Anti- anginal drugs -012
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Transcript of 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