| What are drugs controlling vascular tone? | Ca Channel blockers, Organic Nitrates, Sodium Nitroprusside, a1 adrenergic antagonists, a2 adrenergic antagonists, Potassium Channel Openers |
| How is mechanism of action of Ca channel blockers? | CCB prevent the entry of Ca to myocytes (smooth muscles mainly) through the L type Ca channels by binding on the a1 site, this leads to less actin-myosin interaction thus relaxation of different types of smooth muscles causing vasodilation, in addition to blocking of myocardial contractility, decreased HR and decreased velocity of conduction w/in heart (negative ionotropy, chronotropy, and dromotropy) |
| What are types of angina? | Classical (Stable, due to atherosclerosis reduced blood flow to heart)
Variant/Prinzmetal's (due to coronary vasospasm)
Unstable Angina (progression of coronary artery occlusion, rupture of atheromatous plaque and platelet aggregation |
| What are main classes of Ca Channel Blockers? | Phenilalkylamines (Verapamil)
Benzothiazepines (Diltiazem)
Dihydropyridines (1st gen : Nifedipine, 2nd gen: Isradipine/ Nicardipine/ Felodipine, 3rd gen: Amlodipine)
Each has different pharmacokinetics and clinical indications. |
| What is Verapamil? | Phenylalkylamine, slows cardiac AV conduction and decreases HR, contractility and O2 demand and BP.
Used to treat angina and SVTs and HTA
Greater negative inotropic (contractility) effect than Nifedipine but is a weaker vasodilator.
Extensively metabolized by liver (careful for Liver disease)
Contraindication (depressed cardiac function/ AV conduction abnormality)
Side effects (Constipation) |
| What is Diltiazem? | Benzothiazepine, both cardiac and vascular effects.
Decrease SA and AV node and negative inotropic effect.
Reduces HR (less than verapamil) and BP
Anti HTA, Anti Arrythmia in case of paroxysmal SVT, chronic stable angins.
relieves coronary vasospasm so useful in variant angina.
Metabolized extensively by liver.
Favorable side effect profile |
| What is Nifedipine? | Dihydropyridine 1st gen, mainly arteriolar vasodilator.
Minimal effect on cardiac conduction and HR
Useful for angina by spontaneous coronary vasospasm
Oral short T1/2, hepatic metabolism eliminated in urine and feces
Side effects (flushing, headache, hypotension, peripheral edema and constipation (Major))
May cause reflex tachycardia if marked vasodilation |
| What is Amlodipine? | Dihydropyridine 3rd gen, ideal for outpatient use because of extended anti HTA effect <30 hours but not ideal for inpatient due to delayed onset (1-2 days)
NOTE that Nifedipine is better for inpatient (lowers BP for 6-8 hours <24 hours) |
| How is pharmacokinetics of Ca channel blockers? | A: PO (all), IV (Diltiazem and verapamil)
Bioavailability (Nifedipine, diltiazem and verapamil low bioavailability due to first-pass)
Onset (w/in 30-60 min oral dose except ones that are more slowly acting (Amlodipine))
Distribution (bind plasma proteins (90%) most have short half-life (3-8 hours) except amlodipine no need for sustained release formulation)
Excretion (Nifedipine and Verapamil by kidney, Diltiazem by liver) |
| What are therapeutic uses of Ca channel blockers? | Management of HTA, initial therapy or add-on, if people have asthma, diabetes and HTA better than B blockers
Treat Angina
A fib treated (Diltiazem and Verapamil) |
| Table for Ca channel blockers action as antiarrythmatic? | . |
| What are Ca channel blockers side effects? | First degree AV block and constipation (dose dependent Verapamil)
Should be avoided in pt w/HF/AV blocks (Verapamil and Diltiazem)
Dizziness, headaches, fatigue, peripheral edema
Gingival hyperplasia (Nifedipine) |
| How is mechanism of action of organic nitrates? | Simple nitric and nitrous esters of glycerol, NO activates guanylyl cyclase, increases cGMP, dephosphorylates myosin causing relaxation of smooth muscles, so rapid decrease in O2 demand leading to rapid resolution of symptoms of angina. |
| How is pharmacological action of nitrates? | Venous dilation more than arterial
Coronary artery dilation (decrease bed resistance [relieved vasospasm], increase flow and increase O2 supply)
Reduction on peripheral arterial pressure (secondary to dilatation of aorta, decrease BP)
Dilation of large veins (decrease afterload, preload, O2 demand) |
| What are indications for organic nitrates/nitroglycerin? | They represent oldest cardiac therapies, nitroglycerin is short acting, others are long acting (Isosorbide)
Indications (Stable angina, unstable angina, variant angina, MI, acute/chronic HF) |
| What are adverse effects and contraindications of organic nitrates? | Adverse effects (severe headache, flushing of face, dizziness, postural HTA , tachycardia, methemogloinemia long term agents)
Contraindications (pt w/intracranial pressure (dilation of intracranial arteries ) and obstructive cardiomyopathy (decreased preload worsens obstruction) |
| How is organic nitrates drug-drug interaction? | The combination of Sildenafil and other phosphodiesterase 5 (PDE5) inhibitors with organic nitrate vasodilators can cause extreme hypotension.
(PDE5) is responsible of the metabolic degradation of cGMP |
| How is tolerance of nitrates? | Tolerance to the actions of nitrates develops rapidly for their vasodilatory effects.
Tolerance to nitroglycerin in vivo is associated with reduced biotransformation ofnitrates to NO by endothelial intracellular sulfhydryl depletion as a cause oftolerance.
This abnormality in nitrate biotransformation is associated with increasedmitochondrial formation of free radical oxygen species
Tolerance can be overcome by providing a “daily nitrate free interval” to restoresensitivity to the drug, typically 10 to 12 hours. |
| How is structure of sodium nitroprusside? | Sodium nitroprusside is a nitrate compound that consists of a nitroso group, five cyanide groups, and an
iron atom |
| How is mechanism of action of sodium nitroprusside? | • Sodium nitroprusside is a nitrodilator that acts as organic nitrates by releasingNO
• Unlike organic nitrates, NO is liberated by non enzymatic process- Direct action on arterioles and venioles
• NO activates the Guanylate cyclase pathway leading to the relaxation of thesmooth muscle and thus vasodilation.
• Sodium nitroprusside is a nonselective vasodilator, it dilates both arteriolesand venules (unlike nitrates). It causes a reduction in myocardial O2 demand. |
| What are therapeutic indications, pharmacokinetics and contraindications of sodium nitroprusside? | Therapeutic (acute HTA crisis, acute decompensated HF, induction of periop Hypotension)
Pharmacokinetics (Admin IV, onset w/in 30 s, peak in 2 min, 3 min effect disappears)
Contraindication (impaired renal/kidney function leads to cyanate toxicity leading to cyanide poisoning symptoms |
| How is toxicity of sodium nitroprusside? | Nitroprusside combines with hemoglobin and is subsequently metabolized to 5 cyanide ions and cyanmethemoglobin.
Cyanide then converts to thiocyanate via rhodanese-mediated donation of a sulfur group (liver) (from thiosulfate or cysteine); this final step can quickly become overwhelmed with large quantities of the drug.
Antidotal therapy given, preferably using a combination of hydroxocobalamin (to bind intracellular cyanide) and sodium thiosulfate (to act as a sulfur donor). |
| How are a1 blockers involved in vascular tone? | a1 receptor antagonists inhibit vasoconstriction in arterioles and veins decreasing peripheral resistance |
| How are a2 agonists involved in vascular tone? | Used as primary tx of systemic HTA
Clonidine (decrease NE from sympathetic NS, tx HTA resistant, preop sedation relief anxiety, transdermal patches for hot flashes post menopause, adverse effects are rebound HTA, dry mouth and sedation)
Methyldopa (centrally acting antiHTA, imp for HTA w/renal insufficiency, used in pregnant, adverse effects dry mouth, sedation and drousiness) |
| What are K+ channel openers? | Minoxidil and hydralazine |
| How is mechanism of action of minoxidil? | Activate ATP sensitive K+ channels which hyperpolarizes smooth muscles of vessels closing Ca channels lead to dilation of resistance vessels (arterioles) but not venules. |
| What are therapeutic uses of minoxidil? | Tx severe HTA resistant.
Topical to females tx pattern baldness and androgenic alopecia (2-5% topical solution) |
| What are minoxidil compensatory effects? | Increase renin (increase water and Na retention so give with it a loop diuretic)
Reflex tachycardia positive chronotrop.
Side effects (volume overload, edema, congestive HF, hypertrichosis [hair growth]) |
| How is mechanism of action of hydralazin? | Hydralazine inhibit inositol trisphosphate-induced Ca2+ release from the sarcoplasmic reticulum in arterial smooth muscle cells
It acts by producing relaxation of vascular smooth muscle, primarily in arteries andarterioles.
This results in decreased peripheral resistance and, therefore, blood pressure. The directacting smooth muscle relaxants, is not used as primary drugs to treat hypertension.
Used to treat moderately severe hypertension |
| What are compensatory and side effects of hydralazine? | Reflex tachycardia, increase angina, MI, Hf..
Side effects (stopped by admin b blocker/diuretic, headache, tachycardia, sweat, arrhythmia, angina increase + Lupus like symptoms if high dose) |
