Coronary Vascular insufficiency (Ischemic Heart Disease)

Coronary V. Insufficiency
Disease of coronary artery is almost due to atheroma and its complications particularly thrombosis. Clinical manifistation: 1. Stable angina 2. Unstable angina 3. Myocardial Infarction M.I. 4. Heart Failure 5. Arrhythmia

Angina Pectoris: Chest pain due to myocardial ischemia. Ischemia occurs when there is imbalance between myocardial oxygen supply ( coronary blood flow) and myocardial oxygen demand ( myocardial work)
Imbalance between

Decrease oxygen supply due to fixed atherosclerotic narrowing Increase Oxygen Demand due to increase heart rate, Increase ventricular contraction, exercise, emotional stress.

Types of Angina
1. Classic, effort, stable angina present with retrosternal pain, transient 2-5 min precipitated by exertion and RELIVED BY REST. 2. Unstable angina Prolonged severe chest pain or pain at rest. It is a rapid worsening angina that may progress to M.I. * Myocardial infarction: is due to the death of an area of myocardium due to prolonged ischemia more than 15 min induced by coronary thrombosis. Present by severe prolonged pain pallor, breathlessness, vomiting, collapse, hypotension and bradycardia ( vagus stimulation).
3. Vasospastic, Variant angina: Transient spasm present with acute episode of coronary artery spasm with severe chest pain AT REST

Causes of Angina

1. Fixed athermatous narrowing of large coronary vessels (common). { Stable (effort) angina, Unstable (resting) angina } 2. Transient spasm of localized portion of coronary vessels with / without atheroma (less common) (vasospastic, variant, prinzmetals angina)

Coronary V. Insufficiency
30% Narrowing 50% Narrowing 70% Narrowing

No Angina

Potential of Angina 99% Obstruction

Stable Angina

100% Obstruction

Unstable Angina

Occlusion M.I.

General Goals Of Anti anginal Therapy

1. To Increase Oxygen delivery to the myocardium & increase coronary perfusion . vasodilators (e.g. nitrates &nifedipine) OR 2. To decrease Oxygen demand. By drugs which depress the cardiac work (e.g CCB or B-blockers)

Determinants of Myocardial oxygen demand

Preload
Depend and venous tone

After load
ABP depends on PVR

Heart rate

Cardiac contractility

Management of Angina

1. Avoid risk factors Smoking, obesity, hypertension, diabetes, increased cholesterol level

2. Drug therapy Organic nitrates, CC blockers, Blockers, Aspirin Heparin

3. Invasive measures coronary bypass, or angioplasty

Organic nitrates

1. Increase myocardial oxygen supply a. Dilatation of large coronary vessels b. Redistributio n of coronary flow c. Dilatation of collaterals

2. Decrease of oxygen demand Decrease of cardiac work indirectly. a. Decrease preload (venodilators ). b. Decrease after load arteriolar dilators.

3. Antithrombotic action of Nitrates. Decrease platelets aggregation by virtue of increased synthesis of (c GMP)

Mechanism of Action of Nitrates (NO3-)

administered Nitrates
Glu tath tran ione S sfer ase

Nitrites NO2

Vascular smooth Muscle relaxation

Nitric oxide NO
Dephosphrylation of myosin light chain

cGMP

Preparations of nitrates

1. Rapid acting (acute attack) a. Nitroglycerine sublingual tablets or spray ( onset : 2 min, duration : 25 min) b. Isosorbid dinitrate sublingual( onset : 5 min,
duration : 1 hour)

2.Short & Long term (Prophylaxis) Nitroglycerine Oral, sustained release Isosorbid dinitrate tablets ( onset : 30 min) (duration : 8 hours) I. Nitroglycerine Transdermal Patch II. Isosorbid mononitrate ( onset : 30 min) (duration : 8 -14hours)

Used in all types of angina ( treatment and prophylactic)

Pharmacokinetics of nitrates

NG is well absorbed from GIT but undergoes extensive first- pass metabolism in the liver to inactive metabolites .So NG is given SL (0.5 mg. ) , buccal ,Transdermal ,&I.V. ( in acute attack ) Slow release (SR) oral preparations of NG (2.5mg-12.5mg ) as prophylactic. Isosorbide dinitrate also has extensive firstpass metabolism It has relatively longer duration of action than NG (it is metabolized to active ISMN )

Isosorbid 5-mononitrate is an active metabolite of ISD , it is not subjected to first-pass metabolism so used orally.

Therapeutic
uses a)In all types of Angina.

b)Congestive heart failure

Side effects: 1. Postural hypotension &reflex tachycardia .

Side Effects and Precaution s

2. Flushing 3. Throbbing headache 4. Visual disturbance 5. Drug rash 6. Nitrate Tolerance Precautions:

1. 8-10 hours nitrate free period 2. Never stop nitrate therapy suddenly 3. Do not take double dose 4. Do not use after expiry date.

Drug interaction :

Sever hypotension if Sildenafil (a potent PDEI )is given with nitrates .

CALCIUM CHANNEL BLOCKERS: 1-Non-dihydropyridines. 2-Dihydropyridines.

Calcium channel blockers What is their mechanism of action? Block calcium channels in the cardiac muscles and smooth muscle calcium influx decrease cardiac contractility and VSM relaxation.

non dihydropyridines e.g. verapamil&diltiazem .

1- They have mainly cardiac effect. They cause increase of coronary flow as they cause coronary dilatation . They decrease myocardial oxygen demand by decreasing cardiac work through their ve inotropic & chronotropic effects . 2-They have reduced vasodilator effect ( less reflex tachycardia suitable for hypotensive patient .

The dihydropyridines e.g. NIEDIPINE (LA) & AMLODIPINE .

They have mainly vascular effect : 1- They cause dilation of coronary artery so prevent or relief coronary vasospasm, and improve myocardial blood flow . 2- They cause arteriolar dilation so decreasing PR &cardiac work. 3-They have reduced ve inotropic & -ve chronotropic effect on the heart .

CCBs Mechanism of anti-ischemic action

arteriolar vascular resistance afterload myocardial contractility & heart rate with the use of verapamil and diltiazem

CCBs dilate the large epicardial vessels. 2 3. Prevent focal coronary artery spasm
primary cause of variant angin

What is the role of CCB in the treatment of angina?

myocardial oxygen demand

arteriolar vascular resistance afterload myocardial contractility & heart rate with the use of verapamil and diltiazem

myocardial oxygen supply

coronary dilatation

AMLODIPINE :

1- It is a long acting CCB. 2-It is slowly but completely absorbed from GIT . 3-Has very long half life of about 1 -2-days . 4- Reduces the ABP gradually & causes little reflex tachycardia .

Therapeutic causes of CCB .

1-Vasospastic angina .

2-Stable angina alone or in combination with blockers .

Beta blocking drugs Mechanism of anti-ischemic action

A.. Myocardial oxygen demands

1. Heart Rate ( resting & exercise HR) 2. Force of contraction 3. Blood pressure
B. Perfusion of ischemic areas by prolongation of diastole

-Adrenergic antagonists

Selective (preferred) Atenolol 50-100 mg / day Bisoprolol 5-10 mg / day Metoprolol S.R. 200 mg/ day

Non selective(not used )due to their B2 action. propranolol

COMBINATION OF ANTIANGINAL DRUGS:

1- Combination of B Blockers with nitrates and nifedipine to 1- increase the efficiency 2-decrease the dose of each drug 3- block the reflex tachycardia that occurs with theses drugs. (good combination) 2- Combination of B-blockers and verapamil is a bad combination, as it will potentiate the negative inotropic effect of verapamil which may lead to heart block. (bad combination )

VD
Nitrates
1. VD epicardial coronaries

Coronary Vessels )O2 supply(

VD
CCB

2. Redistribution to ischemic areas 3. VD collaterals

Preload
Nitrates

Heart Afterload Blockers (O2 demand) HR& CCB Contractility Nitrates

Blockers CCB
Effect of Anti-anginal drugs on myocardial O2 supply and work done by the heart (O2 demand)

Antiplatelet Drugs
Aspirin: Aspirin irreversibly inhibit COX (up to the life-time of the platelets 8-10 days). Both PGI2 and TXA2 synthesis are inhibited. Aspirin in small dose 75-100 mg/day inhibits TXA2 synthesis without significant effect on the endothelial PGI2. A/E: peptic ulcer bleeding in patients > 60 years.

Uses of antiplatele drugs: They are used in patient at high risk e.g. after angina pectoris, MI, atheroma or prothetic valves to protect against: Stroke, MI or death

ASPIRIN

It must be given to all cases of angina . In low doses 70 -150 mg /day it will decrease platelet aggregation . N.B. Loading dose is sometimes required for a rapid onset of effect ,chewed before swallowing to aid early absorption .

VASOSPASTIC OR VARIENT ANGINA .

In vasospastic angina : Nitates , CCB are the drugs of choice .

Unstable angina

UASTABLE ANGINA .

Better transfer to ICU or CCU.

MORPHIE-OXYGEN-NG-ASPIRINE. Aspirin as loading dose (150 -300 mg )

then small daily dose (75-150 mg/day ) . The addition of other anti platelet e.g.

Clopidogrel to aspirin is more effective . Full anticoagulation with heparin

produces additive benefit .

A adrenergic antagonist e.g.Metoprolol is first choice antianginl drugs .

Myocardial infarction . 1-Acute management .

Aim of therapy : 1-Pain relief . 2-Reperfusion of occluded artery . So drugs will include : Analgesics e.g. Diamorphine 2.5 -5 mg IV . SL nitrates (3 doses of nitroglycerine with 5m intervals) or IV nitrates . Aspirin 150- 300 mg orally (loading dose ) .Continue with Aspirin in small dose 75-150 mg/ day . Oxygen 60% facemask inhalation .

Thrombolytics : to induce clot lysis & restore blood flow e.g. streptokinase . Anti emetics.as myocardial patient suffer N &V during acute attack of MI. e.g. Metoclopramide -adrenergic antagonists IV 4-6 h s after MI reduce the infarct size & mortality . If thrombolytics are contraindicated surgery is indicated .

Define the initial drug to Define the initial drug to start with upon start with upon admission: Morphine admission:
Potent opiod analgesic that relives severe pain. Morphine pain a-To alleviate the Has anxiolytic effect. Dilates veins leading to decreased pulmonary venous congestion.

B-to stop progression of etiopathological cause

Fibrinolytics Inhibitors (e.g. streptokinase) lyse thrombus occluding artery

leading to revasclarization, since attack is within 1 Chewable aspirin 160 mg: because of hr. its antiplatelet effect .

Anticoagulants, e.g. heparin. Oxygen and IV fluids. Nitroglycerine IV infusion.

Beta blockers reduce the infarct size.

Myocardial infarction . Secondary prophylaxis .

Aim of therapy is to reduce mortality after MI . Stop smoking . Low dose aspirin 75-150 mg/ day reduces re occlusion of the vessels that undergoes natural or therapeutic thrombolysis .

adrenergic receptor antagonist started orally soon after the MI reduces later deaths and re infarction . ACEIs should be initiated within 24 hs after MI , they prevent HF after MI . Long term anticoagulant with warfarin reduces mortality & reinfarction . Cholesterol reduction .

Identify whether or not there is a place for ACE inhibitors. YES

To avoid post MI cardiac remodeli ng

If the patient is proved to be hypertensive.

Suggest whether there is a place for CCBs. Explain your reasons.

Nondihydropyrines have no place because of their negative inotropic effects. All dihydropyridines have no place because of their

vasodilatory effect-induced reflex tachycardia.(EXCEPT long acting e.g. amlodipine which can be used because being long acting they do not induce reflex tachycardia.

When the patient is discharged after being controlled Enumerate the drugs that the patient has to continue on , to prevent occurrence of a second attack.

ACEIs or ARBs Beta blockers Nitrates, e.g. isosorbide dinitrate Antiplatelets,e.g. aspirin

Oral anticoagulants ,e.g.warfarin Hypocholesterolo mic drugs ,e.g. statins Avoid smoking. Control diet.

Angioplasty

CABG

Drug in concomitant diseases Selection 1. None 2. Recent M.I. 3. Asthma COPD 4. Hypertension 5. Diabetes
L.N. Nitrates Blockers Blockers C.C.

x x

Case Study 1
1- A 56 year old patient C/O effort chest pain, he is diagnosed as atherosclerotic angina and prescribed SL NG for treatment of acute chest pain. Which of the following adverse effects is likely to be experienced by the patient: a) Hypertension b) Throbbing Headache Correct Answer = b) NG Causes Throbbing Headache in 30%-60% of Patients c) Bradycardia d) Sexual dysfunction

Case Study 1. ( Cont.)

The patient is also prescribed metoprolol to prevent episodes of angina, The B-blocker has the added benefit of preventing which of the following side effects of SL NG ?

a) Dizziness

Correct Answer = d) b) Methemoglobinemia NG Causes Reflex tachycardia due to its vasodilatation. c) Throbbing Headache d) Reflex tachycardia

Case Study 2
A 68 year old patient was successfully treated for exercise induced angina for several years. Recently he has CO of chest pain at night. Which of the following drugs will be useful in preventing this patients nocturnal angina? a) Hydralazine b) Nitroglycerin (SL) Correct Answer = C) Transdermal NG(transdermal) level for 24 hours c) Nitroglycerin sustains blood d) Propranolol

MCQs:
1- Metoprolol decrease the anginal attacks by the following mechanisms except: a) Decrease myocardial contractility b) Decrease heart rate c) Dilates coronary blood vessels d) Decrease the arterial blood pressure

Correct Answer = C) Metoprolol is not coronary vasodilator

MCQs:
2- Which of the following drugs is considered to be most effective in relieving & preventing ischemic episodes in patients with variant angina? a)Metoprolol b) Nitroglycerine c) Sodium Nitroprusside d) Amlodepine (Nifedipine) Amlodepine

I-MENTION
A-Why the combined use of beta blockers and nitrates can be very effective in treatment of typical angina?
This combination is a useful combination because: The two effects of the drugs synergize , allowing lower doses of each drug to be used. Beta blockers decrease the rate and force of contraction and nitrates decrease cardiac preload and afterload ;both . Myocardial O2 consumption. The compensatory sympathetic reflexes produced by nitrates are inhibited by beta blockers.

I-MENTION
c-Drug of choice in treatment of hypertension and ischemic heart disease Beta blockers: Treat both hypertension (by its antihypertensive effects) and IHD( by its antianginal effects).

5-Match the following antianginals to their mechanism of action:

1.Glyceryl trinitrate(b) a-By decreasing sympathetic tone to the heart 1.Glyceryl trinitrate a-By decreasing sympathetic tone to the heart 2. Propranolol. ( a) b.By reducing cardiac work load. 2. Propranolol.(c) B.By reducing cardiac work Ca by myocardial cel 3. Verapamil. c.By inhibiting uptake of load. 3. Verapamil. C.By inhibiting uptake of Ca by myocardial cells

7.All of the following statements concerning nitroglycerine are correct EXCEPT: a. It causes elevation of intracellular cGMP. b. It causes significant first pass metabolism in the liver. c. It may cause reflex tachycardia. d.It significantly decreases AV conduction. e-It can cause postural hypotension.

V-MARK TRUE (T) OR FALSE (F) and correct the false

1. All organic nitrate esters undergo significant renal excretion which accounts for their short half lives. undergo significant hepatic metabolism 2.Isosorbide dinitrate is a fully nitrated compound, which can be metabolized to an active metabolite. 3.Development of tolerance to the organic nitrates can be avoided by intermittent therapy. 4.Typical angina is usually not associated with atherosclerosis. is usually associated

V-MARK TRUE (T) OR FALSE (F) and correct the false

5. The vasodilatory effects of organic nitrates are greater in arterioles than in veins. than arterioles greater in veins 6.Abrupt withdrawal from long term nitrate therapy can lead to myocardial ischemia, infarction or death. 7.Beta blockers are especially effective in vasospastic angina. contraindicated in vasospastic angin 8.Organic nitrates decrease oxygen demand of the heart by their direct negative inotropic and decrease . chronotropic effectsoxygen demand of heart by indirect e

T F

VI.Choose the correct answer: 1-All of the following statements describing the cardiovascular effects of organic nitrates are true EXCEPT:
a-They reduce myocardial work by decreasing preload and afterload. b.They selectively dilate large epicardial vessels without impairment of autoregulation in small vessels. c.They are effective in relieving all three types of angina. d.They directly alter the inotropic and chronotropic state of the heart.

Choose the correct answer: 2-All of the following are rational drug combinations for the treatment of typical angina EXCEPT:
a-Nitroglycerine and nifedipine. b.Verapamil and propranolol. c.Nitroglycerine and propranolol. d. Nifedipine and propranolol.

Choose the correct answer: 3-All of the following statements regarding the mechanism of action of organic nitrates in vascular smooth muscles are true EXCEPT:
a-They lead to generation of nitrous oxide(N2O). b.Activation of guanylate cyclase eventually occurs. c.Cellular calcium concentrations are decreased. d. Concentrations of cGMP are increased.

Choose the correct answer: 4-All of the following statements regarding antianginal agents are true EXCEPT:
a-Calcium channel blockers dilate arterioles more than veins. b.Organic nitrates decrease calcium levels in smooth muscles cells by decreasing their cGMP levels. c.Beta blockers are effective in treating exertional angina by decreasing cardiac O2 demand. d. Nifedipine can aggravate angina as a result of its reflex inotropic & chronotropic effects.

Choose the correct answer: 10-Side effects common to calcium channel blockers include all of the following EXCEPT :
a-Dizziness and flushing . b.Worsening of myocardial ischemia. c.Tachycardia. d.Excessive vasodilatation. e.Diarrhoea.

Choose the correct answer: 11-Effective administration route of nitroglycerine for angina pectoris include all of the following EXCEPT :
a-Transdermal . b.Rectal. c.Sublingual. d.Intravenous. e.Oral.

Choose the correct answer: 12-In the treatment of angina pectoris :

a-Beta adrenergic antagonists provide effective vasodilatation . b.propranolol is the only beta blocker that is therapeutically effective. c. Beta adrenergic antagonists are most effective in vasospastic angina. d. Beta adrenergic antagonists withdrawal may cause myocardial infarction. e.The combination of organic nitrates and beta adrenergic antagonists is contraindicated.

Good Luck