggregation

4. Nitrite ion + hemoglobin methemoglobin Methemoglobin has low affinity for oxygen Pseudocyanosis, tissue hypoxia, death

NITRATESClinical Uses

1. Sublingual tabletStandard form for treatment of acute anginal

pain Duration of action 10-30 minutes

 

2. Oral (Swallowed)Normal-releaseDuration of action 4-6 hoursSustained-releaseLonger duration

NITRATES

3.Transferal formulations:

Ointment or patchMaintains blood level up to 24 hoursTolerance develops after 8-10 hours with rapidly

diminishing effectivenessRemove after 10-12 hours to allow recovery of

sensitivity to the drug

NITRATES

Toxicities

Tachycardia (baroreceptor reflex)Orthostatic hypotension Throbbing headache (from meningeal artery

vasodilatation)Interact with Sildenafil (Viagra) and similar drugs

promoted for erectile dysfunctionSynergistic relaxation of vascular smooth muscle

with potentially dangerous hypotension and hypoperfusion of critical

Calcium Channel Blockers

Nifedipine, Dihydropyridine, Diltiazem, VerapamilDiffer markedly in structure but all are orally active with

half-lives of 3-6 hoursNimodipine

Member of the dihydropyridine familyApproved only for the treatment of stroke associated with

subarachnoid hemorrhageBepridil

Similar structure to verapamil, Longer duration of action, Greater cardiovascular toxicity

Chemistry of Ca++ Channel Blockers

Five major classes of Ca++ channel blockers are known with diverse chemical structures:

1. Benzothiazepines: Diltiazem2. Dihydropyridines: Nicardipine, nifedipine,

nimodipine, amlodipine, and many others. There are also dihydropyridine Ca++-channel activators (Bay K 8644, S 202 791)

3. Phenylalkylamines: Verapamil4. Diarylaminopropylamine ethers: Bepridil5. Benzimidazole-substituted tetralines: Mibefradil

Calcium Channel Blockers

Mechanism of ActionBlock voltage-gated “L-type” calcium channels

(channel most important in cardiac and smooth muscle)

Reduce intracellular calcium concentration and muscle contractility

Mibefradil Blocks cardiac “T-type” and “L-type” channels

SAR of Calcium Channel Blockers

In phenyldihydropyridine derivatives the structural features essential for

activity are:

(a)the dihydropyridine ring;

(b)the secondary nitrogen in the ring; this N remains uncharged at

physiological pH; and

(c)a bulky substituent (such as phenyl) in the 4-position of the heterocycle.

On the other side, the nitro group and the ester moieties are nonessentials.

Amlodipine

In Verapamil and related drugs the essentials features are:

(a) the benzene ring,

(b) a tertiary amino nitrogen, which is almost completely

charged at physiological pH.

(c) The isopropyl group and the ring substituents are not

essential for activity.

Verapamil hydrochloride

CALCIUM CHANNEL BLOCKERS

EffectsRelax blood vessels, and to a lesser extent, the

uterus, bronchi and the gut

Diltiazem and Verapamil ● Reduce cardiac rate and contractility (block Ca-

dependent conduction in the AV node of the heart)● May be used to treat AV nodal arrythmia

Nifedipine and other dihydropyridines ● Evoke greater vasodilation ● The resulting sympathetic reflex prevents

bradycardia and increases heart rate

CALCIUM CHANNEL BLOCKERS

Clinical Use

Nifedipine has also been used to abort acute anginal attacksCombined with nitrates in the treatment of atherosclerotic

anginaMigrainePreterm laborStrokeRaynaud’s phenomenonProphylactic therapy in effort and vasospastic anginaNimodipine is used for hemorrhagic stroke

CALCIUM CHANNEL BLOCKERS

Toxicities

Constipation, pretibial edema, nausea flushing and dizziness

Heart failure, AV blockade and sinus node depression (Verapamil)

BETA BLOCKING DRUGS

β-BlockersProphylaxis of atherosclerotic anginal attacksReduce the double product

EffectsBeneficial effects

Decreased heart rateDecreased cardiac forceDecreased BP

Detrimental effectsIncreased heart sizeLonger ejection period

BETA BLOCKING DRUGS

Clinical Use

Only for prophylactic therapyNo value for acute attacksPrevents exercise-induced angina but not the

vasospastic formCombination with nitrates reduces the undesirable

compensatory effects like tachycardia and increased cardiac force

BETA BLOCKING DRUGS

Nonpharmacologic Therapy

Myocardial revascularization Coronary artery bypass grafting (CABG) Percutanous transluminal coronary angioplasty

(PTCA)Increase coronary flow in atherosclerotic angina

SAR for Beta Blockers

1. The O-CH2 group between aromatic ring and the ethylamino side chain is responsible for the antagonistic property.

2. Replacement of catechol hydroxyl group with chlorine or phenyl ring retains the beta blocking activity.

3. N,N- di substitution decrease beta blocking activity. Activity is maintained when phenylethyl, hydroxyl phenyl ethyl or methoxy phenyl ethyl groups are added to amine as a part of molecule.

4. The two carbon side chain is essential for the activity.

5. Nitrogen atom should be of secondary amine for optimum

beta blocking activity.

6. The carbon side chain having hydroxyl group must be S-

configuration for optimum affinity to beta receptor.(Ex-

Levobunolol, Timolol).

7. The aryloxy propanolamines are more potent than aryl

ethanolamines.

8. Replacement of ethereal oxygen in aryloxy propanolamines

with S, CH2 or N-CH3 is decreased the beta blocking activity.

9. The most effective substituents at amino group is

isopropyl and tertiary butyl group.

10. The aromatic portion of the molecules could be varied

with good activity.

11. Converting the aromatic portion to phenanthrene or

anthracene decrease the activity.

12. Cyclic alkyl substituents are better than corresponding

open chain substituents at nitrogen atom of amine.

13. Alpha methyl group at side chain decrease activity.

Adverse Effects & Contraindications

May exacerbate heart failureContraindicated in patients with asthmaShould be used with caution in patients with

diabetes since hypoglycemia-induced tachycardia can be blunted or blocked

May depress contractility and heart rate and produce AV block in patients receiving non-dihydropyridine calcium channel blockers (i.e. verapamil and diltiazem)

Combination Therapy of AnginaGood Ones:

● A dihydropyridine calcium channel blocker and a beta-blocker-

coronary vasodilation, decreased afterload, lower heart rate, suppression of reflex tachycardia

● A nitrovasodilator and a beta-blocker- coronary vasodilation, decreased preload, lower heart rate, suppression of reflex tachycardia

●A nitrovasodilator and a non-dihydropyridine calcium channel blocker- coronary vasodilation, decreased preload and afterload, lower heart rate, suppression of reflex tachycardia

●A nitrovasodilator, a dihydropyridine calcium channel blocker, and a beta-blocker-coronary vasodilation, decreased preload and afterload, lower heart rate, suppression of reflex tachycardia

●Bad Ones:A beta-blocker and non-dihydropyridine calcium channel blocker bradycardia, AV block, depressed LV function

Additional consideration in treating Angina

Modify risk factors associated with atherosclerosis (smoking, hypertension, hyperlidemia)

Statins can reduce coronary artery disease in some patients

Patients with stable angina who are refractory to drug therapy may require surgical revascularization (bypass) or angioplasty

Patients with vasospastic angina are not good candidates for these surgical procedures

● Unstable angina is an acute coronary syndrome that may require maximally tolerated doses of conventional antianginal drugs, and additional drugs including:

1. Antiplatelet drugs (aspirin, platelet glycoprotein IIB/IIIA inhibitors, and/or platelet ADP antagonists)

2.Thrombolytic drugs (tissue plasminogen activator, streptokinase, or similar fibrinolytic agent)

3.Heparinoid anticoagulants including heparin or low molecular weight heparins

4.Surgical revascularization or angioplasty is often required in these patients