Drug Treatment of Drug Treatment of Ischemic Heart Ischemic Heart

DiseaseDiseaseFixed "Stable" AnginaFixed "Stable" Angina

Variant AnginaVariant Angina

Unstable AnginaUnstable Angina

Myocardial InfarctionMyocardial Infarction

Mechanism of AnginaMechanism of Angina

OO22 Supply (Coronary Blood Supply (Coronary Blood Flow)Flow)

OO22 Demand (Work of the Demand (Work of the Heart) Heart)

Secondary AnginaSecondary Angina Primary AnginaPrimary Angina

ClassicalClassical Variant Variant (Prinzmetal’s) (Prinzmetal’s)

Angina of EffortAngina of Effort Angina at RestAngina at Rest

TypicalTypical AtypicalAtypical

17681768 19571957

Small vesselsSmall vessels Large vesselsLarge vessels

Single or multipleSingle or multiple SingleSingle

AtherosclerosisAtherosclerosis VasospasmVasospasm

ST depressionST depression ST elevationST elevation

Control of vascular smooth muscle Control of vascular smooth muscle contractioncontraction

Organic NitratesOrganic Nitrates

►Nitroglycerine (GTN):Nitroglycerine (GTN):►Prototype, used for more than 125 Prototype, used for more than 125

years.years.►Nonspecific smooth muscle Nonspecific smooth muscle

relaxant.relaxant.►Action not antagonized by any Action not antagonized by any

known antagonist.known antagonist.

Mechanism of action of nitrates, nitrites, and other Mechanism of action of nitrates, nitrites, and other substances that increase the concentration of nitric oxide substances that increase the concentration of nitric oxide

(NO) in vascular muscle(NO) in vascular muscle

Nitroglycerine (GTN)Nitroglycerine (GTN)►Usually administered sublingually.Usually administered sublingually.►Can be administered by various Can be administered by various

routes.routes.►Fast onset of action(1-Fast onset of action(1-

3minutes,Peaks at 10 minutes). 3minutes,Peaks at 10 minutes). ►Short duration (15-30minutes).Short duration (15-30minutes).►Reductase enzyme in liver will Reductase enzyme in liver will

breakdown the drug. breakdown the drug.

Nitroglycerine (GTN)Nitroglycerine (GTN)

►Causes general vasodilation:Causes general vasodilation:►Arteriolar dilationArteriolar dilation: short lived (5-10 : short lived (5-10

min)min)►Will decrease systemic blood Will decrease systemic blood

pressure (afterload) and cause reflex pressure (afterload) and cause reflex tachycardia and increased tachycardia and increased contractility, ?might increase MVO2.contractility, ?might increase MVO2.

►Venous dilationVenous dilation: more intense, even : more intense, even with low doses, lasts for 30 minutes, with low doses, lasts for 30 minutes, decreases venous return (preload) decreases venous return (preload) and decreases MVO2. and decreases MVO2.

Beneficial and Deleterious Effects of Nitrates in the Treatment of Beneficial and Deleterious Effects of Nitrates in the Treatment of Angina.Angina.

EffectEffect ResultResult

Potential beneficial effectsPotential beneficial effects     

    Decreased ventricular volumeDecreased ventricular volume Decreased myocardial oxygen Decreased myocardial oxygen requirementrequirement

    Decreased arterial pressureDecreased arterial pressure

    Decreased ejection timeDecreased ejection time

    Vasodilation of epicardial coronary Vasodilation of epicardial coronary arteriesarteries

Relief of coronary artery Relief of coronary artery spasmspasm

    Increased collateral flowIncreased collateral flow Improved perfusion to Improved perfusion to ischemic myocardiumischemic myocardium

    Decreased left ventricular diastolic Decreased left ventricular diastolic pressurepressure

Improved subendocardial Improved subendocardial perfusionperfusion

Potential deleterious effects Potential deleterious effects    

    Reflex tachycardiaReflex tachycardia Increased myocardial oxygen Increased myocardial oxygen requirementrequirement

    Reflex increase in contractilityReflex increase in contractility   

    Decreased diastolic perfusion time Decreased diastolic perfusion time due to tachycardiadue to tachycardia

Decreased coronary perfusionDecreased coronary perfusion

Nitroglycerine (GTN)Nitroglycerine (GTN)►Side Effects:Side Effects:►Headache.Headache.►Hypotension and tachycardia.Hypotension and tachycardia.► Increased intraocular and intracranial Increased intraocular and intracranial

pressures.pressures.►Methemoglobinemia.Methemoglobinemia.► Tolerance: only for the arteriolar effects.Tolerance: only for the arteriolar effects.►Withdrawal: in workers in ammunition Withdrawal: in workers in ammunition

industry.industry.

Nitrate and Nitrite Drugs Used in the Treatment of Angina.Nitrate and Nitrite Drugs Used in the Treatment of Angina.

DrugDrug Duration of ActionDuration of Action

Short-acting: Short-acting:       

    Nitroglycerin, sublingualNitroglycerin, sublingual 10–30 minutes10–30 minutes

    Isosorbide dinitrate, Isosorbide dinitrate, sublingualsublingual

10–60 minutes10–60 minutes

    Amyl nitrite, inhalantAmyl nitrite, inhalant 3–5 minutes3–5 minutes

Long-acting: Long-acting:    

    Nitroglycerin, oral sustained-Nitroglycerin, oral sustained-actionaction

6–8 hours6–8 hours

    Nitroglycerin, 2%Nitroglycerin, 2% ointment ointment, , transdermaltransdermal

3–6 hours3–6 hours

    Nitroglycerin, slow-release, Nitroglycerin, slow-release, buccalbuccal

3–6 hours3–6 hours

    Nitroglycerin, Nitroglycerin, slow-release slow-release patchpatch, transdermal, transdermal

8–10 hours8–10 hours

    Isosorbide dinitrate, Isosorbide dinitrate, sublingualsublingual

1.5–2 hours1.5–2 hours

    Isosorbide dinitrate, oralIsosorbide dinitrate, oral 4–6 hours4–6 hours

    Isosorbide dinitrate, Isosorbide dinitrate, chewable oralchewable oral

2–3 hours2–3 hours

    Isosorbide mononitrate, oralIsosorbide mononitrate, oral 6–10 hours6–10 hours

Beta Adrenergic BlockersBeta Adrenergic Blockers►Prevent actions of catecholamines, Prevent actions of catecholamines,

so more effective during exertion.so more effective during exertion.►No increase in collateral blood flow.No increase in collateral blood flow.►Cause subjective and objective Cause subjective and objective

improvement: decreased number of improvement: decreased number of anginal episodes, nitroglycerine anginal episodes, nitroglycerine consumption, enhanced exercise consumption, enhanced exercise tolerance, and improved ECG.tolerance, and improved ECG.

Beta Adrenergic BlockersBeta Adrenergic Blockers

Calcium Channel BlockersCalcium Channel Blockers

Particularly beneficial in Particularly beneficial in vasospasm.vasospasm.

Can affect platelets aggregation. Can affect platelets aggregation.

May be dangerous in heart failure May be dangerous in heart failure and in patients susceptible to and in patients susceptible to hypotension.hypotension.

Properties of Several Recognized Voltage-Activated Calcium Channels.Properties of Several Recognized Voltage-Activated Calcium Channels.

TypTypee

Channel Channel NameName

Where FoundWhere Found Properties Properties of the of the Calcium Calcium CurrentCurrent

Blocked Blocked ByBy

LL CaCaVV1.1–1.1–

CaCaVV1.31.3

  

Cardiac, skeletal, smooth Cardiac, skeletal, smooth muscle, neurons (Camuscle, neurons (CaVV1.4 is 1.4 is

found in retina), endocrine found in retina), endocrine cells, bonecells, bone  

Long, large, Long, large, high high thresholdthreshold

Verapamil, Verapamil, DHPs, CdDHPs, Cd2+2+, ,   -aga-IIIA   -aga-IIIA  

TT CaCaVV3.1–3.1–

CaCaVV3.33.3

  

Heart, neuronsHeart, neurons Short, small, Short, small, low thresholdlow threshold

sFTX, sFTX, flunarizine, flunarizine, NiNi2+2+, , mibefradilmibefradil11

  

NN CaCaVV2.22.2

  Neurons, spermNeurons, sperm22

  Short, high Short, high thresholdthreshold

Ziconotide,Ziconotide,33 gabapenti gabapentin,n,44   -CTX-   -CTX-GVIA,   -GVIA,   -aga-IIIA, aga-IIIA, CdCd2+2+

  

P/QP/Q CaCaVV2.12.1

  NeuronsNeurons Long, high Long, high

thresholdthreshold      -CTX--CTX-MVIIC,   -MVIIC,   -aga-IVAaga-IVA

RR CaCaVV2.32.3

  Neurons, spermNeurons, sperm22

  PacemakingPacemaking SNX-482, SNX-482,

  -aga-IIIA  -aga-IIIA

Calcium Channel BlockersCalcium Channel Blockers

►Side Effects:Side Effects:►Hypotension.Hypotension.►Headache, dizziness.Headache, dizziness.►Flushing.Flushing.►Peripheral edema.Peripheral edema.

Effects of Nitrates Alone and with Beta Blockers or Calcium Effects of Nitrates Alone and with Beta Blockers or Calcium Channel Blockers in Angina Pectoris. Channel Blockers in Angina Pectoris.

   Nitrates Nitrates AloneAlone

Beta Blockers or Beta Blockers or Calcium Channel Calcium Channel BlockersBlockers

Combined Nitrates with Combined Nitrates with Beta Blockers or Calcium Beta Blockers or Calcium Channel BlockersChannel Blockers

Heart Heart raterate

ReflexReflex11increaseincrease    

DecreaseDecrease  

DecreaseDecrease

Arterial Arterial pressurepressure

DecreaseDecrease DecreaseDecrease DecreaseDecrease

End-End-diastolic diastolic volumevolume

DecreaseDecrease IncreaseIncrease   None or decreaseNone or decrease

ContractilitContractilityy

ReflexReflex11increaseincrease    

DecreaseDecrease NoneNone

Ejection Ejection timetime

Decrease1Decrease1 IncreaseIncrease   NoneNone

DipyridamoleDipyridamole►Inhibits the uptake of adenosine Inhibits the uptake of adenosine and inhibits adenosine and inhibits adenosine deaminase enzyme.deaminase enzyme.

►Thought to be a good coronary Thought to be a good coronary dilator.dilator.

►Increases the blood flow to the Increases the blood flow to the normal area i.e.normal area i.e.“Coronary Steal “Coronary Steal Phenomenon”.Phenomenon”.

►Still used as an antiplatelet drug Still used as an antiplatelet drug (in TIAs), but not better than (in TIAs), but not better than aspirin. aspirin.

OthersOthers ►ACEI.ACEI.

►Anticoagulants and/or Anticoagulants and/or Thrombolytic Therapy.Thrombolytic Therapy.

►Cholesterol Lowering Agents.Cholesterol Lowering Agents.

►AngioplastyAngioplasty

►Surgery.Surgery.

Newer Antianginal Drugs Newer Antianginal Drugs ►Metabolic modulators: Ranolazine.Metabolic modulators: Ranolazine.►Direct bradycardic agents: Ivabradine.Direct bradycardic agents: Ivabradine.►Potassium channel activators: Potassium channel activators:

Nicorandil.Nicorandil.►Rho-kinase inhibitors: Fasudil.Rho-kinase inhibitors: Fasudil.►Sulfonylureas: Glibenclamide.Sulfonylureas: Glibenclamide.►Thiazolidinediones.Thiazolidinediones.►Vasopeptidase inhibitors.Vasopeptidase inhibitors.►Nitric oxide donors: L- arginine.Nitric oxide donors: L- arginine.►Capsaicin.Capsaicin.►Amiloride.Amiloride.