Cardiovascular Pharmacology

*Remember one of the possible mechanisms for primary essential hypertension is increased Na(Due to increased retention/decreased excretion) that reaches Vascular smooth muscle cells, thus more of it enters the cells and opens up voltage-gated Calcium channels, so more calcium enters the cells>Contraction>Increase in TPR>Increase in BP(remember BP=TPRxCO).*NOW remember thiazide diuretics inhibit Na/Cl transporter in Distal convoluted tubule(They directly compete with CL )and inhibition of transporter leads to decreased Na reabsorbtion.(+remember that water follows Na, so as u promote its excretion u also get rid of too much fluid)*Now we can use dihydropyridine Calcium channel blockers to block the effects of calcium on smooth muscles(Contraction and increase in TPR).*We can also use ACE inhibitors and ARBs(Angiotensin 2 RECEPTOR blockers-used if patient developes cough/edema on ACE inhibitors) to counteract the effects of RAAS system(we want to remove excess Na/water).*Note that even in well managed diabetes melitus without renal manifestations ACE inhibitors/ARB would still be 1st line(To prevent the damage) but never use thiazides in diabetics as they can cause hyperglycemia.

*Diuretics(Loop diuretics are first line and they prevent pulmonary congestion)*ACE inhibitors and ARBs(Latter if patient develops cough on ACE inhibitors)-you remove excess Na/water by decreasing activity of RAAS.*B-Blockers(To decrease the sympathetic response but u would do this if patient's ejection fraction is in the range of normal/in COMPENSATED HF, as B-blockers are associated with long-term better survival rates, however you should use these drugs with caution in Decompensated HF and never use them in Cardiogenic shock.)*Aldosterone antagonists-to remove too much Na and H2O by decreasing activity of RAAS.

*Really know ACE inhibitors/ARB.prevent renal vascular damage by preventing vasoconstriciton of Efferent arteriole(Exitting) to decrease GFR and thus prevent hyperfiltration damage(we do it by preventing Angiotensin2 synthesis or by blocking its receptors in efferent arterioles with ACE inhibitors/ARB respectively).*Remember in diabetes, too much glucose attaches to proteins on endothelial cells and you have Non-enzymatic glycation, we receive Reactive advanced glycation end products that can cause oxidative damage to endothelial cells of renal arterioels(By production of free radicals like O2: and H2O2) +Damaged endothelial cells release Vasoconstrictors like Endothelin 1, which would cause vasoconstriction(So we reduce vasoconstriction by preventing additional vasoconstrictive effects of angiotensin 2 )*Calcium channel blockers can be added to relax the constricted smooth muscle.*B-blockers(By blocking B1 receptors on JGA>Decreased release of renin>Less RAAS activity>less Na/Water retention) and Thiazide diuretics(remove excess Na/water) can also be used..*Avoid thiazides in patients with Hypertension+DIABETES as thiazdes can cause Hyperglycemia.(As they open ATP dependent K channels and decrease insulin secretion)-but thiazides are used for Hypecalciuria(Very commonly tested), Thiazides are also used for Nephrogenic diabetes insipidus as we recombine the excess free water with Salt.*Remember B-blockers can mask symptoms of hypoglcyemia like tremor-(in Diabetic who takes too much insulin) but FA says that both Thiazides and B-blockers can be used in those with Hypertension+DM, probably benefits outweigh risks.

*Hydralazine(Increases cGMP and causes Vasodilation of ARTERIOLES hence it decreases TPR=AFTERLOAD), note that hydralizine is often coadministered with B-blocker to prevent reflex Tachycardia.*Labetalol(Non-selective B blocker which has some alpha blocking effects too)*Methyldopa(Alpha 2 AGONIST, by promoting feedback inhibition trough presynaptic a2 receptors it decreases sympathetic outflow-decreases circulating Catecholamine levels<testable.)*Nifedipine-Dihydropyridine Calcium channel blocker .

*Patient likely has "Monday disease" due to industrial exposure to nitrates, he is symptom free during most of the week as he develops tolerance to Vasodilatory effects of nitrates(Cerebral Vasodilation is mechanism of headache), but as he has weekend(isn't exposed to nitrates for 2 days), he looses tolerance and upon new exposure symptoms re appear.(in addition to headache reflex tachycardia,dizziness are often seen)*Mechanism at molecular level involves increase in Nitric Oxide which increases cGMP in Vascular smooth muscles(Esp. in smoth muscle of large veins)>Dilation, highest yield fact here is that it causes preferential VENOdilation(In comparison to arteries)>Decreased PREload.Decreased O2 demand.(Hence the use in angina)*Hypotension and flushing are common side effects of nitrates(Vasodilation)
*Some Nitrates:NITROGLYCERIN,isosorbide dinitrate,isosorbide mononitrate.(You want BTCH question-??? they ask you which of them has Highest Bioavailability(amount of drug that reaches plasma unchanged) when given orally(P.O) and that is ISOSORBIDE MONONITRATE(Around 100% bioavailability-P.O)while Nitroglyceirn when given orally(NOT sublingually)is subject to significant first-pass affect,that's why we use it sublingually(to be absorbed trough oral mucosa)-you can find more about isosorbide MONOnitrate in uw.....
*Note that nitrates decrease MVO2(Myocardial O2 consumption-Hence the use for angina)/End diastolic volume and they also can decrease Ejection Time(Reflex increase in HR).*Nitrates can be used for Acute coronary syndrome and pulmonary edema.*Remember nitrate use is good example of tachyphylaxis(Rapid tolerance)-well at least good way to think about it.

*Rate limiting step is conversion of HMG-CoA to MEVALONATE by enzyme HMG-Coa Reductase(3-hydroxy-3-methyl-glutaryl-coenzyme A reductase)INDUCED by INSULIN.*we can inhibit HMG-CoA reductase by STATINS(REVERSIBLE and COMPETITIVE inhibition,-we increase Km-the amount of substrate to give us the same effect without altering maximal effect Vm, thus dose-response curve is shifted towards right)*remember mevalonate is precursor to cholesterol, statins are used for their ability to decrease LDL(Greatest effect of all other drugs)But it also INCREASES HDL and decreases triglycerides know that it Decreases Mortality in CAD patients.*Monitor LFT in patietns receiving Statins as they are hepatotoxic.*Also patients are at risk of Myopathy(Can range from Mild myalgias to Rhabdomyolysis) especially when combined with Fibrates(e.g Gemfibrozil)/Niacin.(they can describe to u patient who has trouble walking,climbing stairs,bilateral weakness of arms who is on statins and ask you which medication was added to statins so know BOTH of them.)kaplan wants u to know that mannitol can be used to prevent kidney damage in these cases but aggresive hydration is best initial management.

*To avoid entry into the portal circulation and thus avoid first-pass effect which markedly affects Oral bioavailability.

*Remember quinidine can Increase AV conduction(Has ANTImuscarinic effects in heart)-Thus atrial rate transmitted via 2:1 by AV node now is transmitted 1:1 to ventricles hence even though we decreased atrial rate we increased rate of ventricle contraction(Simply equilibrated it with atrial rate).
*We can avoid this by pre-administration of AV conduction blockers like Digoxin and Verapamil.

*Angiotensin Converting Enzyme normally degrades BRADYKININ, so when u inhibit it with PRILs(Like captopril)you increase Bradykinin which is responsible for Dry cough and possible edema.(By increasing prostaglandin synthesis)*Angiotensin II AT1 receptor blockers (like loSARTAN)are unlikely to cause these side effects as they block receptors and don't alter activity of ACE.However, both groups of drugs interfere with renal development in the fetus and are contraindicated in pregnancy.*Remember bradykinin is Peptide contrast this with Histamine which is a hormone.

*ETHACRYNIC Acid<Works like loop diuretics but unlike them does NOT contain sulfa drug(Thiazide and Carbonic anhydrase inhibitors also contain sulfa groups)*Sulfa groups are added to increase lipid solubility of drugs.

*Hypertension+CHF<He was likely treated by Loop diuretic..*RA treatment can include NSAIDs.*Responses of kidney to Loop diuretics(Furosemide) depends are in part PGE-mediated.*NSAIDs inhibited PGE synthesis and decreased diuresis which was originally promoted by our diuretic(To alleviate symptoms of HF and treat his Hypertension)

*Those(first 3) that cause HYPOkalemia-as digoxin competes with K on Na/K ATPase, thus when you have hypokalemia due to Loop/thiazide diuretics you can get increased effects/TOXICITY of Digoxin.(Note that one of the side effects of Digoxin is actually HYPERkalemia as it inhibits Na/K atpase and thus uptake of K into cells, thus more of it is left in circulation)*Spironolacotne actually causes HYPERkalemia and to balance levels of Potassium we often actually use these 2 groups together.

*PR is increased Due to blockade of B1 receptors leading to slowing of AV conduction.(They are Class 2 antiarrhythmics and are used for SVT-Metoprolol and Esmolol)*They love to ask this and they also love to ask why renin levels decrease with B-blockers and that is due to B1 receptor blockade in JGA, decreased RAAS leads to decreased Na/Water retention and decreased vasoconstriction.(contributes to antihypertensive effects)

*Everyone knows that They increases NO sytnhesis and subsequently increase in cGMP, but they can go deeper and you should know that Myosin Dephosphorylation is the core basis for the relaxation of the smooth muscle>Vasodilation.*Remember nitrates do VENOdilation more than Dilation of arteries hence they mainly Decrease PRELOAD.(Blood is retained in dilated veins and less enters heart.)*Important point is that Main therapeutic effect of Nitrates in Angina pectoris stems from their ability to decrease preload and thus Left ventricular Volume during diastole.(MC wrong answer is increase in coronary blood flow but that is not true, even though nitrates can have mild dilatory effect on coronaries, this is not accounable therapeutic effect and at higher levels nitrates also cause serious systemic arteriolar dilation and can actually decrease the coronary blood flow>worsen ischemia and can kill u) increase in coronary blood flow due to nitrates can be seen in settings of myocardial ischemia due to atherosclerotic narrowing when blood doesn't go to ischemic myocardium but flows trough pharmacologically dilated coronaries which aren't effected by narrowing, hence"Coronary Steal Syndrome", so ischemia of the myocardium can actually get worse here too....

*It increases NO synthesis(From arginine) and its release.*Endothelial cells lining blood vessels have noninnervated muscarinic receptors.,these M3 receptors use the Gq-coupling protein to activate phospholipase C, which releases inositol 1,4,5-trisphosphate and diacylglycerol from membrane lipids. eNOS is activated and NO is released, causing vasodilation.*Note that Heme and hemoglobin inactivate NO