Download - Antianginal Drugs
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