TREATMENT OF ANGINA AND MYOCARDIAL INFARCTION

ZHIYAR MUHAMMADNAZIF IBRAHIM

PARWEEN DLOVAN MUHAMMAD

TABAN FADHIL NABI

BASNA KAMAL MUHAMMADSUPERVISED BY :

Dr. chro

Dr. suzan

Prepared by: Supervised by

What is angina pectoris??

Types of angina?

Myocardial infarctionMyocardial cell death due to prolonged ischemia

Antianginal Drugs

Principle of action:• Angina can be viewed as a problem of

oxygen supply and demand , so these drugs will either increase supply of oxygen and nutrients of reduce myocardial oxygen demand or both.

Supply can be increased by :1*dilating coronary artery2*slowing the heart (coronary flow, uniquely occurs in diastole, which lengthens as heart rate falls).Demand can be reduced by :1*reducing afterload (i.e. reducing peripheral resistance) Reducing the work of heart in perfusing the tissues.2*reducing preload( i.e. venous filling pressure ) according to starling's law of the heart, workload and oxygen demand varies with stretch of cardiac muscle fibers3*slowing the heart

Classification:1- NITRATES:

a)Short acting: glyceryl trinitrate( GTN, nitrogylerine)

b)Long acting : isosorbide dinitrate (if given sublingually its short acting),

isosorbide mononitrate,erythrityl tetranitrate, pentaerythritol tertanitrate.

2- B BLOCKERS: propranolol, metoprolol, atenolol , carvidelol and others

3- CALCIUM CHANNEL BLOCKERS:

a)Dihydropyridines : nefidepine, nicardepine, felodepine, amlodepine,

nitrendepine, lercanidepine, benidepine.

b)Non dihydropyridines: verapamil, diltiazem

4-POTASSIUM CHANNEL OPENER: nicorandil

5-Antiplatelet Drugs: Aspirin , Warfarin (Coumadin

Clopidogrel

6- OTHERS:

Dipyridamole,trimetazidine,ranolazine,oxyphedrine

1-NITRATES AND NITRITES

Are simple nitric and nitrous acid esters of glycerol

Classification of nitrates:1. Rapidly acting nitrates

* used to terminate acute attack of angina

* e.g.- Nitroglycerin and Amyl nitrate

* usually administered sublingually

2. Long acting nitrates

* used to prevent an attack of angina

* e.g. -Erythrytyl tetranitrate, Isosorbide dinitrate, Pentaerythrytol tetranitrate

* administered orally or topically

pharmacokinetics

• The onset of action varies from 1 minute as in

nitroglycerine to one hour as in isosorbide mononitrate

• Nitroglycerine undergoes significant first pass

metabolism in the liver so its given sublingually or as

transdermal patches

• The stability of isosorbide mononitrate against liver

break down gives it its long duration of action and high

bioavailability

• Isosorbide dinitrate gives 2 molecules of isosorbide

mononitrate in the body

• The onset of action varies from 1 minute as in

nitroglycerine to one hour as in isosorbide mononitrate

• Nitroglycerine undergoes significant first pass

metabolism in the liver so its given sublingually or as

transdermal patches

• The stability of isosorbide mononitrate against liver

break down gives it its long duration of action and high

bioavailability

• Isosorbide dinitrate gives 2 molecules of isosorbide

mononitrate in the body

EFFECTS

Coronary artery dilatation

Decrease coronary bed resistance

( Relieved coronary vasospasm)

Increase coronary blood flow

Increase oxygen supply

Reduction on peripheral resistance

(Secondary to dilatation of aorta)

Decrease blood pressure

Decrease after load

Decrease workload

Decrease oxygen consumption

Reduced venous return(Due to dilatation of the veins)

Decrease left ventricular volume

Decrease preload

Decrease workload

Decrease oxygen consumption

ADVERSE EFFECT

1. Throbbing headache

2. Flushing of the face

3. Dizziness – especially at the beginning

of treatment

4. Postural Hypotension – due to pooling of

blood in the dependent portion of the

body

Tolerance

• Tolerance to the action of nitrates develop rapidly in

which blood

• vessels will be desensitized to the vasodilatory effect of

the drug.

• Tolerance can be overcome by a daily nitrate free

interval which is typically of 8 to 12 hours.

• Nitrate free interval is usually at night as the oxygen

demand increase

• But in variant angina which worsen during early morning

due to the circadian catecholamin attack the nitrate free

interval should be at late afternoon.

Tolerance to the Antianginal and

hemodynamic effects of nitrates develops:

higher doses

Drugs have longer half-lives.

It is common in patients being treated with

topical, transdermal or continuous i.v.

infusions

MECHANISM OF ACTION

1. Sublingual route 2. Oral route 3. Intravenous Route 4. Topical route

ROUTES OF ADMINISTRATION

NITROGYLECERINE

-Prototypical nitrate

-Large first-pass effect with PO forms

-Used for symptomatic treatment of ischemic heart conditions (angina)

-IV form used for

• BP control in perioperative hypertension.

• treatment of CHF.

• ischemic pain.

• pulmonary edema associated with acute MI.

Drug interaction

with cGMP-dependent phosphodiesterase

inhibitors (e.g., sildenafil ).

The reason for this adverse reaction is that

nitrodilators stimulate cGMP production and drugs

like sildenafil inhibit cGMP degradation. When

combined, these two drug classes greatly

potentiate cGMP levels, which can lead to

hypotension and impaired coronary perfusion.

CONTRAINDICATION

1. Renal ischemia

2. Acute myocardial infarction

3. Patients receiving other antihypertensive agent

2-B BLOCKERS

atenolol (Tenormin)metoprolol (Lopressor)propranolol (Inderal)nadolol (Corgard)

2 types : non selective and cardioselective

pharmacokinetics

B blockers are orally active.

Propranolol undergoes significant first pass

metabolism

They may take several weeks to develop

full effect

B-BlockersDecrease heart rate & Contractility

Increase duration of diastole

Increase coronary blood flow

Increase oxygen supply

Decrease workload

Decrease O2 consumption

Side effects

Bradycardia

CNS side effects as fatigue, lethargy, insomnia and hallucination.

Hypotension

Decrease in libido

Decreases serum HDL and increases TG

Withdrawal syndrome : rebound hypertension

CONTRAINDICATION

1. Congestive heart failure

2. Asthma and COPD

3. Complete heart block

4. Patients with bradycardia

5.  patients with history of cocaine use or in cocaine-induced tachycardia or MI.

ATENOLOL (TENORMIN)

Atenolol is a selective β1 receptor antagonist

PHARMAKOKINETICS

tcmax = 2 to 4 hours after oral

The mean elimination half-life is 6 hours. However, the action of the usual oral dose of 25 to 100 mg lasts over a period of 24 hours.

Atenolol is a hydrophilic drug. The concentration found in brain tissue is approximately 15% of the plasma concentration only. The drug crosses the placenta barrier freely. In the milk of breastfeeding mothers, approximately 3 times the plasma concentrations are measured.

Atenolol is almost exclusively eliminated renally and is well removable by dialysis. A compromised liver function does not lead to higher peak-activity and/or a longer half-life with possible accumulation.

Ca - Channel Blockers

a)Dihydropyridines : nefidepine, nicardepine, felodepine, amlodepine, nitrendepine, lercanidepine, benidepine.

b)Non dihydropyridines: verapamil, diltiazem

Effects1. Coronary artery

dilatation

2. Reduction on peripheral arterial resistance – decrease after load

Coronary artery dilatation

Decrease coronary bed resistance

( Relieved coronary vasospasm)

Increase coronary blood flow

Increase oxygen supply

Reduction on peripheral resistance

(Secondary to dilatation of aorta)

Decrease blood pressure

Decrease after load

Decrease workload

Decrease oxygen consumption

Pharmacokinetics:

Calcium channel blockers are well absorbed form GIT and their bioavailability depends on the extent of first pass metabolism in the gut wall and liver which varies between the drugs.

Interaction:

- Both diltiazem and verapamil cause increase to exposure to carbamazepine ,quinidine and metoprolol. -Verapamil increase plasma concentration of digoxin.

Most commonly used Ca Channel Blockers:

verapamil (Calan)diltiazem (Cardizem)nifedipine (Procardia

NEFIDEPINE

• Nifedipine, a dihydropyridine derivative, functions mainly as an arteriolar vasodilator. This drug has minimal effect on cardiac conduction or heart rate.

• Other members of this class, amlodipine, nicardipine, and felodipine, have similar cardiovascular characteristics except for amlodipine, which does not affect heart rate or cardiac output.

• Nifedipine is administered orally, usually as extended-release tablets.

• It undergoes hepatic metabolism to products that are eliminated in both urine and the feces.

• The vasodilation effect of nifedipine is useful in the treatment of variant angina caused by spontaneous coronary spasm.

verapamil

The diphenylalkylamine verapamil slows cardiac atrioventricular (AV) conduction directly, and decreases heart rate, contractility, blood pressure, and oxygen demand.

Verapamil causes greater negative inotropic effects than nifedipine, but it is a weaker vasodilator.

_The drug is extensively metabolized by the liver; therefore, care must be taken to adjust the dose in patients with liver dysfunction.

ADVERSE EFFECT

Contraindication

Cardiogenic shock. Recent myocardial infarction. Heart failure. Atrioventricular block. in patients with preexisting

depressed cardiac function or AV conduction abnormalities.

In hypotensive patients.

Combination Therapy

Nitrates and b blockers : to prevent the reflex tachycardia produced by nitrates

Ca channel blockers with b blockers for same reason

Ca channel blockers and Nitrates

Nitrates reduce preload and after load

Ca channels reduces the after load

Net effect is on reduction of oxygen demand

STABLE ANGINA

NITRATES , CALCIUM CHANNEL BLOCKER AND B BLOCKERSUNSTABLE ANGINA

NITRATES & CALCIUM CHANNEL BLOCKERVARIANT ANGINA

NITRATES & CALCIUM CHANNEL BLOCKER

4 -POTASSIUM CHANNEL OPENER

NICORANDIL : an effective vasodilator through 2 actions:

1-it acts as nitrates by activating cGMP.

2- opens ATP dependent potassium channels. Leading to hyperpolarization and relaxation of vascular smooth muscle.

Its given orally as an alternative to nitrates incase of tolerance .

Adverse effect : similar to those of nitrates with headache in 35% of patients.

contraindication

People with low blood pressure.

People with cardiogenic shock.

People with heart failure with low filling pressure.

People using drugs for impotence such as sildenafil & tadalafil.

In pregnancy.

In breastfeeding.

PharmacokineticNicorandil is well absorbed with no significant first pass metabolism, metabolism is mainly by denitration into nicotinamide pathway and less than 20% is excreted into urine.

5-ANTIPLATELETS

1-Aspirin-inhibits synthesis of prostacyclin and thromboxane A2- prevent platelet aggregation- decrease thrombosisIndications- several. For angina- primarily used to prevent MI in patients with unstable angina

2-Other agentsClopidogrel (Plavix)- in place of aspirin

Warfarin (Coumadin)

ASPIRIN

WARFARIN

Myocardial infarction

Goals of treatmentThe most important goal of drug therapy early in the course of acute myocardial infarction is to improve the oxygen supply/demand ratio for the heart. The reduction in this ratio that occurs when coronary flow is compromised is the primary reason cardiac function is impaired, which leads to the clinical signs associated with myocardial infarction. There are two strategies to improve the coronary supply/demand ratio, 1) restore normal coronary blood flow.2) decrease myocardial oxygen consumption.

Further treatment is based on the following:

Restoration of the balance between the oxygen supply and demand to prevent further ischemia

Pain relief

Prevention and treatment of any complications that may arise

Classes of Drugs Used to Treat Myocardial Infarction

1•Vasodilators (dilate arteries and veins)- nitrodilators- angiotensin converting enzyme inhibitors (ACE inhibitors)- angiotensin receptor blockers (ARBs)

2•Cardiac depressant drugs (reduce heart rate and contractility)- beta-blockers

3•Antiarrhythmics (if necessary)

4•Anti-thrombotics (prevent thrombus formation)- anticoagulant- anti-platelet drugs

5•Thrombolytics (dissolve clots - i.e., "clot busters")- plasminogen activators

6•Analgesics (reduce pain)- morphine

ACEI(angiotensin converting enzyme inhibitors)

Cardiorenal Effects of ACE Inhibitors

Vasodilation (arterial & venous)- reduce arterial & venous pressure- reduce ventricular afterload & preload

Decrease blood volume- natriuretic- diuretic

Depress sympathetic activity

Inhibit cardiac and vascular hypertrophy

Specific Drugs

• benazepril• captopril• enalapril• fosinopril• lisinopril• moexipril• quinapril• ramipril

Note that each of the ACE inhibitors named above end with "pril".

captopril

Captopril is a potent, competitive inhibitor of angiotensin-converting enzyme (ACE), the enzyme responsible for the conversion of angiotensin I (ATI) to angiotensin II (ATII). ATII regulates blood pressure and is a key component of the renin-angiotensin-aldosterone system (RAAS).

PharmacokineticsAbout 70% of orally administered

captopril is absorbed. Bioavailability is reduced by presence of food in stomach. It is partly metabolized and partly excreted unchanged in urine.

Adverse reactions

CNS: headache, dizziness, drowsiness, fatigue, weakness, insomnia

CV: angina pectoris, tachycardia, hypotension

EENT: sinusitis

GI: nausea, diarrhea, anorexia

GU: proteinuria, erectile dysfunction, gynecomastia, renal failure

Hematologic: anemia, agranulocytosis, leukopenia, pancytopenia, thrombocytopenia

Metabolic: hyperkalemia

Respiratory: cough, asthma, bronchitis, dyspnea, eosinophilic pneumonitis

Skin: rash, angioedema

Other: altered taste, fever

contraindication

Hypersensitivity to drug or other ACE inhibitors

Angioedema (hereditary or

Idiopathic)

Pregnancy

Angiotensin receptor blockers

Specific Drugs

• candesartan• eprosartan• irbesartan• losartan• olmesartan• telmisartan• valsartan

Note that each of the ARBs named above ends with "sartan."

Losartan

Losartan is an oral medication that belongs to a class of drugs called angiotensin receptor blockers (ARBs)

Losartan (more specifically, the chemical formed when the liver converts the inactive losartan into its active form) blocks the angiotensin receptor. By blocking the action of angiotensin, losartan relaxes muscle cells and dilates blood vessels thereby reducing blood pressure.

Losartan was approved by the FDA in April 1995.

Adverse effect

CNS: dizziness, insomnia, headache, asthenia, fatigue

CV: hypotension

EENT: sinus disorders

GI: nausea, vomiting, diarrhea, dyspepsia, abdominal pain

Metabolic: hyperkalemia

Musculoskeletal: joint pain, back pain, muscle cramps

Respiratory: symptoms of upper respiratory infection, dry cough

Other: hypersensitivity reactions including angioedema

Contraindications• Hypersensitivity to drug or its components

INTERACTION

Drug-drug. Diuretics, other antihypertensives: increased risk of hypotension

Fluconazole: inhibited losartan metabolism, increased antihypertensive effects

Indomethacin: decreased losartan effects

Phenobarbital, rifamycins: enhanced losartan metabolism, decreased antihypertensive effects

Potassium-sparing diuretics, potassium supplements: hyperkalemia

Drug-diagnostic tests. Albumin: increased level

Drug-food. Salt substitutes containing potassium: hyperkalemia

Beta-adrenergic receptor blocking agents (beta-blockers) are drugs with multiple actions on the heart. Blockade of beta-1 receptors results in slowing of heart rate, reduction in myocardial contractility, and lowering of systemic blood pressure. In the context of acute myocardial infarction (AMI), which represents a state of reduced oxygen supply to the affected portion of the heart, these effects may be beneficial as they result in reduced myocardial workload and oxygen demand. Furthermore, beta-blockers may reduce the risk of ventricular arrhythmias, which are an important cause of death following AMI.

B BLOCKERS IN MI

nadololpropranololtimololatenololMetoprololcarvidelol

carvidelol

Reduces morbidity and mortalility rate due to myocardial infarction its called third generation b locker because of its effects:Inhibits lipid peroxidationInhibits release of free radicals from

neutrophilsScavenger of free radicals

Side effects

slow or uneven heartbeats;

feeling light-headed, fainting;

feeling short of breath, even with mild exertion;

swelling of your ankles or feet;

nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing...

Antiarrhythmic Drugs

• The aim is to restore normal rhythm and conduction. And prevent arrhythmias that follow MI

Quinidine

Procainamide

Disopyramide

• Used to:

Decrease/increase conduction velocity.

Alter the excitability of cardiac cells by changing the duration of the effective refractory period.

Suppress abnormal automaticity.

Quinidine

Antiarrythmic drug

Na Channel Blocker

Decreases speed of electrical current that travels through heart muscle.

Prolongs period during which heart muscle cells become electrically stimulated to contract.

Prolongs recovery period after contraction.

Given: Orally

Side Effects: • Vomiting• Headache• Dizziness• Chest Pain

Drug Interactions: SaquinavirIncrease Quinidine levels by inhibiting removal of Quinidine by liver. 

Contraindications:Patients with Heart Failure

Thrombolytic Drugs

Used to dissolve blood clots.

The thrombolytic drugs include:

tissue plasminogen activator t-PA:

alteplase (Activase)

reteplase (Retavase)

tenecteplase (TNKase)

anistreplase (Eminase)

streptokinase (Kabikinase, Streptase)

urokinase (Abbokinase)

Streptokinase & Mechanism of Action

• Given by: Injection

• Side Effects• Low Blood Pressure• Nausea• Headache• Easy Bruising

Drug Interaction: • Aprotinin• Reverses effect of Streptokinase

Contraindications: • Injury & Trauma

Analgesics

Used to reduce pain.

CLASSES:

Paracetamol and NSAIDs

COX-2 inhibitors

Opiates and morphinomimetics

Flupirtine

Combinations

Morphine

Powerful Narcotic Analgesic.

Mechanism of Action:

Acts on Opioid receptors in brain.

Binds to & inhibits GABA inhibitory interneurons.

Inhibits pain.

Given: Orally/ Injection

Side Effects:• Slow breathing• Slow heartbeat• Sedation• Confusion

Drug Interactions: Sedatives that make you sleepy and slow your breathing.

Contraindications:In alcoholic patients which can lead to increased sedation & death.

THANK YOU

references

Richard D. howland , Mary J. Mycek.2000. pharmacology.USA. Williams & wilkins.

Rand,Dale,Ritter,Moore.2004. pharmacology.Uk.churchil livingstone, Elsevier limited.

Bertram Katzung.2007.basic and clinical pharmacology.singapore.McGRawHill.

http://www.cvpharmacology.com/clinical%20topics/angina.htm

http://www.cvpharmacology.com/Angina/antianginal.htm

http://www.cvpharmacology.com/vasodilator/vasodilators.htm

http://www.cvpharmacology.com/vasodilator/ACE.ht

m

http://www.cvpharmacology.com/antiarrhy/antiarrhythmic.htm http://www.medicinenet.com/quinidine/article.htm http://www.medicinenet.com/streptokinase-injection/article.htm http://www.cvpharmacology.com/thrombolytic/thrombolytic.htm

 http://www.medterms.com/script/main/art.asp?articlekey=10223 http://www.everydayhealth.com/drugs/morphine http://www.rochester.edu/uhs/healthtopics/Alcohol/interactions.html

http:/drugs.webmd.boots.com/drugs/drug-328-nicorandil.aspx?