A-23. Drugs used for hypertension II. Ca2+-channel blockers and other vasodilators Flashcards
What are the dihydropyridine calcium channel blockers (10)
Nifedipine Nitrendipine Nimodipine Nicardipine Nisoldipine Clevidipine Felodipine Amlodipine Lacidipine Isradipine
What is the phenylalkylamines calcium channel blockers
Verapamil
What are the Benzothiazepine calcium channel blockers?
Diltiazem
Mode of action of calcium channel blockers?
Inhibition of L-type calcium channel
Where do CCB have their effect?
They cause vasodilation and reduces BP in the smooth muscle, including bronchiolar, GI, and uterine SM
(Makes them good meds for COPD since they relax the bronchi SM)
And in some cases (Verapamil, Diltiazem) affect cardiac muscle as well
Which CCB are coronary specific
Nicardipine and nisoldipine (50x more affinity)
Which CCB is cerebral vessel specific
Nimodipine
The CCB that act on cardiac muscle specifically causes?
act on L type calcium channel causing decreased pacemaker activity, AV conduction, and contractility
Indications of CCB listed
- ) Hypertension
- ) Angina
- ) Arrhythmias
- ) Atherosclerosis
- ) Raunaud’s phenomenon
- ) Peripheral vasoconstriction
- ) Migraine prophylaxis
- ) GI spasms
- ) Subarachnoid hemorrhage prevention
Which CCB is used in pregnancy? In combination of what?
In the 1st and 2nd trimester nifedipine is used in combo with alpha-methyldopa
What is used in hypertensive emergencies? Chronic?
Sublingual/mouth spray nifedipine (5 min onset) or IV nifedipine/clevidipine
For chronic treatment use longer release CCB
How does CCB work for Angina and which drugs?
Used for Prinzmetal Angina?
Effort Angina?
1.)They increase peripheral vasodilation decreasing afterload
2.)Coronary vasodilation (such as Nifedipine and nicardipine)
3.)Cardio-depressant effects and tissue protective effects via decreased Ca levels causes decreased oxidation
Prinzmetal angina is treated with any CCB as first line treatment (usually nifedipine)
Effort angina treated with verapamil or diltiazem, decreased inotropy causes decreased load on heart and longer time in diastole phase (more oxygen)
Unstable angina contraindications?
Nifedipine is contraindicated due to coronary steal syndrome and reflex tachycardia
Drugs used in Supraventricular tachycardias like A Fib
Verapamil and Diltiazem
CCBs used in atherosclerosis
Lacidipine and isradipine
Lacidipine mechanism of action
high affinity for cholesterol rich tissues, so atherosclerotic plaque, and slowly diffuses out to receptor like depot
Isradipine MOA
Improves lipid profile and increases HDL
Nimodipine used for?
subarachnoid hemorrhage prevention in patients with berry aneurysms or prevent vasospasms following an SAH
Which drug is used for Migraine
Verapamil
Which drug is used for GI spasms
Pinacerine
Kinetics of of CCBs
Good oral absorption, high pass effect, high plasma protein binding, and extensive metabolism
Short acting (2-7 hours) CCBs
Verapamil, Diltiazem, Nicardipine, Nimodipine, and Nifedipine (the shortest acting one lasting 2 hours)
Medium acting (8-11 hours) CCBs
Isradipine, Nisoldipine, and Nitrendipine
Long acting (11-50 hours) CCBs
Amlodipine, Lacidipine
Adverse effects of CCBs
- ) Cardiac depression
- Verapamil and diltiazem causes bradycardia, AV block, and cardiac arrest - ) Reflex Tachycardia (usually fast acting drugs)
- immediate-acting nifedipine increases MI risk in HF patients via increased HR - )Gingival Hyperplasia (with verapamil)
- )Vasodilatory side effects-flushing, dizziness, headache, peripheral edema
- ) GI effects- nausea, constipation (via GI SM relaxation; >25% with verapamil)
Contraindications/Interaction of CCBs
Heart block
Heart failure in advanced or acute HF
Beta blockers- coadministration of BB and non-DHPs can excessively depress nodal/ventricular function however BBs can be helpful with DHPs to decreased reflex tachycardia
Specific Drugs contraindications
Verapamil- greatest cardio-depressant effects
Diltiazem- intermediate cardio-depressive and vasodilatory effects
Nifedipine- higher risk of sfx: flushing, headache and edema; increased mortality risk in post-MI patient due to reflex tachycardia
Nitrate mode of action?
Metabolism in the vascular SM by CYP450 and glutathione S-thransferase causes the release of NO.
NO activates guanylate cylcase increasing cGMP leading to decrease IC Ca2+ and MLC kinase activity causing relaxation of SM and vasodilation
Where do Nitrates have their effect in low doses?
High doses?
Dilates coronaries and vein to decrease preload. In higher doses dilates arteries/arterioles decreasing afterload
What causes tolerance of Nitrates?
metabolism requires -SH group; eventual sulfhydryl depletion
Drugs that reduce the tolerance of nitrates? How do they reduce tolerance
NAS, captopril, antioxidants, or periodic withdrawal will decrease tolerance
Contain sulfhydryl group so can replace metabolized store and remove free radicals
What are the relevant cardiomyocyte function done by nitrates
ATP-dependent K+ channels stimulation reducing intracellular Ca2+ which is high in IHD
Which form of nitrates forms tolerance quicker?
Pills and transdermal pathces
Name of nitrate drugs
- )Nitroglycerin
- )Isosorbide mononitrate
- )Isosorbide dinitrate
- )Amylium nitricum
Nitroglycerin sublingual and oral onset time? DOA?
- ) Sublingual onset is 2-3 minutes with a DOA of 2-3 hours
2. ) Oral onset is longer and DOA is 3-5 hours
Isosorbide mononitrate onset and DOA?
Oral med that takes half an hour-2 hours onset with a 12-14 hour duration
Isosorbide dinitrate absorption. Sublingual and oral onset and DOA?
transformed to mononitrate in liver. Sublingual 5-10 minute onset with a 1 duration of action
Oral onset is 2-4 hour onset and 8 hour duration of action
Amylium nitricum inhaled onset and duration of action
NOT used anymore as a drug in regular practice.
Fast onset with 5 min duration of action
Indications of Nitrate drugs?
- ) Angina- chronic stable (effort) and Prinzmetal angina (w/ CCB + BB)
- )Acute coronary syndromes
- ) Hypertensive emergency
- ) pulmonary edema- as an acute treatment
- ) Ischemic Heart Disease
Contraindication of Nitrate drugs
- ) Right-sided MI due to decreased RV preload (instead IV fluids to increase preload)
- ) PDE5 inhibitor treatment- sildenafil should not be taken within 24 hours of nitrates
- ) HOCM- LV outlfow obstruction + resultant decrease in ejection fraction is worsened by decreased preload from nitrate
Side effects of Nitrate drugs
Lose dose
1.) Headache- strong cerebral vasodilation; increase migraine attack risk
2.) Flushing and dizziness
High dose
1.) Orthostatic hypotension- via venous pooling
2.) Reflex tachycardia- coadmin BB to counteract this
3.) Methemoglobinemia- Prolonged IV infusion; nitrite reacts with hemoglobin causing ferrous to ferric iron conversion in Hgb which lowers Hemoglobin affinity for O2
Nirate-related drugs (2 drugs)
Nicorandil and Molsidomin
MOA of Nicorandil
NO donor (less tolerance) and direct ATP-dependent K+ channel stimulator -decreases preload and dilates coronaries
MOA of Molsidomin
SIN-1 (active metabolite) direct vasodilaters and a spontaneous NO donor (doesn’t need -SH enzymes)
-Decreases preload and dilates the coronaries
Other Vasodilators (5 drugs)
- ) Sodium Nitroprusside
- ) Minoxidil
- ) Diazoxide
- ) Hydralazine
- ) Dihydralazine
Sodium Nitroprusside MOA
Releases NO causing systemic vasodilation (both arterial and venous) which decreases pre/afterload almost immediately
Sodium Nitroprusside Indications
Hypertensive emergency and severe HF that is refractory (doesn’t respond to any other drugs)
Sodium Nitroprusside Side Effects
- ) Lactic acidosis from CN- release causing altered mental status/seizures, monitor lactate continuously
- ) Intoxication after 2 days use causes headache, nausea, vomiting, and disorientation
- )Hypotension
Sodium Nitroprusside Kinetics and byproduct
Onset is 30 seconds and 3 of DOA (given in slow infusion for long duration)
-Sulphocyanide is formed from it in the liver leading to side effects; elimination takes 3 days to occur
Minoxidil and Diazoxide MOA
Stimulates ATP-dependent K channels causing hyperpolarization leading to inhibit Ca influx=SM relaxation
Mainly arterial vasodilation
Minoxidil and Diazoxide side effects
- ) Salt and water retention via indirect renin section increases
- )Increased blood glucose (hyperglycemia)- stimulation of beta cells SUR K channels
- ) Increased Uric acid (hyperuricemia)
- ) Increased hair growth- minoxidil is used as a topical cream for hair loss
Minoxidil and Diazoxide indication
Hypertensive emergencies- combine with BB to reduce tachycardia and diuretic to decrease Na/water retention
Minoxidil and Diazoxide contraindications
Ischemic heart disease since they cause reflex tachycardia
Hydralazine and Dihydralazine MOA
Direct arteriolar dilation (little effect on veins) causing decreased afterload
Hydralazine and Dihydralazine kinetics
Parenteral administration
Hydralazine and Dihyrdalazine Indications
Hypertension emergencies, safe in pregnancy so used in pre-eclampsia
(In combo with nitrate venodilator, to treat symptoms and decrease in LV dysfunction HF)
Hydralazine and Dihyrdalazine Side Effects
- Sudden hypotension- reflex tachycardia and Na/water retention (via SNS and RAAS activation) and may worsen angina (often co-admin with BB to counterat this)
- Lupus-like syndrome athralgia, myalgia, percarditis, pleuritis, rash and fever
