Module 3.2.1: VASODILATORS and ANTI-ANGINA Flashcards by He LP

Imbalance between oxygen requirement of the myocardium and oxygen supply

ISCHEMIC HEART DISEASE

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 Chest pain caused by the accumulation of metabolites
resulting from myocardial ischemia
 The most common condition involving tissue ischemia in
which vasodilator drugs are used
 Atheromatous obstruction of the large coronary vessels

Angina Pectoris

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 Character: Squeezing or pressing; substernal

 Precipitated by effort (“Angina of Effort)

Classic Angina

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 Duration:

Classic Angina

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 Change in character, frequency, and duration of chest pain
 “Crescendo” angina
 High risk for myocardial infarction

Unstable Angina

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Also called acute coronary syndrome, is caused by episodes of increased epicardial coronary artery resistance or small platelet clots occurring in the vicinity of an atherosclerotic plaque.

Unstable Angina

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Unstable Angina is sometimes also referred to as…

pre-infarction angina

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 Vasospastic or Prinzmetal angina

 Transient spasm of portions of the coronary arteries

Variant Angina

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mainstay of therapy for angina

Organic Nitrates

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important for prophylaxis

Calcium Channel Blockers

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not vasodilators, also important for prophylaxis

Beta Blockers

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….provide most of the therapeutic activity of oral nitrates

Dinitro derivatives (metabolites)

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 Sublingual route is preferred because it bypasses the hepatic circulation, drug is absorbed directly into the bloodstream

 Rapid absorption = rapid breakdown, resulting to a very short duration of its action (15-30mins)

 Once absorbed, nitrate compounds have half-lives of only 2-8mins

NITRATES/ NITRITES

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…active metabolite of ISDN (Isosorbide dinitrate); bioavailabity of 100%

Isosorbide mononitrate

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highly volatile, inhaled, avoid first-pass effect, but now obsolete for angina because of its unpleasant odor and short duration of action

Amyl nitrite

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The site of action of the nitrates will be the __________ of your blood vessels particularly the _______ of both the arteries and the veins.

smooth muscles

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prototype of nitrates/nitrites

Nitroglycerine

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[NITRATES/ NITRITES] MOA:

Nitroglycerin, once taken in undergoes Denitration (via __________ ) which causes the release of free nitrite ion, which is converted to nitric oxide that causes activation of _________, increasing cGMP causing smooth muscle relaxation

glutathione S transferase

guanyl cyclase

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… relaxes all types of smooth muscles; but only those that are found in the vasculature. No direct effect on cardiac or skeletal muscles

Nitroglycerine

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Nitrate Side effect:

Increased venous capacitance -> decreased cardiac output -> ________ & _________

orthostatic hypotension and syncope

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Nitrate Side effect:

Meningeal artery pulsations -> Increased cerebral blood flow -> ___________

throbbing headache

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Indirect effects of nitroglycerin -> due to compensatory response evoked by baroreceptors and hormonal mechanisms:

tachycardia and increased contractility

(if your blood vessels dilate, there’s increased capacitance, and decreased CO and BP, which will be detected by your baroreceptors, and in turn your baroreceptors will respond to counteract the hypotension by increasing the HR, thus tachycardia)

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o prototype drug for erectile dysfunction

o Increases cGMP by inhibiting its breakdown

o Taken orally

o Cannot be given together with
nitrates.

Sildenafil (Viagra)

(Sildenafil is also a vasodilator and if combined with nitrates will bring about profound hypotension. Before you prescribe Sildenafil, always ask if they are on nitrates.)

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o newer drug forms, both are PDE5 inhibitors

o Used for treatment of Erectile dysfunction

Tadalafil, vardenafil

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o the drug most commonly used in patients who do not respond to sildenafil o a PGE1 analog that can be injected directly into the cavernosa or placed in the urethra as a mini suppository

Alprostadil

o can be used by injection into the cavernosa o same with alprostadil will cause erection in most men who do not respond to sildenafil

Phentolamine

Nitroglycerin action on platelets:

decreased platelet aggregation | Which is beneficial because it will prevent clogging of narrowed coronaries. Anti-platelet/ Anti-thrombotic activity

Nitrite ion reacts with hemoglobin (which contains ferrous iron) to produce methemoglobin (which contains ferric iron). Methemoglobin has a very low affinity for oxygen, and large doses of nitrites can result in ...

pseudocyanosis, tissue hypoxia, and death

Nitrates are contraindicated, however, if ________

intracranial pressure is elevated.

continuous exposure to nitrates, will decrease/prolong the intended therapeutic effects, sometimes increase in dosage is needed

Tolerance

If on transdermal patches, we tell the patient to put it on for 8hrs, then remove it for 4hrs, and then put it back for another 12hrs

Nitrate-free Interval

Nitrate effect: | Reduction in oxygen consumption is the major mechanism for the relief of .....

Effort angina

Nitrate effect for relief of _____: | Relaxes the smooth muscle of the epicardial coronary arteries and relieving coronary artery spasm.

Variant Angina

Nitrates may exert their beneficial effects for relief of _____, both by:  dilating the epicardial coronary arteries  by simultaneously reducing myocardial oxygen demand

Unstable Angina

dominant type calcium channel in cardiac and smooth muscle

L type calcium channel

______ is the prototype of the dihydropyridine family of calcium channel blockers

Nifedipine

MOA: These drugs bind with receptors in the calcium channel >> reduce the frequency of opening in response to depolarization >> decreases transmembrane calcium current >> smooth muscle relaxation, reduction in contractility, decreased SA and AV node >> decreased conduction velocity

CALCIUM CHANNEL BLOCKERS

_____ is not only used as an anti-angina but also an anti-arrhythmic – can slow down arrhythmias by reducing electrical flow from SA & AV nodes.

Verapamil

a selective T-type calcium channel blocker that was introduced for antiarrhythmic use but has been withdrawn.

Mibefradilis

Potassium channels in vascular smooth muscle are inhibited by ______,thus limiting the vasodilation produced by this drug.

verapamil

Sodium channels as well as calcium channels are blocked by ______, an obsolete antiarrhythmic drug.

bepridil

_________ have a greater ratio of vascular smooth muscle effects relative to cardiac effects than do diltiazem and verapamil.

Dihydropyridines

_________ is claimed to be particularly selective for cerebral blood vessels.

Nimodipine

_____& _____ interact kinetically with the calcium channel receptor in a different manner than the dihydropyridines; they block tachycardias in calcium-dependent cells, eg, the atrioventricular node, more selectively than do the dihydropyridines.

Verapamil and diltiazem

_______ appear to block smooth muscle calcium channels at concentrations below those required for significant cardiac effects; they are therefore less depressant on the heart than verapamil or diltiazem.

Dihydropyridines

_____ appears to reduce morbidity after a subarachnoid hemorrhage; approved for use in patients who have had a hemorrhagic stroke, but it has recently been withdrawn.

Nimodipine

______ is used by intravenous and intracerebral arterial infusion to prevent cerebral vasospasm associated with stroke.

Nicardipine

______ is used by the intra-arterial route in stroke; some evidence suggests that calcium channel blockers may also reduce cerebral damage after thromboembolic stroke.

Verapamil

_____ increased the risk of myocardial infarction in patients with hypertension

Immediate-acting nifedipine

_____ have been reported to increase the risk of adverse cardiac events in patients with hypertension with or without diabetes

Dihydropyridines

_____ have the potential to enhance the risk of adverse cardiac events and should be avoided

short-acting calcium channel blockers

TOXICITY: [CALCIUM CHANNEL BLOCKER] Especially Vermapamil…

 Cardiac depression -> cardiac arrest  Bradycardia  AV block  Heart failure

significant reflex tachycardia in response to hypotension occurs most frequently with _____ and less so with _____ and _____.

nifedipine | diltiazem and verapamil

______ does not affect atrioventricular conduction

Nifedipine

Nonspecific sympathetic antagonism is most marked with ______ and much less with _______.

diltiazem | verapamil

 Beneficial effects are due to their hemodynamic effects |  Decrease heart rate, decrease BP, decrease contractility, decrease myocardial O2 demand

BETA BLOCKERS

May also be valuable in treating silent or ambulatory ischemia

BETA BLOCKERS

Decreases mortality of patients with recent myocardial infarction and improves survival and prevents stroke in patients with hypertension

BETA BLOCKERS

Undesirable effects of B-blocking agents in angina include an ______ and an ______, both of which tend to increase myocardial oxygen requirement

increase in end-diastolic volume | increase in ejection time

BETA BLOCKERS | Contraindications

 Asthma  Severe bradycardia  AV block  Severe LV failure

BETA BLOCKERS | Potential complications

fatigue, impaired exercise tolerance, insomnia, unpleasant dreams, worsening of claudication, and erectile dysfunction.

 Metabolic inhibitors  MOA: Inhibition of fatty acid oxidation in the myocardium >> reduced oxygen requirement

pFOX Inhibitors

...increases elasticity of RBCs, enabling it to roll upon itself, which allows it to pass through even narrow vessels

Trimetazidine

Trimetrazidine before was _____. They say that it is also an oxygen free radical scavenger.

Vastarel

MOA: Reduce cardiac rate thru inhibition of hyperpolarization-activated sodium channel in the SA node >> decrease myocardial O2 demand

Sodium Channel Blockers | - Ibavradine

Very similar to nitroglycerin, slightly longer duration of action

Isosorbide dinitrate

Active metabolite of the dinitrate; used orally for prophylaxis

Isosorbide mononitrate

MOA: Releases nitric oxide in smooth muscle, which activates guanylyl cyclase and increases cGMP

Nitroglycerin

EFFECTS: * Smooth muscle relaxation, especially in vessels * other smooth muscle is relaxed but not as markedly * vasodilation decreases venous return and heart size * may increase coronary flow in some areas and in variant angina

Nitroglycerin

TOXICITY: * Orthostatic hypotension, * tachycardia, * headache * Interactions: Synergistic hypotension with phosphodiesterase type 5 inhibitors (sildenafil, etc)

Nitroglycerin

MOA: Nonselective competitive antagonist at Beta adrenoceptors

BETA BLOCKERS | • Propranolol

EFFECTS: * Decreased heart rate, * cardiac output, and * blood pressure * decreases myocardial oxygen demand

Propranolol

[CLINICAL APPLICATION] Prophylaxis of angina

Propranolol

[CLINICAL APPLICATION] Angina: • Sublingual form for acute episodes • oral and transdermal forms for prophylaxis • IV form for acute coronary syndrome

Nitroglycerin

TOXICITY: * Asthma, * atrioventricular block, * acute heart failure, sedation * Interactions: Additive with all cardiac depressants

Propranolol

Beta1-Selective blockers, less risk of bronchospasm

Atenolol, metoprolol

MOA: Nonselective block of L-type calcium channels in vessels and heart

Verapamil, diltiazem

EFFECTS: Reduced vascular resistance, cardiac rate, and cardiac force results in decreased oxygen demand

Verapamil, diltiazem

TOXICITY: Atrioventricular block, acute heart failure; constipation, edema

Verapamil, diltiazem

MOA: Block of vascular L type calcium channels > cardiac channels

Nifedipine | a dihydropyridine

EFFECTS: Like verapamil and diltiazem; less cardiac effect

Nifedipine | a dihydropyridine

TOXICITY: | Excessive hypotension

Nifedipine | a dihydropyridine

MOA: Investigational inhibitor of sinoatrial pacemaker; reduction of heart rate reduces oxygen demand

Ivabradine

MOA: Inhibits late sodium current in heart, also may modify fatty acid oxidation

Ranolazine

EFFECTS: * Reduces cardiac oxygen demand * fatty acid oxidation modification may improve efficiency of cardiac oxygen utilization

Ranolazine

TOXICITY: • QT interval prolongation, nausea, constipation, dizziness • Interactions: Inhibitors of CYP3A increases this drug's concentration and duration of action

Ranolazine