Module 3.2.1: VASODILATORS and ANTI-ANGINA Flashcards
Imbalance between oxygen requirement of the myocardium and oxygen supply
ISCHEMIC HEART DISEASE
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
Character: Squeezing or pressing; substernal
Precipitated by effort (“Angina of Effort)
Classic Angina
Duration:
Classic Angina
Change in character, frequency, and duration of chest pain
“Crescendo” angina
High risk for myocardial infarction
Unstable Angina
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
Unstable Angina is sometimes also referred to as…
pre-infarction angina
Vasospastic or Prinzmetal angina
Transient spasm of portions of the coronary arteries
Variant Angina
mainstay of therapy for angina
Organic Nitrates
important for prophylaxis
Calcium Channel Blockers
not vasodilators, also important for prophylaxis
Beta Blockers
….provide most of the therapeutic activity of oral nitrates
Dinitro derivatives (metabolites)
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
…active metabolite of ISDN (Isosorbide dinitrate); bioavailabity of 100%
Isosorbide mononitrate
highly volatile, inhaled, avoid first-pass effect, but now obsolete for angina because of its unpleasant odor and short duration of action
Amyl nitrite
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
prototype of nitrates/nitrites
Nitroglycerine
[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
… relaxes all types of smooth muscles; but only those that are found in the vasculature. No direct effect on cardiac or skeletal muscles
Nitroglycerine
Nitrate Side effect:
Increased venous capacitance -> decreased cardiac output -> ________ & _________
orthostatic hypotension and syncope
Nitrate Side effect:
Meningeal artery pulsations -> Increased cerebral blood flow -> ___________
throbbing headache
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)
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.)
o newer drug forms, both are PDE5 inhibitors
o Used for treatment of Erectile dysfunction
Tadalafil, vardenafil
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»_space; reduce the frequency of opening in response to depolarization»_space; decreases transmembrane calcium current»_space; smooth muscle relaxation, reduction in contractility, decreased SA and AV node»_space; 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»_space; 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»_space; 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
