Anti- anginal drugs -012

Professor Mohamed KhedrProfessor of clinical pharmacology

Faculty of medicineBairut Arab University

AnginaPectoris. One of the Ischaemic Heart Diseases (I.H.D.) M.I

Sudden Death.

is a clinicalclinical syndromesyndrome of ChestChest PainPain Sudden, severe pressing,

substernal, radiating to Lt. shoulder& flexor surface of Lt. arm&

lasts for few minutes.

inadequate coronary blood flowinadequate coronary blood flow O2-supplyO2-supply . .

Due to

Angina PectorisAngina Pectoris

Angina PectorisAngina Pectoris

Pathophysiology:OO22 demands Exceed the supply demands Exceed the supply

Myocardial metabolism

Shifts to

AnaerobicAnaerobic metabolismmetabolism

From Fat to CHO Accumulation of substance P

↑↑ glycolysisglycolysis..↑↑lactate & Pyruvate formationlactate & Pyruvate formation

㊉㊉ sympathetic nerve endingssympathetic nerve endings

Pain

GlucoseGlucose 2 ATP2 ATP

Pyruvate → LactatePyruvate → Lactate OO22

Acetyl CO AAcetyl CO A

Citric a cycle→32ATPCitric a cycle→32ATP

Types of Angina PectorisTypes of Angina Pectoris

Stable AnginaStable Angina Variant AnginaVariant Angina Unstable AnginaUnstable Angina

EffortEffort , TypicalTypical .

Atherosclerosis.

Exercise, Emotion ,

Heavy meal.↓

Pain

PrinzmetalPrinzmetal .↓

α- receptor mediated V.C.

With or without atherosclerosis .

↓ Pain even at rest

AccelratedAccelrated .↓

Severe type. ↓ .change in pattern.

. ↑ frequency& or duration of pain .

Treatment of Angina PectorisTreatment of Angina PectorisI- I- GeneralGeneral measuresmeasures::

.Change of life styleChange of life style:. Avoid intolerable → Effort, Stress, Smoking, Heavy meal.

. Daily exercise → walk..CorrectCorrect obesityobesity.

.↓ FoodFood intakeintake

.Treatment of predisposing factorsTreatment of predisposing factors::. . Hyperlipidaemia.

. Hypertension.. Heart failure.. Arrhythmias.

. Diabetes mellitus.

II-Specific DrugsII-Specific Drugs

During Acute AttacksDuring Acute Attacks In-between AttacksIn-between Attacks

.Nitrates & nitrites. (Short acting)

.Sedatives ..Tranquilizers.

.Analgesics.

.Long acting Nitrates..β-Blockers.

.C.C.Bs..Cytoprotectives.

.Dipyridamol..Prenylamine.

.Perhexiline..Aspirin.

NitritesNitrites & & NitratesNitrates

Organic CompoundsOrganic Compounds Inorganic CompoundsInorganic Compounds

Organic nitritesOrganic nitrites Organic nitratesOrganic nitrates

Esters of nitrous a. Esters of nitric a.

Amyl nitriteAmyl nitrite:: Extremely volatileExtremely volatile..

Crushed& InhaledCrushed& Inhaled..Rapid effectRapid effect::

Onset→ 15 secOnset→ 15 sec.. Peak→ 1 minPeak→ 1 min..

Lasts → 5 minLasts → 5 min..

NitroglycerineNitroglycerine::))GlycerylGlyceryl trinitratetrinitrate((

.S.L (0.5mg) 30sec. ,2 min. ,20min.

.Patch→ skin..I.V.

Isosorbid dinitrateIsosorbid dinitrate::)Isosrdil→(Lasts for 3 H.

Orally & S.L.IsosorbidIsosorbid mononitratemononitrate::

Sodium NitriteSodium Nitrite::↓ ↓ usedused

For cyanide poisoning.

H b + Na nitrite. ↓

Met H b↓ + cyanide

Cyan-met H b

+ Na thio sulphate

Na thiocyanate.

)Less toxic,cleared from the body.(

Ineffective drugs for angina.

Time to peak effect and duration of action for some

common organic nitrate preparations

Mechanism of action

Mainly through release of: NONO

↓ ↓ Binding to specific receptors

) Including SH- group( ↓↓

㊉㊉ Guanylate cyclaseGuanylate cyclase

↓ ↓ ↑ ↑ cGMP → cGMP → ΘΘ Ca++ ++ entery

㊉㊉ Ca++ ++ exit ㊉ ㊉ Protein kinaseProtein kinase

Dephosphorylation of Myosin light chainDephosphorylation of Myosin light chain↓ ↓

V.DV.D..

Others

.Production of PGE.

.Production of PGI2..Membrane hyperpol-

arization.

Effects of nitrates and nitrites on smooth muscle. cGMP = cyclic guanosine 3',

5'-monophosphate.

Nitrites & Nitrates

PharmacokineticsWell absorbed:

. Buccal (S.L) → Rapid onset (2-5 min.) . Short duration ( ↓ 30 min).

. GIT (oral)→ more prolonged & prophylactic .. Lung (Inhalation) → Rapid 15 sec, 1 min ,5 min.

. Transdermal (Skin) .Metabolism:

. Liver (90 %) -extensive- → For dinitrate & tetranitrate) bioavailability→10.( %

Mononitrate does not undergo metabolism → bioavailability is very high.

Excretion → Renal .

Pharmacological EffectsPharmacological Effects::I- CVSI- CVS::

Blood VesselsBlood Vessels

HeartHeart

B.PB.P

. . Venodilation..(Less arterial)→→ ↓R.V. & L.V. enddiastolic pressure.

→→ ↓ Preload..Corona. V.D. . ((not diseased coronaries))

..Arterial V.D.. )Flushing face& Neck.(

..V.D of of mening. Arteries → → (Headache).

.Tachycardia. ↓.V. return ↓ →↓ →C.OC.O&

↓ ↓cardiac work

Rapid Administr. → ↓ B.P ↓ C.OC.O

Ven. D. → ↑ Syst. V. capacityVen. D. → ↑ Syst. V. capacity.. ↓ ↓ V. returnV. return..

↓ ↓ P. pressureP. pressure..

II- II- Smooth muscleSmooth muscle::Relaxing biliary, bronchial , uterine smooth muscle.

III- III- RespirationRespiration::Reflex increase of respiratory rate.

)Carotid body & or due to hypotension.(

IV- IV- BloodBlood::Met-H B

Terapeutic Uses

I-Angina Pectoris All types →potent V.DAll types →potent V.D )not on diseased atherosclerosed coronaries(

↓ myocardial O2-demand

)venodil. → ↓ preload & arteriodil.→ ↓ Afterload (

Myocardial perfusion → to ischaemic areas

by.selective dilation of epicardial vessels.

.direct V.D. of coronary collaterals.

ThroughThrough

II- CHFII- CHF Through Through Preload Preload..

III- M.IIII- M.I.. Nitroglycerine Nitroglycerine area of area of myocardial damagemyocardial damage

IV- Other usesIV- Other uses Biliary colic , constriction ring of uterus & treatment of cyanide poisoning.

Adverse Reactions

1-Throbbing headache.

2-Flushing in the face.

3-Tachycardia & palpitation.

4-Postural hypotension , dizziness & syncope.

5-Rarely ( Chronic high doses) → Met H.b.

Sildenafil (Viagra) potentiates this Sildenafil (Viagra) potentiates this action of the nitrates. To preclude the action of the nitrates. To preclude the dangerous hypotension that may occur, dangerous hypotension that may occur,

this combination is this combination is contraindicatedcontraindicated..

6-NitrateTolerance: → due to → i- Oxidation of SH-group (essential for formation of NO) or ii-Depletion of SH-donors. iii-Reflex sympathetic ㊉ n → V.C.

Can be prevented by

Daily nitrate free interval (10-12h.) at nightDaily nitrate free interval (10-12h.) at night..

PrecautionsPrecautions

.Start with the smallest dose ( side effects )..Not abruptly stopped. ( withdrawal symptoms).

.If the dose increased more than 3 tab. S.L. → fear of M.I.

.Expiry date must be checked.

ContraindicationsContraindications.Severe anaemia.

. I.C.P..Idiosyncrasy..w sildenafil.

ββ-Adrenoceptor Blockers-Adrenoceptor Blockers

β-Bs →→ Suppress the activation of the heart ( Suppress the activation of the heart (ββ11)).. Reduce the work of the heart by ↓ heart rateReduce the work of the heart by ↓ heart rate&&

cardiac contractility cardiac contractility →→ ↓ C.O.& slight ↓ B.P ↓ C.O.& slight ↓ B.P..

↓↓

PropranololPropranolol.It is not a vasodilator , so it may worsen variant angina..

.It is used prophylactically to severity& frequency of typical anginal attacks.

.It cardiac O2 demand through:-. ve chronotropic & inotropic actions.

. Slight of B.P.

Propranolol can be combined with Nitrates

for typical angina. ) to side effects of both drugs.(

Ca++ channel blockersCa++ channel blockers

Nifedipine, Verapamil, DiltiazemNifedipine, Verapamil, Diltiazem Mechanism of action on vascular tissueMechanism of action on vascular tissue : :

Blocking of Ca++ transmembraneBlocking of Ca++ transmembrane channels in channels in vascular sm.m.fibersvascular sm.m.fibers..

→ →interference with inward ofinterference with inward of movement of Camovement of Ca ++ ++

→ →affects depolarizationaffects depolarization & & contraction processescontraction processes

→→with relaxant effects mainlywith relaxant effects mainly on arteriol. smooth muscleon arteriol. smooth muscle..

Nifedipine: Prominent vasodilator actions, used in all types

of angina with reflex tachycardia & leg œdema .

Verapamil: .Slows conduction & ↓ Heart rate.. Greater –ve inotropic effect with

little V.D. effects .

Diltiazem: .CVS effects similar to verapamil.. It is used in angina by ↓ coronary

spasm (variant angina) .

Cytoprotective agentsCytoprotective agents

Provide → → Enough EnergyEnough Energy → → to maintain

an efficient myocardial contraction..

TrimetazidineTrimetazidineIt causesIt causes::

.Metabolic switch during ischaemia → Θ FFA oxidation. ㊉ Glucose oxidation. .Θ intracellular acidosis & accumulation of Na+ & Ca++. .Preserve contractile force function & limits cytolysis. .Antioxidant effect→ limits membrane damage induced by by O2-free radicals.

DypyridamolDypyridamolIt has: .coronary V.D activity (on small resistant vesells).

. Antiplatelet activity.Main disadvantage is: Coronary steal

) diverting blood from ischaemic area(

Aggrevate angina .

Selection of antianginal drugsSelection of antianginal drugsFor patients with concomitant diseasesFor patients with concomitant diseases::

Concomitant diseaseConcomitant disease Most preferredMost preferred drugsdrugs

Less preferredLess preferred drugsdrugs

Bronchial asthmaBronchial asthma..

Heart failureHeart failure

HypertensionHypertension..

Diabetes MellitusDiabetes Mellitus..

C.C.Bs, Nitrites& NitratesC.C.Bs, Nitrites& Nitrates..

Nitites & NitratesNitites & Nitrates..

ββ-Bs , C.C.Bs-Bs , C.C.Bs..

C.C,Bs ,Nitrites & NitratesC.C,Bs ,Nitrites & Nitrates..

ββ-Bs-Bs..

ββ-Bs ,verapamil-Bs ,verapamil,,DiltiazemDiltiazem..Nitrites & NitratesNitrites & Nitrates..

ββ-Bs-Bs..

END