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Home , Beta blocker, Vasodilation

Anti-Anginal

•Red : important •Black : in male / female slides •Pink : in female’s slides only •Blue : in male’s slides only •Green : Dr’s notes •Grey: Extra information, explanation

OBJECTIVES:

✓ Recognize variables contributing to a balanced myocardial supply versus demand.

✓ Differentiate between drugs used to alleviate acute anginal attacks and those meant for prophylaxis & improvement of survival.

✓ Detail the of and other drugs used as therapy.

Editing File Extra information(recommended) Ventricular Muscle Cells

4- Resting membrane potential (polarized) 0- Rapid Depolarization Phase: Passage of cations (Sodium and ) from neighboring cardiac cells causes the resting membrane potential to slightly increase, allowing voltage gated Na channels to open, and the cell is said to be depolarized. 1- Initial Repolarization: Short-term Voltage-gated K channels open and Na channels close at peak positivity of the cell and allow the membrane potential to be slightly decreased to create a potential difference for voltage gated Ca channels to open. . 2-Plateau (refractory period): Voltage gated calcium channels are open for about most of the period, but the channels are inactivated around the end of this phase and K efflux starts, if this phase is prolonged inactivated Ca channels can reopen, creating an afterdepolarization () “more on this later in the lecture” 3- Repolarization: Extra specialized K channels are opened to bring about repolarization and a return to the resting membrane potential.

Pacemaker Action Potential

SA Node is made of specialized cardiac cells, (Modified Cardiomyocytes), the cells have high permeability to Na and K, allowing constant, spontaneous action potentials to be generated and a unique way of generating an action potential. (slow depolarization): Slow Na influx and a decreased K efflux, makes the cells more positive gradually. Rapid Depolarization: Calcium channels open, allowing the cells to be depolarized and action potential is reached. Repolarization: Inactivation of calcium channels and K channels are open, the cell repolarizes and Na channels begin to open allowing the cycle to restart. Which signs or symptoms suggest diagnosis of pectoris?

Pain is due to Angina Pectoris: accumulation of • Angina pectoris is a consequence of Myocardial metabolites (K + , A clinical Pain is caused PGs, , demand exceeding myocardial oxygen supply. syndrome of chest either by ….) pain (varying in • Mainly caused by obstruction of flow Resulting in obstruction (e.g. secondary to the severity) due to atherosclerotic ischemia. These ischemia of ischemia. plaque) or spasm metabolites are muscle body’s response to ischemia as vasodilators. Which signs or symptoms suggest diagnosis of angina pectoris? What is Basic mechanism of angina pectoris? 1 • Angina pectoris is a consequence of Myocardial oxygen A clinical syndrome of chest pain (varying in severity) due to ischemia of heart muscle demand exceeding myocardial oxygen supply. • Mainly caused by obstruction of blood flow Resulting in 2 Pain is caused either by obstruction (e.g. atherosclerotic ischemia. plaque) or spasm (usually causes pain even at rest)

Types: 3 Pain is due to accumulation of metabolites (K + , PGs, Kinins, Adenosine….) secondary to the ischemia. These metabolites are body’s response to ischemia as vasodilators. Stable Variant UnstableUnstable angina anginaangina anginaangina known as : known as : known as : Stable angina Variant angina

Effort-induced / typical / Effort-induced / typical / Accelerated angina known as : known as : classical / chronic classical / chronic Effort-induced, typical, Accelerated (Progressive) classical, chronic or crescendo Angina cause: cause: cause: reduction of coronary a form of acute coronary due to a fixed coronary spasm syndrome, caused by obstruction of a coronary (Alpha receptor mediated rupture of an artery produced by ) With or atherosclerotic plaque and atherosclerosis. The heart without Atherosclerotic partial or complete becomes vulnerable to plaque thrombosis of a coronary ischemia whenever there is -Reduction of coronary -A form of acute coronary -Coronary artery spasm artery increased demand perfusion due to a fixed syndrome, caused by (Alpha receptor mediated obstruction of a coronary rupture of an vasoconstriction) With or Frequency of pain: Frequency of pain: Frequency of pain: artery produced by atherosclerotic plaque and without Atherosclerotic Change in pattern of chronic atherosclerosis. partial or complete plaque Pain upon exertion Exercise angina: There’s increased The heart becomes thrombosis of a coronary -Pain even at rest. Pain even at rest. Emotion, Heavy meal frequency & duration of vulnerable when there’s artery. Treatment: pain. increased demand. -There’s increased -coronary vasodilators, Common treatment : Common treatment : Common treatment : -Pain occurs upon frequency & duration of such as and . coronary vasodilators, such as requires hospital admission exertion Exercise pain. calcium channel blockers th rest or nitroglycerin. nitroglycerin and calcium and more aggressive Emotion, Heavy meal. Treatment: 4 type: silent angina → Treatment: -Hospital admission and Ischemia without pain, the most channel blockers. therapy. -Rest or nitroglycerin more aggressive therapy. dangerous What are the determinants of oxygen demand and supply? Oxygen Demand

Myocardial Oxygen Myocardial Oxygen demand is determined demand is diminished 1 Oxygen Demand: by: by:

1- Reducing contractility Contractile Wall tension 2- Reducing heart rate state affected by: O₂ demand is O₂ demand is 3- Reducing the determined by: diminished by: 2- Ventricular 1- LV Pressure volume 4- Reducing the (Afterload). 1-Contractility 1-Reducing contractility (Afterload). 2-Heart rate 2-Reducing Heart rate 3-Wall tension(pressure exerted by the 3-Reducing the Preload fibers itself)(affected by): 4-Reducing the Afterload -LV pressure (Afterload) Peripheral Oxygen Supply -Ventricular volume (Preload)

Myocardial Oxygen Myocardial Oxygen supply is determined supply is enhanced by: by: 2 Oxygen Supply:

1- Reducing coronary Regional Arterio-venous vascular resistance. myocardial oxygen distribution difference. 2- Prolong diastolic period. O₂ supply is O₂ supply is 3- Dilating collateral determined by: enhanced by: Coronary blood vessels. flow, affected by: 4- Reducing external 1-Regional myocardial distribution 1-Reducing coronary vascular compression. 2-Arterio-Venous O₂ difference resistance (difference between O content between atria and 2 2-Reducing external 5- Reducing LV end ventricles, it increases during exercise) compression diastolic pressure. 3-Coronary blood flow (affected by): Coronary vascular 3-Reducing LV + diastolic pressure -Aortic pressure resistance. 4-Prolong diastolic period -Coronary vascular resistance 5-Dilating collateral vessels

6-Optimizing & RBCs It is important to point out that restoration of oxygen supply to ischemic should be restored 3 hours after ischemia at most, after that period the cells will be overly acidic due to lactate accumulation from anaerobic , and the introduction of oxygen to the damaged mitochondria will result in the formation of free radicals, particularly H2O2, as a final product of ETC, causing further damage to the cells and possible inflammatory reaction. This is known pathophysiologically as Inadequate Tissue Reperfusion. 1- Agents that improve symptoms and ischemia. Treatment of angina pectoris

1- Agents that improve symptoms and 2- Agents that improve prognosis Traditional Approaches New Approaches ischemia: (Halt progression, prevent acute insult, improve survival): Traditional Approaches: ● Nitrates. ● Metabolic acting ● Beta-blockers. agents, e.g. ● Nitrates. The main therapy of angina ● Calcium channel Trimetazidine. ● Beta-blockers. ● Calcium channel blockers (CCP). ● Potassium channels A ● (stops cholesterol blockers (CCB). openers, e.g. synthesis) . ● ACE inhibitors ● Late Na+ current New Approaches: C 2nd line or add up therapy ● Beta-blockers inhibition, e.g. . ● Metabolic acting agents, e.g. B ● Aspirin / other Trimetazidine. ● Sinus node inhibition, antiplatelet agents eg. . ● Potassium channels openers, e.g. Nicorandil. ● Late Na+ current inhibition, e.g. Ranolazine. ● Sinus node inhibition, eg. Ivabradine. (↓ Heart rate, without effectinging force of contraction)

2- Agents that improve prognosis (Halt progression, prevent acute insult, improve survival). General mechanism of antianginal Aspirin / other ACE Statins B-blockers antiplatelet inhibitors drugs: agents. Regional flow distribution Heart rate

Oxygen Oxygen Oxygen Cardiac extraction Supply = Demand contractility

Coronary Myocardial blood flow wall tension: -Preload Regional flow distribution: -Afterload Flow to ischemic subendocardial tissue improved by nitrates, CCBs, B-blockers Coronary blood flow: Increased by nitrates and CCBs Heart rate + Cardiac contractility: Decreased by B-blockers and some CCBs Preload: Decrease by nitrates Afterload: Decreased by CCBs Antianginal drugs: 1.Organic Nitrates

Classification Short acting Long Acting Nitroglycerine (GTN) & 1. Organic Nitrates Drugs -Prototype of organic nitrates dinitrate -active ingredient of dynamite (explosive material) Classification Short acting Long Acting •Given sublingual or transdermal patch • Very well absorbed . Mononitrate, Isosorbide mononitrate & or parenteral. 100% bioavailability Drugs Nitroglycerine (GTN) • Can’t be given orally, because it goes • The dinitrate undergoes denitration in dinitrate Pharmaco- through Significant first pass to two mononitrates ➜ both kinetics metabolism in the liver. possess antianginal activity which then •Given sublingual or transdermal patch • Very well absorbed . Mononitrate, • Only (10-20%) bioavailability (if given conjugate to glucuronic acid in liver. or parenteral. 100% bioavailability orally) • T1/2= 1-3 hours. • Can’t be given orally, because it goes • The dinitrate undergoes denitration ➜ • Excreted in urine. Pharmaco- through Significant first pass to two mononitrates both possess metabolism in the liver. antianginal activity which then kinetics • Only (10-20%) bioavailability (if given conjugate to glucuronic acid in liver. • Rapid for terminating an acute attack • For long-term persistent prophylaxis of orally) • T1/2= 1-3 hours. Main use of stable angina. stable angina. • Excreted in urine. IN STABLE ANGINA: IN STABLE ANGINA: ● Prevention; Persistant ● Acute symptom relief • Rapid for terminating an acute attack • For long-term persistent ➜ Main use ➜sublingual GTN prophylaxis Isosorbide mono of stable angina. prophylaxis of stable angina. if the patient or dinitrate. ● Prevention; Situational will do effort prophylaxis➜sublingual GTN • Sublingual tablets or spray: Have • Dinitrate Sublingual tablets. Indications IN VARIANT ANGINA➜ sublingual IN UNSTABLE ANGINA: rapid onset of action and short duration • Dinitrate Oral sustained release. GTN (30min), thus used for: • Mononitrate Oral sustained release. ● ➜ ➞ Acute symptom relief & Situational IN UNSTABLE ANGINA IV GTN CHF Isosorbide mononitrate + • Infusion Preparations. prophylaxis (as in before exercise) in stable ● [ if contraindication to ➞ Used In chronic heart failure Preparations & angina. ● Refractory AHF ➜IV GTN ACE Is used] Isosorbide mononitrate + hydralazine indications ➞ Also used for variant angina. ● AMI➜IV GTN as 2nd line treatment if • I.V. Preparations: used for unstable contraindication to ACEI. angina, refractory acute heart failure & ➞Also used in Persistent ● Sublingual tablets or spray Have rapid ● Dinitrate Sublingual tablets acute . onset of action and short duration ● Dinitrate Oral sustained release prophylaxis. • Transdermal patch (8-14h). (30min), ● Infusion Preparations ● Transdermal patch(8-14h) ● Mononitrate Oral sustained release • Oral or buccal sustained release. Preparations ● Oral or bucal sustained release ● I.V. Preparations 1. release nitric oxides through enzymatic reaction by nitrosothiols. then binds to in vascular cell 1. Release NO through interactions with intracellular SH groups to form cGMP. and with further enzymatic degradation, NO is produced. Not Active, needs to Mechanism 2. cGMP activates PKG (Protein Kinase G) be converted to Nitric oxide then binds to guanylate nitrosothiol which to produce relaxation contains sulfhydryl *For the action of Nitrates we need sulfur. Mechanism cyclase in cell group to form cGMP. The damaged in angina patients can’t 2. cGMP activates PKG (Protein Kinase G) produce NO, this group of to produce relaxation drugs donate it *For the action of Nitrates we need SH groups. • Nitrates can treat angina pectoris by one of 4 mechanism: 1- Decrease the preload (due to venodilation) • Nitrates can treat angina pectoris by one of 4 mechanism: 2-Increase the myocardial perfusion (O2 supply) by dilating the coronary 1- Decrease the preload (in low concentrations, it causes venodilation) vessels. 2-Increase the myocardial perfusion (O2 supply) by dilating the coronary vessels. Hemodynamic 3- Arterial ➞ ⬇ Afterload.() 3- Arterial vasodilation ➞ ⬇ Afterload. (in higher concentrations) effects of 4- Shunting of flow from normal area to Hemodynamic 4- Shunting of flow from normal area to ischemic area by dilating collateral vessels nitrates ischemic area by dilating collateral vessels effects of (blood in ischemic area increases). Collateral blood vessels are normally microvessels (blood in ischemic area increases). nitrates between , when an infarct happens adenosine from infarcted cells will be released causing a dilation in these vessels, but takes years for them to dilate sufficiently, therefore pharmacological intervention is preferrable. Antianginal drugs: Organic Nitrates (cont.) • WHEN ? Loss of vasodilator response of nitrates on use of long-acting • WHEN ? Loss of vasodilator response of nitrates on use of long-acting preparations (oral, transdermal) or continuous intravenous infusions, for more preparations (oral, transdermal) or continuous intravenous infusions, for more than a few hours without interruption. than a few hours without interruption. • How?, mechanism: • How?, mechanism: Like baroreceptors and RAAS tolerance 1. Compensatory neurohormonal counter-regulation 1. Compensatory neurohormonal counter-regulation due to continuous vasodilatation 2. Depletion of free-SH groups. (Note that For the action of Nitrates we need Nitrate tolerance 2. Depletion of free-SH groups. (Nitrates are converted to NO through sulfur.) various intermediate reactions that require SH groups from tissues for the • How to overcome tolerance? by: free periods (Smaller doses at increasing enzymes to function). intervals) & Giving drugs that maintain tissue SH group e.g. . • How to overcome tolerance? by: free periods (Smaller doses at increasing intervals) & Giving drugs that maintain tissue SH group e.g. Captopril, 1.Throbbing headache (most common), due to dilation of cranial blood vessels. N-acetyl . 2. Postural , and . ADRs 3.Reflex and palpitation. Leading to increasing oxygen demand. 1. Known sensitivity to organic nitrates. 4. of blush area (due to dilation of cutaneous blood vessels). 2. . nitrates increase synthesis of aqueous humor thus increase IOP 5. Rarely Methemoglobinemia 3. Head trauma or cerebral haemorrhage ➞ Increased intracranial pressure . 4. Uncorrected hypovolemia, because reduction of volume in the body will result in 1. Known sensitivity to organic nitrates. Contra- vasoconstriction. Hypovolemia must be corrected before administration of nitrates. 2. Glaucoma. nitrates increase synthesis of aqueous humor thus increase IOP 5. Concomitant administration of PDE5 Inhibitors. indications ➞ 3. Head trauma or cerebral haemorrhage ➞ Increased intracranial pressure . + nitrates Severe hypotension & death Sildenafil (viagra), inhibit PDE which responsible for 4. Uncorrected hypovolemia, because reduction of volume in the body will result in inactivation of cGMP , thus increase the effect of NO> vasoconstriction. Hypovolemia must be corrected before administration of nitrates. severe vasodilation lead to severe hypotension could Contra- 5. Concomitant administration of PDE5 Inhibitors. cause death. ● Sildenafil + nitrates ➞ Severe hypotension & death indications ADRs

Reflex tachycardia and Throbbing headache palpitation (most common), due to dilation of cranial Leading to increasing oxygen demand. blood vessels.

Flushing of blush area Postural hypotension , (due to dilation of cutaneous blood dizziness and syncope. vessels).

Rarely bind to HB, converts ferrous “Fe+2” to ferric “fe+3” Methemoglobinemia which's not able to carry O2 Effects of nitrates in treatment of angina and their results

Effects Results

↓ arterial pressure ↓ O2 demand

Reflex ↑ in contractility ↑ O2 demand

↑ Collateral flow Improved perfusion to ischemic myocardium

↓ Ventricular volume ↓ O2 demand

Reflex tachycardia ↑ O2 demand

↓ Left ventricular diastolic pressure Improve subendocardial perfusion

↓ Diastolic perfusion time due to tachycardia ↓ Myocardial perfusion

Vasodilatation of epicardial coronary arteries Relief of coronary artery spasm 2. Calcium channel blockers (CCBs) 2.Calcium Channel Blockers Class Dihydropyridine Phenylalkylamine Benzothiazepine classification: selectivity: ●Nifedipine Dihydropyridines: Selective for VSMCs more than Drugs ●Amlodepine Nifedipine, Nicardipine (short acting) myocytes. (VSMCs= vascular smooth Amlodepine (long acting). muscle cells). ●Nicardipine Drugs Dihydropyridine group act has intermediate Phenylalkylamines e.g. Verapamil. Cardiomyocytes more than VSMCs mainly on smooth muscle. Selectivit act more on myocardium effect. (thus, more selective as as cardiac . Do both actions but with y vasodilators than cardiac less effectiveness ). e.g. Diltiazem Intermediate (act on both) Calcium channel blockers ➞Bind to L Type Ca channels (the most important type, Calcium channel blockers ➞Bind to L Type Ca channels ➞ decrease their involved in anginal pain) ➞ decrease their frequency of opening in response to frequency of opening in response to depolarization ➞ ↓ entry of Ca ➞ ↓ Ca MOA depolarization ➞ ↓ entry of Ca ➞ ↓ Ca release from internal stores ➞ Mechanism release from internal stores ➞ No Stimulus-Contraction Coupling ➞ RELAXATION No Stimulus-Contraction Coupling ➞ RELAXATION 1-verapamil & diltiazem ↓ Cardiomyocyte Contraction ↓ VSMC Contraction ➞ arteriolar ↓ Cardiomyocyte Contraction ➞ (verapamil & diltiazem) vasodilation (as Dihydropyridines) ↓ cardiac work through their –ve inotropic & action ➞ Pharmac ↓ myocardial oxygen demand Pharmaco- o- 2-Dihydropyridines dynamic ↓ cardiac work through their –ve 1- ↓ Afterload ➞ ↓ cardiac work ➞ ↓ dynamic ↓ VSMC Contraction ➞ arteriolar vasodilation ↓ Afterload ➞ ↓ cardiac work ➞ ↓ Antianginal inotropic & chronotropic action ➞ myocardial oxygen demand Antiangin myocardial oxygen demand actions ↓ myocardial oxygen demand 2-coronary dilatation al actions

↑ myocardial oxygen supply 3-coronary dilatation ↑ myocardial oxygen supply

Stable Regular prophylaxis. • IN VARIANT ANGINA: Attacks are prevented by dilation of coronary vessels. Indication • IN UNSTABLE ANGINA: Seldom (rarely) added in refractory cases. Indications s Unstable Seldom (rarely) added in refractory cases.

• IN STABLE ANGINA: Regular prophylaxis. in Angina Variant Attacks are prevented

Should the short acting dihydropyridines (Nifedipine , Nicardipine) be AVOIDED? Yes, because it is a short acting calcium that works on blood vessels, which means that it will lead to vasodilation, hypotension, and syncope. Thus, the sympathetic response will be activated leading to reflex tachycardia, less diastolic duration, impaired coronary filling, ischemia or MI.

Is a a useful antianginal in patients with CHF (Congestive heart failure)?

Yes, dihydropyrdine.To reduce the afterload (vasodilator) and thus decrease the cardiac workload.

Can we combine Calcium Channel Blocker with a ? Except verapamil Yes, dihydropyrdine: because beta blockers work on the heart so we can not combine it with CCB that also works on the heart (cardiomyocyte). but we can give something that works on the like the long acting dihydropyrdnes: amlodepine

Can we combine Calcium Channel blocker with Nitrate ?

Yes, Verapamil: Because Nitrate is a vasodilator, that causes hypotension which leads to reflex tachycardia (increasing in the heart rate) and increasing in the force of contraction, so we can combine it with a CCB that works on the heart (cardiomyocyte) like verapamil to reduce the heart rate and the contraction. β blockers 3. β1 Selective blockers Drugs ● ● ●

Acts on cardiomyocyte: 1. Negative inotropic effect (force of contraction) Pharmaco- 2. Negative chronotropic effect (Heart rate = ) 3. ↓cardiac work dynamic 4. Increase diastolic duration Due to the bradycardia 5.Increase coronary blood flow 6.↓ myocardial oxygen demand 7.↑ myocardial oxygen supply.

1.Cardioselective (beta 1 blockers) are preferred Stable 2.prolonged use reduces incidence of sudden death by preventing ventricular tachycardia due to their antiarrhythmic action. Indication as Contraindicated, because they are ineffective and may actually Variant antianginal worsen symptoms.

Unstable halts (stops) progression to AMI improve survival

Indication as acute Given early to ↓ Infarct size, morbidity & mortality (↓ incidence of sudden death) Myocardial infarction

Are Cardioselective beta blockers preferred in angina?

Yes, beta 1 blockers are preferred, and non-selective beta blockers are better avoided as they block vasodilatory effects of sympathetic stimulation that tend to increase afterload & O2 consumption. Especially if the patient has tachycardia Prolong use of beta blocker reduces incidence of sudden death?

Yes, they are 1st choice on prolonged use to reduce incidence of sudden death especially due to preventing ventricular tachycardia by their antiarrhythmic action (the Negative chronotropic effect)

should Beta blocker be withdrawn gradually?

Yes, because sudden stoppage will give rise to a withdrawal syndrome: Increase pain, Rebound angina, , myocardial infarction & (due to stimulation or Up-regulation of beta-receptors).

Can we give a beta blocker to a diabetic patient with ischemic heart disease? if benefits are more than risks ﺑﺣذر ,We can give it CAUTIOUSLY They cause masking of in diabetics (increase insulin and reduce ) and mask its symptoms, they also inhibit the counter-regulatory mechanism and thus prevent recovery of hypoglycemia. They inhibit insulin release ﺑﺎﻟﺗﺎﻟﻲ ﻧﻘﯾس ﻓﺎﺋدﺗﮭﺎ ﻋﻠﻰ اﻟﻣرﯾض، إذا ﺿررھﺎ أﻛﺛر ﻣن ﻧﻔﻌﮭﺎ ﻓﺎﻷﻓﺿل طﺑﻌًﺎ ﻋدم إﻋطﺎءه. New Approaches Antianginal drugs: K+ Channel Openers 4. K+ channel openers Nicorandil

1.Opening of KATP channels. 2. Acting as NO donner

On VSMCs :K+ channel opening ➞ Hyperpolarization with shutting off the Pharmaco- calcium channel leading to relaxation ➞ dynamic VASODILATATION (improve coronary On VSMCs: (dual flow & ↓ afterload) NO donner ➞ cGMP/ PKG mechanism) ➞ VASODILATATION On Cardiomyocyte : K channel opening Repolarization ➞ relaxation of myocardial cells ➞ ↓ Cardiac work

1. Prophylactic 2nd line therapy in stable angina.

2. Refractory (not responding) variant angina if not responding to nitrate and Indications CCB.

Flushing, headache, Hypotension, palpitation (due to nitrate effect) ADRs Weakness, Mouth & peri-anal ulcers, and

5.Metabolically Acting Agents Drug Trimetazidine

During ischemia, metabolism shifts to oxidation of FFA (fatty acids), which provides more energy but requires more O2 than Pharmaco- dynamic utilization. So, to decrease O2 consumption & demand, we can (dual mechanism) enhance utilization of glucose (less O2 requirement) by giving Partial FFA Oxidation Inhibitors (e.g. Trimetazidine)

Used as an add on therapy Indications

GIT disturbances ADRs

• reaction Contra-

indications •In pregnancy & lactation (excreted in milk)

Trimetazidine Ranolazine

6.Late Na+ current inhibition

Drug Ranolazine Drugs Trimetazidine Ranolazine

•Inhibits the late sodium current, which increases during ischemia and affects Na -During ischemia, metabolism shifts to -Inhibits the late sodium current, Pharmaco dependent-Ca Channels The late sodium current is active in the plateau phase, it prolongs the plateau oxidation of FFA (fatty acids), which which increases during ischemia and -logical phase (therefore QT interval), trapping more Ca in the cell, normally we’d expect that by blocking the channel provides more energy but requires more affects Na dependent-Ca Channels the QT interval would be shortened, but this drug also blocks potassium efflux so the effect is reversed and it O2 than Glucose utilization. So, to causing after-depolarization contraction effect increases it. However, it has been shown that this mechanism decreased the risk of Torsades de pointes in susceptible patients (congenital QT syndromes, by preventing afterdepolarization by Na.) Pharmacolo decrease O2 consumption & demand, we gical effect can enhance utilization of glucose (less O2 requirement) by giving Partial FFA Used in chronic angina concomitantly (in combination) with other Oxidation Inhibitors (e.g. Trimetazidine) Indication drugs

Used as an add on therapy ADRs dizziness & Indication -

GIT disturbances Contra- indications - - ADRs •It prolongs the QT interval so contraindicated with Class Ia & III antiarrhythmic drugs . Precautions • Toxicity develops due to interaction with CYT 450 inhibitors as; diltiazem, ● Hypersensitivity reaction verapamil, ketoconazole, macrolide , grapefruit juice

● In pregnancy & lactation - Contra- indications 7.Sinus node inhibition ● It prolongs the QT interval so contraindicated with Class Ia & Drug Ivabradine III antiarrhythmic drugs ● Toxicity develops due to -Selectively blocks If - interaction with CYT 450 ( I current is an inward Na+/K+ current that activates pacemaker cells of the SA M.O.A f inhibitors as; diltiazem, node) verapamil, ketoconazole, Precautions macrolide antibiotics, Precautions Pharmaco -Acts on the “ Funny Channel” a special Na channel in SAN, reduces slope of grapefruit juice dynamic depolarization HR myocardial work Myocardial O2 demand effect

Indication -Used in treatment of chronic stable angina in patients with normal sinus rhythm 6.Ivabradine who cannot take ß-blockers. -Used in combination with beta blockers in people with heart failure with LVEF lower than 35 percent inadequately controlled by beta blockers alone and whose heart rate exceeds 70/min

ADRs luminous phenomena Helmi’s case Helmi, a 62-year-old male smoker with type 2 mellitus and hypertension presents with a 4-month history of exertional chest pain. Physical examination shows a of 152/90 mm Hg but is otherwise unremarkable. The ECG is normal, and laboratory tests show a fasting blood glucose value of 110 mg/dL, glycosylated hemoglobin 6.0%, creatinine 1.1 mg/dL, total cholesterol 160, LDL 120, HDL 38, and triglycerides 147 mg/dL. He exercises for 8 minutes, experiences chest pain, and is found to have a 2-mm ST-segment at the end of exercise.

Q1) Which signs or symptoms of Helmi A1) Exercise induce, chest pain and depression suggest diagnosis of angina pectoris? of ST segment*. *sign of ischemia. Questions and answers Q2) What lifestyle modifications should A2) Quit smoking, control of diabetes, diet Helmi carry out? control and moderate exercise. ● Q1) Which signs or symptoms of Helmi ● Q7)If Helmi was prescribed nitrates & suggest diagnosis of angina pectoris? tolerance developed to their effects, Q3) What triggers the onset of symptoms A3) Exercise. how to overcome tolerance to in Helmi case? -Exercise induced chest pain and nitrates? depression of ST segment. -Pain is caused either by obstruction,or Nitrate tolerance can be overcome by: Q4) What factors worsen the symptoms in A4) Smoking, hypertension, diabetes and spasm. Smaller doses at increasing intervals case of Helmi? enhanced LDL. (Nitrate free periods twice a day) & ● Q2) What triggers the onset of Giving drugs that maintain tissue SH symptoms in Helmi case? group e.g. Captopril. Q5) What is the possible underlying cause A5) Atherosclerotic plaque. of Helmi’s exertional pain? Exercise.(increase in cardiac demand) ● Q8) Which antianginal drug is the best choice for the case of Helmi? ● Q3)What factors worsen the symptoms And Why? Q6) If Helmi was prescribed nitrates & A6) Nitrate tolerance can be overcome by: in case of Helmi? tolerance developed to their effects, how to Smaller doses at increasing intervals (Nitrate We should avoid B-blocker because he overcome tolerance to nitrates? free periods twice a day) & Giving drugs that maintain tissue SH group e.g. Captopril. Smoking, hypertension, diabetes and is Diabetic , we can start with Nitrate or enhanced LDL. Ca++ channel blocker. A7) Nitroglycerine, if become tolerant to Q7) Which antianginal drug is the best nitrates choose Ca channel blockers or beta ● Q4) What lifestyle modifications ● Q9)If Helmi does not respond to choice for the case of Helmi? And Why? blockers. should Helmi carry out? monotherapy, what other drug should be added to his regimen? Quit smoking, control of diabetes, diet Q8) If Helmi does not respond to A8) Ca channel blockers (selective to blood control and moderate exercise. Aspirin, to improve prognosis monotherapy, what other drug should be vessels e.g. ) + beta blockers. and we will treat added to his regimen? ● Q5)What is the possible underlying Hypercholesterolaemia. cause of Helmi’s exertional pain? if this didn’t work, we will give add up Q9) Which antihyperlipidemic drug should A9) Statins, to decrease LDL levels. therapy be prescribed to Helmi? Coronary artery occlusion due to (2nd line) atherosclerotic plaque. ● Q10)Which antihyperlipidemic drug ● Q6)What are the determinants of should be prescribed to Helmi? oxygen demand & supply? Statins + QUIZ

1- A 52 year old man with stable Angina is participating in a race. Which of the following is the drug/administration method of choice: MCQ A) , orally. 1-A 72-year-old male presents to the primary care clinic complaining of chest tightness and B) Isosorbide dinitrate, transdermal patch. pressure that is increasing in severity and frequency. His current include atenolol, C) Nitroglycerin, subcutaneously. lisinopril, and nitroglycerin. Which intervention is most appropriate at this time? D) Nitroglycerin, orally.

A. Add amlodipine. B. Initiate isosorbide mononitrate. 2- Side effects of nitrates and nitrite drugs are, EXCEPT: C. Initiate ranolazine. D. Refer the patient to the nearest emergency room for evaluation.

A) 2- Which side effect is associated with amlodipine? B) Tachycardia and palpitation

C) GI disturbance A. Bradycardia. B. Cough. D) Throbbing Headache C. Tachycardia. D. QT prolongation.

3- A 47-year-old man recently diagnosed with stable angina started a treatment with 3- A 68-year-old male with a history of angina had a MI last month, and an echocardiogram sublingual nitroglycerin, as needed, and oral isosorbide mononitrate. Which of the following reveals heart failure with reduced . He was continued on his previous home is a potential detrimental effect of nitrates in the prophylactic treatment of stable angina? medications (diltiazem, enalapril, and nitroglycerin), and atenolol was added at discharge. He

has only had a few sporadic episodes of stable angina that are relieved with nitroglycerin or A) Decreased ejection time. rest. What are eventual goals for optimizing this regimen? B) Increased cardiac rate.

C) Increased capacitance of systemic . A. Add isosorbide mononitrate. B. Increase atenolol. D) Decreased arterial pressure. C. Stop atenolol and increase diltiazem. D. Stop diltiazem and change atenolol to bisoprolol

4- A 54-year-old man complained to his physician of , flushing of the face 4- Which of the following medications would be safe to use in a patient taking ranolazine? and . The man had been suffering for gastroesophageal reflux disease for three years. Two weeks ago he was diagnosed with exertional angina and started the A. Carbamazepine. B. Clarithromycin. prescribed therapy. Which of the following drugs most likely caused the patient's C. Enalapril. D. . symptoms?

5- Which medication should be prescribed to all anginal patients to treat an acute attack? A)

B) Verapamil A. Isosorbide dinitrate. B. Nitroglycerin patch. C) Nifedipine C. Nitroglycerin sublingual tablet or spray. D. Ranolazine. D) Nitroglycerin

6- A 65-year-old male experiences uncontrolled angina attacks that limit his ability to do 5- A 71-year-old man with congestive heart failure (treated with ) also suffers household chores. He is adherent to a maximized dose of β-blocker with a low heart rate and from angina. Which of the following is the drug of choice? low blood pressure. He was unable to tolerate an increase in isosorbide mononitrate due to

headache. Which is the most appropriate addition to his antianginal therapy? A) Amlodipine

B) Diltiazem A. Amlodipine. B. Aspirin. C) Verapamil C. Ranolazine. D. Verapamil. D) Nifedipine

6- Which of the following iscontraindicated in variant angina? C 6) C 5) C 4) D 3) C 2) D 1) A) Nicorandil B) Nicardipine C) Metoprolol D) Verapamil QUIZ

SAQ A 55 year old hypertensive woman presented to the clinic with episodes of severe crushing chest pain despite minimal to no effort exerted. Recently, her hypertension combined with her chest pain developed into CHF. Past medical history showed she had been taking NSAIDs to relieve the pain.

1) Which drug is most suitable to relieve her case? and mention Hemodynamic effects.

2) Name another drug that can be combined for better efficacy

3) What effect did NSAIDs have in making your drug choices? Answers: 1) Nitroglycerine (GTN) 2) - Venous vasodilation (Decrease the preload) and decrease diastolic pressure. - Coronary vasodilation (Increase the myocardial perfusion). - Arterial vasodilation (decrease afterload). - Shunting of flow from normal areato ischemic area by dilating collateral vessels.

2) Hydralazine.

3) They eliminated the option to use ACEi

GOOD LUCK

Team Leaders:

May Babaeer Zyad Aldosari

Team Members: Alwaleed Alsaleh Bassam Alkuwaiter Khalid Nagshabandi Mohaned Makkawi Mohamed ajaarm Mohamed alotaibi

Special thanks to: Nouf Alshammari

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