Drug Treatment of Ischemic Heart Disease Munir Gharaibeh, MD, PhD, MHPE Faculty of Medicine, The University of Jordan The University of Jordan November,

Drug Treatment of Drug Treatment of Ischemic Heart DiseaseIschemic Heart Disease

Munir Gharaibeh, MD, PhD, MHPEMunir Gharaibeh, MD, PhD, MHPEFaculty of Medicine,Faculty of Medicine,

The University of JordanThe University of Jordan

November, 2014November, 2014

Categories of Ischemic Heart Categories of Ischemic Heart DiseaseDisease

Fixed "Stable“, Effort AnginaFixed "Stable“, Effort Angina

Variant Angina “Primary Angina”Variant Angina “Primary Angina”

Unstable AnginaUnstable Angina

Myocardial InfarctionMyocardial Infarction

04/20/23 3Munir Gharaibeh MD, PhD, MHPE

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 elevation04/20/23 4Munir Gharaibeh MD, PhD, MHPE


►Stunning?:Stunning?: Myocardial stunningMyocardial stunning is the reversible is the reversible

reduction of function of reduction of function of heart contraction after after reperfusion not accounted for by not accounted for by tissue damage or reduced blood flow.tissue damage or reduced blood flow.

04/20/23 Munir Gharaibeh MD, PhD, MHPE 6

Control of smooth muscle contractionControl of smooth muscle contraction► Contraction is triggered by influx of calcium Contraction is triggered by influx of calcium

through L-type transmembrane calcium through L-type transmembrane calcium channels. channels.

► The calcium combines with calmodulin to form The calcium combines with calmodulin to form a complex that converts the enzyme myosin a complex that converts the enzyme myosin light-chain kinase to its active form (light-chain kinase to its active form (MLCKMLCK*). *).

► MLCK phosphorylates the myosin light chains, MLCK phosphorylates the myosin light chains, thereby initiating the interaction of myosin thereby initiating the interaction of myosin with actin. with actin.

► Beta2 agonists (and other substances that Beta2 agonists (and other substances that increase cAMP) may cause relaxation in increase cAMP) may cause relaxation in smooth muscle by accelerating the smooth muscle by accelerating the inactivation of MLCK and by facilitating the inactivation of MLCK and by facilitating the expulsion of calcium from the cell. expulsion of calcium from the cell. 04/20/23 7Munir Gharaibeh MD, PhD, MHPE

Control of vascular smooth muscle Control of vascular smooth muscle contractioncontraction


Mechanism of IHDMechanism of IHD

Due to an imbalance of the ratio:Due to an imbalance of the ratio:

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

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



Pharmacological modification of the major Pharmacological modification of the major

determinants of myocardial O2 supplydeterminants of myocardial O2 supply



Drug effects on vascular smooth muscle Drug effects on vascular smooth muscle contraction.contraction.

► Calcium influx is inhibited by CCBs, leading to Calcium influx is inhibited by CCBs, leading to muscle relaxation.muscle relaxation.

► Organic nitrates release nitric oxide, which Organic nitrates release nitric oxide, which activates guanylyl cyclase and increases formation activates guanylyl cyclase and increases formation of cyclic guanosine monophosphate. of cyclic guanosine monophosphate. cGMP causes smooth muscle relaxation by cGMP causes smooth muscle relaxation by

activating kinases that increase myosin activating kinases that increase myosin phosphatase activity and decrease myosin phosphatase activity and decrease myosin phosphate levels. phosphate levels.

► α 1-Adrenoceptor agonists activate phospholipase C α 1-Adrenoceptor agonists activate phospholipase C (PLC), which increases formation of inositol (PLC), which increases formation of inositol triphosphate (IP 3) from phosphatidylinositol triphosphate (IP 3) from phosphatidylinositol bisphosphate (PIP 2), leading to increased release bisphosphate (PIP 2), leading to increased release of calcium from the sarcoplasmic reticulum. of calcium from the sarcoplasmic reticulum.

► β 2-Adrenoceptor agonists increase formation of cyclic β 2-Adrenoceptor agonists increase formation of cyclic adenosine monophosphate (cAMP), which activates kinases adenosine monophosphate (cAMP), which activates kinases that inhibit myosin light-chain kinase. that inhibit myosin light-chain kinase.



Organic NitratesOrganic Nitrates►Nitroglycerine (GTN):Nitroglycerine (GTN):►Prototype, used for more than 140 Prototype, used for more than 140

years.years.►Nonspecific smooth muscle relaxant.Nonspecific smooth muscle relaxant.►Action not antagonized by any Action not antagonized by any

known antagonist.known antagonist.


Nitrates, nitrites, and other substances that increase the Nitrates, nitrites, and other substances that increase the

concentration of nitric oxide (NO) in vascular muscleconcentration of nitric oxide (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(1-3minutes, Fast onset of action(1-3minutes,

Peaks at 10 minutes). 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) Decreases systemic blood pressure Decreases systemic blood pressure

(afterload) and causes reflex (afterload) and causes 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) and Decreases venous return (preload) and

decreases MVO2. decreases MVO2. 04/20/23 18Munir Gharaibeh MD, PhD, MHPE



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, Nitroglycerin, sublingualsublingual 10–30 minutes10–30 minutes

Isosorbide dinitrate, Isosorbide dinitrate, sublingualsublingual

10–60 minutes10–60 minutes

Amyl nitrite, Amyl nitrite, inhalantinhalant 3–5 minutes3–5 minutes

Long-acting: Long-acting:

Nitroglycerin, Nitroglycerin, oral sustained-oral sustained-actionaction

6–8 hours6–8 hours

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


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


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


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


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.►Do not dilate coronary arteries.Do not dilate coronary arteries.►Do not increase collateral blood flow.Do not increase 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 gabapentin,gabapentin,44 -CTX- -CTX-GVIA, -GVIA, -aga-IIIA, Cdaga-IIIA, Cd2+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-IIIAaga-IIIA04/20/23 26Munir Gharaibeh MD, PhD, MHPE






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 AloneNitrates Alone Beta Blockers Beta Blockers or Calcium or Calcium Channel Channel BlockersBlockers

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

Heart rateHeart rate ReflexReflex11increaseincrease DecreaseDecrease DecreaseDecrease

Arterial Arterial pressurepressure

DecreaseDecrease DecreaseDecrease DecreaseDecrease

End-diastolic End-diastolic volumevolume

DecreaseDecrease Increase Non or decrease

ContractilityContractility ReflexReflex11increaseincrease DecreaseDecrease Non

Ejection timeEjection time DecreaseDecrease Increase Non04/20/23 33Munir Gharaibeh MD, PhD, MHPE

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. 04/20/23 35Munir Gharaibeh MD, PhD, MHPE



Newer Antianginal DrugsNewer 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.


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Drug Treatment of Ischemic Heart Disease Munir Gharaibeh, MD, PhD, MHPE Faculty of Medicine, The University of Jordan The University of Jordan November,