Download Pharm 7- Vasodilators Hypertension, Angina (Exertional, variant

Pharm 7- Vasodilators
Hypertension, Angina (Exertional, variant (at rest), unstable (acute coronary syndrome—coronary
thrombosis), Arrhythmias
CCB’s
Bind L type Ca channel and inhibit calcium influx
Cardiac: decrease contractility (negative inotropic effect), SA node automatic (negative
chronotropic), decrease AV node conduction (negative dromotropic)
Smooth muscle: vasodilation (decreases PVR)
Dihydropyridines (bv’s): Nifedipine, Amlodipine, etc
Get baroreceptor response (increase HR when vasodilates)
AE’s: peripheral edema (dose-dependent, bilat, not caused by fluid overload), gingival
hyperplasia, reflex tachycardia
CI’s: unstable angina (Short-acting—ie Nifedipine)
Non-dihydropyridines (heart): Verapamil, diltiazem
AE’s: Bradycardia, Constipation
CI’s: acute MI, severe LV dysfunction, sick sinus syndrome, 2nd or 3rd degree AV block
DI’s: All 3A4 substrates, inhibit 3A4 (simvastatin, alprazolam, cyclosporine)
Verapamil inceases serum digoxin 50-75%-- inhibits renal clearance
Bradycardia with BB’s, hypotension with other antihypertensives
FDA Cat C—DHP’s used for preterm labor “tocolytic”—relax the uterine smooth muscle
Preferred in pregnancy due to lack of effects on cardiac conduction
All CCB’s come in long-acting products—short half-life (except amlodipine that doesn’t need it)
Nifedipine, verapamil and diltiazem in IV form
Vascular smooth muscle is more sensitive to CCB’s than bronchiolar, GI and uterine smooth muscle
Clinical Use: Hypertension: use long-acting agents; AA’s respond well
Angina: alternative to BB (but not first choice for secondary cardiac protection)
Do not use in heart failure (cannot prevent ventricular dilatation)
Evidence (CV events):
Primary prevention with amlodipine- equivalent to thiazide diuretic or ACE inhibitor
Primary protection with verapamil- similar to diuretic or BB based therapy
Nordic Diltiazem: overall CV event rates similar for diltiazem and combo of diuretic and BB
Hypertension: arterial vasodilation (DHP>non-DHP)
Angina: Both classes of drugs work (coronary artery vasodilation, arterial vasodilation (reduce afterload
and decrease IV pressure); relieve and prevent coronary vasospasms in variant angina
Non-DHPs: decrese contractility and HR (reduce myocardial O2 consumption)
Arrhythmia: Non-DHPs only—reduce SA node firing and AV node conduction
Nimodipine: CCB with more effect on cerebral vessels (subarachnoid hemorrhage)
Pharm 7- Vasodilators
Other Vasodilators
Hydralazine
MOA: unclear, possible inhibits release of Ca2+ in arteries, may stimulate NO release
Potent arteriolar vasodilator reflex tachycardia
Decrease arterial pressure kidney system retains salt and water to increase the pressure
must block the other pathways to keep the water off
Baroreceptors will increase renin, heart tachycardia (BB to prevent the sympathetic output)
Must give with other drugs to keep the
Indications: Hypertensive emergency, preeclampsia/eclampsia, heart failure (with nitrates)
Hypertension: arterial vasodilation
Heart failure: reduced afterload and IV pressure (reduced myocardial O2 consumption)
Pharmacokinetics: metabolized hepatically via acetylation (slow acetylatiors have stronger effects)
Dose 3 times daily
AE’s: tachycardia, peripheral edema, Systemic Lupus Erythematosus (SLE)
SLE: 10-20% high doses (400 mg), slow acetylators
Lupus-like syndrome: arthralgia, myalgia, skin rash, fever (goes away when stop drug)
DI’s: additive hypotensive effects
Precaution: pt with Ischemic heart disease use drug, reflex tachycardia angina, ischemic arrhythmias
Minoxidil
MOA: K+ atp Channel opener; hyperpolarizes vascular smooth muscle cells (attenuates cellular response
to depolarizing stimuli)
Powerful arteriolar vasodilator (peripheral edema and reflex tachycardia)
Coprescribe betablocker and loop diuretic
Pharmacokinetics: peak time is slow, so do not use in a hypertensive emergency (duration 24hr)
AE’s: headache, sweating, tachycardia, peripheral edema, hypertrichosis (hair growth)
DI’s: additive hypotensive effects
Neither hydralazine nor minoxidil are preferred in hypertension management due to lack or morbidity
and mortality benefit and AEs
Fenoldopam
MOA: Agonist at dopamine D1 receptor dilates arterioles in systemic vascular beds
Coronary, Renal, Mesenteric vessels
Admin IV for severe HTN
AE’s: reflex tachycardia, headache, flushing, hypokalemia
Cautions: glaucoma (increase IOP), BB’s, acetaminophen
Diazoxide
Long-acting parenteral arteriolar vasodilator
Not used for hypertensive emergencies anymore due to AE’s (excessive hypotension ischemia)
Indicated for hypoglycemia due to insulinoma (inhibits insulin release from pancreas)
Pharm 7- Vasodilators
Nitric Oxide
Nitroprusside, Organic nitrates (nitroglycerine, isosorbide di/mono nitrate; amyl nitrite
NO Donors: biotransformation liberates NO activate guanylyl cyclase increases cyclic guanosine
activates cGMP-dependent protein kinase (PKG) PKG phosphorylates myosin-light chain
phosphate MLCP dephosphorylates myosin light chain phosphate muscle relaxation
vasodilation
Nitroprusside
Pharmacology: MOA of NO release is unclear (enzymatic or nonenzymatic)
Non-selective vasodilator (dilates arterial and venous vessels)
Do NOT develop tolerance to nitroprusside unlike nitroglycerine
Only a modest increase in heart rate—net decrease in myocardial O2 consumption
Pharmacokinetics: Complex of iron, cyanide, nitroso
Metabolized by rapid uptake into RBCs with liberation of cyanide thiocyanate (leaves in ECF)
With prolonged administration, thiocyanate may accumulate (esp in renal insufficiency)
Indication: Hypertensive emergency (IV, onset within 30sec, peak 2min, cessation 3min)
Toxicity: thiocyanate accumulation (weakness, disorientation, psychosis, muscle spasms, convulsions)
Nitroglycerin (glyceryl trinitrate)
Decomposes rapidly because of air—make sure it stays in date
Angina: give sublingual form
Control Angina: ER product with longer duration of action
Require an on/off period (give once a day)
Pharmacology: requires exzymatic activity to release NO
Denitrated by: glutathione S-transferase, Aldehyde dehydrogenase isoform 2 (ALDH2) most imp
1,2-dinitroglycerin provides most vasodilator activity
Clinical Use: all 3 types on angina
IV to treat MI to increase coronary blood flow in ischemic areas
Relaxes venous smooth muscle: increase venous capacitance, reduce preload (decrease O2
consumption)
AE’s: excessive vasodilation headache, hypotension, dizziness, reflex tachycardia
Remove patch before use of external defibrillators
DI’s: Sildenafil extreme hypotension (increase cGMP, decrease breakdown of cGMP)
Tachyphlaxis: tolerance attenuation of pharmacologic effects
Nitrate-free interval of 8-10h/day to restore responsiveness
Tolerance to nitroglycerin is greater than other nitrates
Mechanism: systemic compensation, inhbits guanylate cyclase
Oxidation and inactivation of ALDH2 (prevents enzymatic activation of nitroglycerin
Treatment of cyanide poisoning: amyl nitrite, sodium nitrite, sodium thiosulfate
CN tox is result of mitochondrial respiratory chan collapse caused by high affinity of CN for
cytochrome C-oxidase and methemoglobin
High dose of nitrates converts hemoglobin to methemoglobin (pulls cyanide off cytochrome)
Cyanmethemoglobin to thiocyanate ion less toxic product that can be excreted
Pharm 7- Vasodilators