Antianginal student222

8/2/2019 Antianginal student222

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Coronary Vascular

insufficiency

(Ischemic Heart Disease)


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Coronary V. Insufficiency

Clinical manifistation:Clinical manifistation:

Disease of coronary artery is almost due to atheroma

and its complications particularly thrombosis.

1. Stable angina

2. Unstable angina

3. Myocardial Infarction M.I.

4. Heart Failure

5. Arrhythmia


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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 atheroscleroticnarrowing

Increase Oxygen Demand due to

increase heart rate, Increase

ventricular contraction, exercise,

emotional stress.


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1. Classic, effort, stable angina

present with retrosternal pain, transient 2-5 minprecipitated by exertion andRELIVED 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 painAT

REST

Types of Angina


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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)

Causes of Angina


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Coronary V. Insufficiency

30% Narrowing 50% Narrowing 70% Narrowing

99% Obstruction 100% Obstruction

No Angina Potential of Angina Stable Angina

Unstable Angina Occlusion M.I.


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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)

General Goals Of Anti anginal

Therapy


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Determinants of MyocardialDeterminants of Myocardial

oxygen demandoxygen demand

PreloadDepend and venous tone

After loadABP depends on PVR

Heart rate Cardiac contracti l ity


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1. Avoid riskfactors

Smoking,

obesity,

hypertension,diabetes,

increased

cholesterol

level

Management of Angina

3. Invasivemeasures

coronary

bypass, or

angioplasty

2. Drug therapyOrganic

nitrates,

CC blockers,

Blockers,

Aspirin

Heparin


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1. Increase

myocardial

oxygen

supply

a. Dilatation of

large

coronary

vessels

b. Redistribution of coronary

flow

c. Dilatation of

collaterals

Organic nitrates

2. Decrease of

oxygen

demand

Decrease ofcardiac work

indirectly.

a. Decrease

preload (veno-

dilators ).

b. Decrease after

load arteriolar

dilators.

3. Antithrombotic

action of

Nitrates.

Decrease

platelets

aggregation by

virtue of

increased

synthesis of (c

GMP)


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Mechanism of Action of Nitrates (NO3-)

Nitrites

NO2-

GlutathioneStransferase

Nitric oxide

NO

cGMP

administeredNitrates

Dephosphrylation

of myosin

light chain

Vascular smooth

Muscle

relaxation


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1. Rapid acting (acuteattack)

a. Nitroglycerine sublingual

tablets or spray ( onset : 2

min, duration : 25 min)

b. Isosorbid dinitrate

sublingual( onset : 5 min,duration : 1 hour)

Preparations of nitrates

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)


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Pharmacokinetics of nitratesPharmacokinetics of nitrates

NG is well absorbed from GIT butNG is well absorbed from GIT butundergoes extensive first- passundergoes extensive first- passmetabolism in the liver to inactivemetabolism in the liver to inactivemetabolitesmetabolites .So NG is given SL (0.5 mg. ) ,.So NG is given SL (0.5 mg. ) ,

buccal ,Transdermal ,&I.V. ( in acutebuccal ,Transdermal ,&I.V. ( in acuteattack )attack ) Slow release (SR) oral preparations of NGSlow release (SR) oral preparations of NG

(2.5mg-12.5mg ) as prophylactic.(2.5mg-12.5mg ) as prophylactic. Isosorbide dinitrate also has extensive first-Isosorbide dinitrate also has extensive first-

pass metabolismpass metabolism It has relatively longer duration of actionIt has relatively longer duration of action

than NG (it is metabolized to active ISMN )than NG (it is metabolized to active ISMN )


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Isosorbid 5-mononitrate is anIsosorbid 5-mononitrate is an

active metabolite of ISD , it isactive metabolite of ISD , it isnot subjected to first-passnot subjected to first-pass

metabolism so used orally.metabolism so used orally.


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a)In all types of

Angina.

b)Congestive

heart failure

Therapeuticuses


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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.

Side effects:

1. Postural hypotension

&reflex tachycardia .

2. Flushing

3. Throbbing headache

4. Visual disturbance

5. Drug rash

6. Nitrate Tolerance

Side Effects

andPrecaution

s


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Drug interaction :Drug interaction :

Sever hypotension if SildenafilSever hypotension if Sildenafil

(a potent PDEI )is given with(a potent PDEI )is given with

nitrates .nitrates .


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CALCIUM CHANNELCALCIUM CHANNEL

BLOCKERS:BLOCKERS: 1-Non-dihydropyridines.1-Non-dihydropyridines.

2-Dihydropyridines.2-Dihydropyridines.


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Block calcium channels in the

cardiac muscles and smooth muscle

calcium influxdecreasecardiac contractility and VSM

relaxation.

Calcium channel blockersCalcium channel blockers

What is their mechanism ofWhat is their mechanism of

action?action?


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non dihydropyridines e.g.non dihydropyridines e.g.

verapamil&diltiazem .verapamil&diltiazem .

1-1- They have mainly cardiac effect.They have mainly cardiac effect. They cause increase of coronary flow asThey cause increase of coronary flow as

they cause coronary dilatation .they cause coronary dilatation .

They decrease myocardial oxygen demandThey decrease myocardial oxygen demandby decreasing cardiac work through their by decreasing cardiac work through their ve inotropic & chronotropic effects .ve inotropic & chronotropic effects .

2-They have reduced vasodilator effect2-They have reduced vasodilator effect( less reflex tachycardia suitable for( less reflex tachycardia suitable forhypotensive patient .hypotensive patient .


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The dihydropyridines e.g.The dihydropyridines e.g.

NIEDIPINE (LA) & AMLODIPINE .NIEDIPINE (LA) & AMLODIPINE .

They have mainly vascularThey have mainly vasculareffect :effect :

1- They cause dilation of coronary1- They cause dilation of coronary

artery so prevent or relief coronaryartery so prevent or relief coronary

vasospasm, and improve myocardialvasospasm, and improve myocardialblood flow .blood flow .

2- They cause arteriolar dilation so2- They cause arteriolar dilation so

decreasing PR &cardiac work.decreasing PR &cardiac work.

3-They have reduced ve inotropic &3-They have reduced ve inotropic &

-ve chronotropic effect on the heart .-ve chronotropic effect on the heart .


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CCBsCCBs

Mechanism of anti-ischemic actionMechanism of anti-ischemic action

arteriolar vascular resistance afterloadmyocardial contracti l i ty & heart ratewith the use of verapamil and dilt iazem

2.CCBs dilate the large epicardial vessels

3. Prevent focal coronary artery spasmprimary cause of variant angin


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What is the role of CCB in the

treatment of angina?

myocardial oxygen demandarteriolar vascular resistance afterload myocardial contracti l i ty & heart ratewith the use of verapamil and di lt iazem

myocardial oxygen supplycoronary di latation


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AMLODIPINE :AMLODIPINE :

1- It is a long acting CCB.1- It is a long acting CCB.

2-It is slowly but completely2-It is slowly but completely

absorbed from GIT .absorbed from GIT .

3-Has very long half life of about3-Has very long half life of about

1 -2-days .1 -2-days .

4- Reduces the ABP gradually &4- Reduces the ABP gradually &causes little reflex tachycardia .causes little reflex tachycardia .


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Therapeutic causes of CCB .Therapeutic causes of CCB .

1-Vasospastic angina .1-Vasospastic angina .

2-Stable angina alone or in2-Stable angina alone or in

combination withcombination with blockers .blockers .


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BetaBetablocking drugsblocking drugs

Mechanism of anti-ischemic actionMechanism of anti-ischemic action

1. Heart Rate ( resting &

exercise HR)

2. Force of contraction

3. Blood pressure

A.. Myocardial oxygen demands

B. Perfusion of ischemic areas by

prolongation of diastole


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-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


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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 heartblock. (bad combination )

COMBINATION OF ANTIANGINAL DRUGS:COMBINATION OF ANTIANGINAL DRUGS:

VD

VD


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NitratesCoronary Vessels

(O2 supply)

CCB

Heart

(O2 demand) HR&Contractility

BlockersCCB

BlockersCCB

NitratesNitrates

VD

AfterloadPreload

Effect of Anti-anginal drugs on myocardial O2 supply

and work done by the heart (O2 demand)

1. VD epicardial coronaries

2. Redistribution to ischemic areas

3. VD collaterals

VD


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Antiplatelet DrugsAntiplatelet Drugs

Aspirin:Aspirin:

AspirinAspirin irreversibly inhibit COXirreversibly inhibit COX (up to(up tothe life-time of the platelets 8-10 days).the life-time of the platelets 8-10 days).

Both PGIBoth PGI22 and TXAand TXA22 synthesis aresynthesis are

inhibited.inhibited.

Aspirin inAspirin in small dose 75-100 mg/daysmall dose 75-100 mg/day

inhibits TXAinhibits TXA22 synthesis withoutsynthesis without

significant effect on the endothelialsignificant effect on the endothelial

PGIPGI22.. A/E: peptic ulcerA/E: peptic ulcerbleeding in patients >bleeding in patients >

60 years.60 years.

U f ti l t l dUses of antiplatele drugs:


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Uses of antiplatele drugs:Uses of antiplatele drugs:

They are used in patient at highThey are used in patient at high

risk e.g.risk e.g.

after angina pectoris, MI, atheromaafter angina pectoris, MI, atheroma

oror

prothetic valvesprothetic valves to protect against:to protect against: Stroke,Stroke,

MIMI

or deathor death


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ASPIRINASPIRIN

It must be given to all cases ofIt must be given to all cases ofangina . In low doses 70 -150angina . In low doses 70 -150mg /day it will decrease plateletmg /day it will decrease platelet

aggregation .aggregation . N.B. Loading dose is sometimesN.B. Loading dose is sometimes

required for a rapid onset ofrequired for a rapid onset ofeffect ,chewed beforeeffect ,chewed beforeswallowing to aid earlyswallowing to aid earlyabsorption .absorption .


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VASOSPASTIC OR VARIENTVASOSPASTIC OR VARIENT

ANGINA .ANGINA .

In vasospastic angina :In vasospastic angina :

Nitates , CCB are the drugs ofNitates , CCB are the drugs ofchoice .choice .


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Unstable anginaUnstable angina


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UASTABLE ANGINA .UASTABLE ANGINA .

Better transfer to ICU or CCU.Better transfer to ICU or CCU. MMORPHIE-ORPHIE-OOXYGEN-XYGEN-NNG-G-AASPIRINE.SPIRINE. AspirinAspirin as loading dose (150 -300 mg )as loading dose (150 -300 mg )

then small daily dose (75-150 mg/day ) .then small daily dose (75-150 mg/day ) .

The addition of other anti plateletThe addition of other anti platelet e.g.e.g.ClopidogrelClopidogrelto aspirin is moreto aspirin is moreeffectiveeffective ..

Full anticoagulationFull anticoagulation with heparinwith heparinproduces additive benefit .produces additive benefit .

AA adrenergic antagonistadrenergic antagoniste.g.Metoprolol is first choice anti-e.g.Metoprolol is first choice anti-anginl drugs .anginl drugs .


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Myocardial infarction .Myocardial infarction .

1-Acute management .1-Acute management .

Aim of therapy :Aim of therapy :

1-Pain relief .1-Pain relief .

2-Reperfusion of occluded artery . So drugs2-Reperfusion of occluded artery . So drugs

will include :will include : Analgesics e.g. Diamorphine 2.5 -5 mg IV .Analgesics e.g. Diamorphine 2.5 -5 mg IV .

SL nitrates (3 doses of nitroglycerine withSL nitrates (3 doses of nitroglycerine with5m intervals) or IV nitrates .5m intervals) or IV nitrates .

Aspirin 150- 300 mg orally (loading dose )Aspirin 150- 300 mg orally (loading dose ) .Continue with Aspirin in small dose 75-150.Continue with Aspirin in small dose 75-150

mg/ day .mg/ day . Oxygen 60% facemask inhalation .Oxygen 60% facemask inhalation .


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Thrombolytics :Thrombolytics : to induce clot lysis & restore bloodto induce clot lysis & restore blood

flow e.g. streptokinase .flow e.g. streptokinase .

Anti emetics.as myocardial patient suffer N &VAnti emetics.as myocardial patient suffer N &V

during acute attack of MI. e.g. Metoclopramideduring acute attack of MI. e.g. Metoclopramide

-adrenergic antagonists IV 4-6 h s after MI reduce-adrenergic antagonists IV 4-6 h s after MI reduce

the infarct size & mortality .the infarct size & mortality . If thrombolytics are contraindicated surgery isIf thrombolytics are contraindicated surgery is

indicated .indicated .


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Define the initial drug to

start with uponadmission:Morphine

Morphine

Define the initial drug to

start with uponadmission:

a-To alleviate the painPotent opiod analgesic that relives

severe pain.Has anxiolytic effect.Dilates veins leading to decreasedpulmonary venous congestion.


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Fibrinolytics Inhibitors (e.g.streptokinase) lyse thrombus occluding arteryleading to revasclarization, since attack is within 1hr.

B-to stop progression ofetiopathological cause

Chewable aspirin 160 mg: because ofits antiplatelet effect .

Oxygen and IV fluids.Nitroglycerine IV infusion.

Anticoagulants, e.g. heparin.

Beta blockers reduce the infarct size.


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Myocardial infarction .Myocardial infarction .

Secondary prophylaxis .Secondary prophylaxis .

Aim of therapy is to reduceAim of therapy is to reduce

mortality after MI .mortality after MI .

Stop smoking .Stop smoking .

Low dose aspirin 75-150 mg/Low dose aspirin 75-150 mg/

day reduces re occlusion ofday reduces re occlusion of

the vessels that undergoesthe vessels that undergoes

natural or therapeuticnatural or therapeutic

thrombolysis .thrombolysis .


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adrenergic receptor antagonist startedadrenergic receptor antagonist started

orally soon after the MI reduces later deathsorally soon after the MI reduces later deathsand re infarction .and re infarction .

ACEIs should be initiated within 24 hs after MI ,ACEIs should be initiated within 24 hs after MI ,

they prevent HF after MI .they prevent HF after MI . Long term anticoagulant with warfarin reducesLong term anticoagulant with warfarin reduces

mortality & reinfarction .mortality & reinfarction .

Cholesterol reduction .Cholesterol reduction .


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Identify whether or notthere is a place for ACE

inhibitors.

To avoid

post MIcardiacremodeli

ng

YES

If the patient is proved to be


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If the patient is proved to behypertensive.

Suggest whether there is a place for CCBs. Explain yourreasons.Nondihydropyrines have no placebecause of their negative inotropiceffects.l l dihydropyridines have no place because of theirvasodilatory effect-induced reflex tachycardia.(EXCEPTlong acting e.g. amlodipine which can be used becausebeing long acting they do not induce reflex tachycardia.

When the patient is discharged after


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When the patient is discharged afterbeing controlled

Enumerate the drugs that the patienthas to continue on , to preventoccurrence of a second attack.


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Oralanticoagulants,e.g.warfarin

Hypocholesterolomic drugs ,e.g.statinsAvoid smoking.

Control diet.

ACEIs orARBsBeta blockers

Nitrates, e.g.isosorbidedinitrateAntiplatelets,e.g.

aspirin


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AngioplastyAngioplasty


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CABGCABG


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Selection

Drug in concomitant diseases

L.N. Nitrates Blockers C.C.Blockers

1. None

2. Recent M.I.

3. Asthma COPD

4. Hypertension

5. Diabetes

x x x x


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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

c) Bradycardia

b) Throbbing Headache

d) Sexual dysfunction

Correct Answer = b)

NG Causes Throbbing Headache in 30%-60% of Patients

C S d 1 ( C )


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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

c) Throbbing Headache

b) Methemoglobinemia

d) Reflex tachycardia

Correct Answer = d)

NG Causes Reflex tachycardia due to its vasodilatation.


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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?

c) Nitroglycerin (transdermal)

b) Nitroglycerin (SL)

d) Propranolol

a) Hydralazine

Correct Answer = C)

Transdermal NG sustains blood level for 24 hours

MCQ


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MCQs:

1- Metoprolol decrease the anginal attacks by the following

mechanisms except:

a) Decrease myocardial contractility

c) Dilates coronary blood vessels

b) Decrease heart rate

d) Decrease the arterial blood pressure

Correct Answer = C)

Metoprolol is not coronary vasodilator

MCQ


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MCQs:2- Which of the following drugs is considered to be most

effective in relieving & preventing ischemic episodes inpatients with variant angina?

a)Metoprolol

c) Sodium Nitroprusside

b) Nitroglycerine

d) Amlodepine (Nifedipine)

Amlodepine


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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 O2consumption.

The compensatory sympathetic reflexes produced by

nitrates are inhibited by beta blockers.


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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).


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5-Match the following antianginals to their

mechanism of action:

1.Glyceryl trinitrate a-By decreasing sympathetic tone to the heart

2. Propranolol. B.By reducing cardiac work load.3. Verapamil. C.By inhibiting uptake of Ca by myocardial cells

1.Glyceryl trinitrate(b) a-By decreasing sympathetic tone to the hear

2. Propranolol. ( a) b.By reducing cardiac work load.

3. Verapamil. (c) c.By inhibiting uptake of Ca by myocardial cel


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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.


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V-MARK TRUE (T) OR FALSE (F)and correct the false1. All organic nitrate esters undergo significant

renal excretion which accounts for their short

half lives.

2.Isosorbide dinitrate is a fully nitrated compound,

which can be metabolized to an activ

metabolite.

3.Development of tolerance to the organic nitrates

can be avoided by intermittent therapy.

4.Typical angina is usually not associated with

atherosclerosis.

F undergo significant hepatic metabolism

T

T

Fis usually associated


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V-MARK TRUE (T) OR FALSE (F)and correct the false5. The vasodilatory effects of organic nitrates are

greater in arterioles than 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.

8.Organic nitrates decrease oxygen demand of the

heart by their direct negative inotropic and

chronotropic effects .

Fgreater in veins than arteriole

T

Fcontraindicated in vasospastic angi

F decrease oxygen demand of heart by indirect


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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 smal

vessels.c.They are effective in relieving all three types of

angina.

d.They directly alter the inotropic and chronotropic

state of the heart.


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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.


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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.


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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 smoothmuscles 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.


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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.


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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.


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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 causemyocardial infarction.

e.The combination of organic nitrates and beta

adrenergic antagonists is contraindicated.


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Good Luck

Antianginal student222

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