Antihypertensive Drugs PDF

3/22/2024 Antihypertensive Drugs Part II Renin-Angiotensin Aldosterone System Inhibitors Brent Gravelle, M.D., Ph.D. 1 3/22/2024 Objectives Same as last topic on hypertension basics Renin-AngiotensinAldosterone Renin-Angiotensin-Aldosterone system (RAAS) plays a significant role in various diseases...

3/22/2024 Antihypertensive Drugs Part II Renin-Angiotensin Aldosterone System Inhibitors Brent Gravelle, M.D., Ph.D. 1 3/22/2024 Objectives Same as last topic on hypertension basics Renin-AngiotensinAldosterone Renin-Angiotensin-Aldosterone system (RAAS) plays a significant role in various diseases including hypertension, congestive heart failure (CHF) and myocardial infarction (MI). In this section we will discuss: Biochemistry, molecular and cellular biology, and physiology of the RAS. Pharmacology of drugs that interrupt the RAAS. 2 3/22/2024 3 3/22/2024 ← Renin release Renin secretion controlled by 3 pathways: 1. Macula densa: ↑ flux of NaCl → ↑ adenosine and ↓ renin while ↓ flux of NaCl → ↑ prostaglandins and ↑ renin. Most profound factor is luminal [Cl-] 2. Intrarenal baroreceptor: stretch of preglomerular vessels ↓ renin, while ↓ tension stimulates renin secretion. 3. Beta-adrenergic receptor pathway: NE from postganglionic nerves stim β1 receptors on JG cells ↑ renin secretion. 4 3/22/2024 Summary Angiotensinogen Substrate for renin, converted to Angt-1 Synthesized mainly in the liver A glycoprotein with MW of 55-60,000 Synthesis is stimulated by inflammation, insulin, estrogens, glucocorticoids, thyroid hormone and Angiotensin II. During pregnancy, plasma levels of angiotensinogen increase several fold due to increased estrogen. 5 3/22/2024 Angiotensin Receptors AT1 and AT2 receptors have been identified AT1 and AT2 have very little homology but both involve G-protein coupled effector coupling. Most biological effects of Angt-II are mediated by AT1 receptors which activate the PLC-IP3-Ca+ pathway Angiotensin receptors Agonistic auto antibodies against the AT1 is associated with preeclampsia AT2 receptors are restricted and their functional role is poorly defined but, may exert antiproliferative, proapoptotic, vasodilatory and antihypertensive effects though it may be linked to cardiac fibrosis. 6 3/22/2024 7 3/22/2024 Inhibitors of the R-A System ACE inhibitors (Prils) AT1 receptor blockers (Sartans) Direct Renin Inhibitors BP 8 3/22/2024 ACE Inhibitors Have proven effective in controlling hypertension, decreasing morbidity and mortality Minimal adverse effects Can be used as initial therapy Can be used as monotherapy Less effective in African Americans ACE Inhibitors Compelling indications in: Diabetes CHF Acute MI with systolic dysfunction 9 3/22/2024 ACEI’s (Prils) Benazepril (Lotensin) Captopril (Capoten) Cilazapril (in Canada only) Enalapril (Enalaprilat & Vasotec, Epanedpowder for oral soln but mega $$$$$) Fosinopril (Monopril) Trandolapril (Mavik) Lisinopril (Zestril/Prinivil, Qbrelis-oral solution) Moexipril (Univasc) Perindopril (Aceon) Quinapril (Accupril) Ramipril (Altace) Physiology of ACEI’s 10 3/22/2024 11 3/22/2024 Clinical Pharmacology ACEI’s differ with regard to: Potency Active Drug, prodrug or active metabolite Pharmacokinetics: Extent of absorption Effect of food on absorption Plasma half-life Tissue distribution Mechanisms of elimination Clinical Pharmacology All ACEI’s have similar Indications Adverse effect profiles Contraindications Half Life – generally 10-12 hours Therefore no compelling reason to favor one over another. 12 3/22/2024 Captopril (Capoten) First ACEI marketed in the U.S. The only ACEI containing a sulfhydryl group Pharmacokinetics Absorption from GI: Rapid Bioavailability: 75% Food reduces oral availability, can make soln/susp Peak [plasma]: 1 hr T1/2: 2 hr Excretion: Urine Enalapril (Enalaprilat, Vasotec) 2nd ACEI approved in the U.S. A prodrug hydrolyzed by hepatic esterases to active metabolite: Enalaprilat & is a highly potent ACEI (Ki=0.2 nM). Can make susp Pharmacokinetics: Absorption from GI: rapid Bioavailability: 60% Bioavailability not reduced by food Peak [plasma]: Enalapril 1 hr Enalaprit: 3-4 hr T1/2: 11 hr (tightly bond) Excretion: Urine 13 3/22/2024 Lisinopril (Prinivil-scored, Zestril-unscored) Third ACEI approved for use in the US Stucturally similar to enalaprit so can make oral soln-Qbrelis. Pharmacokinetics: Absorption from GI: Slow, variable (30%) Bioavailability not reduced by food Peak [plasma] 7 hr T1/2 : 12 hr Excretion Urine Therapeutic Uses of ACEI’s Hypertension Lower systemic vascular resistance Lower mean diastolic, & systolic blood pressure Used in various hypertensive states but should be avoided in hypertension due to primary aldosteronism. Effective in mild to moderate hypertension: ACEI alone in 50% of pts ACEI + either CCB, or B-blocker or diuretic in 90% of patients 14 3/22/2024 JNC-7/8 on African Americans “The prevalence, severity and impact of hypertension are increased in African Americans, who also demonstrate somewhat reduced BP responses to monotherapy with BBs, ACEIs or ARBs compared to diuretics or CCBs. These differential responses are largely eliminated by drug combinations that include adequate doses of a diuretic.” Therapeutic Uses of ACEI’s Left Ventricular Systolic Dysfunction LVSD: ranging from asymptomatic reduction in systolic performance to severe impairment of LVF (Grade IV CHF) Several large prospective, randomized, placebocontrolled clinical studies (HOPE, EUROPA) clearly show that Unless contraindicated, ACEI’s should be given to all patients with LVSD. Do not give ACEI within 36 hrs of switching to or from a neprilsyn sacubitril/valsartan-Entresto 15 3/22/2024 Acute MI Therapeutic Uses Many quality clinical studies (SAVE, CONSENSUS II, SMILE) clearly indicate that ACEI’s reduce overall mortality Particularly useful in pts with MI and hypertension and/or diabetes. In acute MI, ACEI’s should be started immediately unless contraindicated. ACEI’s can be combined with thrombolytics, aspirin, and adrenergic antagonists Reduction in ischemic CV events Renal and retinal protection in diabetics Adverse Effects of ACEI’s Hypotension: associated with first dose in pts with plasma renin activity (PRA). Cough develops in 1 to 6 weeks in 5- 20% of pts. More frequently in women which is reduced by aspirin and iron supplementation. Cough ↓ within 4 days when ACEI’s stopped. Pregnancy: BBW: Fetopathic potential (esp 2-3 tri) Should be discontinued or not started! DO NOT BREAST FEED while on ACEI 16 3/22/2024 Warnings & Contraindications Renal failure: ARF: May severely ↓ GFR in renal artery stenosis pts or if also on (Entresto: sacubitril/valsartan) & diabetic. CRF: elevations of up to 30% from Cr baseline warrant NO changes HYPERKALEMIA Angioedema in < 1% of pop esp AA’s and smokers, CI within 36 hrs of neprilysin inhibitor (Entresto: sacubitril/valsartan) or ACEI + aliskiren w/ diabetes Most Common Side Effects of ACEI’s Proteinuria Dysgeusia Neutropenia Glycosuria Hepatotoxicity Drug interaction: antacids may reduce bioavailability; capsaicin may worsen cough ACEI’s may increase levels of digoxin and lithium May increase hypersensitivity to allopurinol 17 3/22/2024 Angiotensin Receptor Blockers (ARBS) or (Sartans) Angiotensin Receptor Blockers 18 3/22/2024 AT1 Receptor Blockers(ARBs) Bind to AT1 receptor 10,000 > than AT2 Inhibit most biological effects of Angt-II: Contraction of vascular smooth muscle Pressor responses Vasopressin release Aldosterone secretion Release of adrenal catecholamines Enhancement of noradrenergic neurotransmission Increase in sympathetic tone Changes in renal function Cellular hypertrophy and hyperplasia AT1 Antagonists ≠ ACEIs Inhibition of AT1 receptors: AT1 antagonists > ACEIs Activation of AT2 receptors AT1 antagonists > ACEIs Increasing bradykinin levels ACEIs > AT1 antagonists 19 3/22/2024 AT1 receptor antagonists or blockers (Sartans) Candesartan Cilexetil(Atacand) K-33,L-67% Eprosartan (Teveten) K,L Irbesartan (Avapro) K-20%, L-80% Losartan* (Cozaar) L Olmesartan Medoxomil (Benicar) K,L Telmisartan* (Micardis) L Valsartan* (Diovan) L-70% Azilsartan (Edarbi) L: sensitive to light & moisture Drug % Oral Bioavailibilit y % protein binding Time to peak hr Elimination t1/2, hr Elimination Fecal/renal Azilsartan Medoxomil 60 99 1.5-3.0 11 55/42 Candesartan Cilexetil 15 99 3-4 9 67/33 Eprosartan 15 98 1-2 5-9 90/10 Irbesartan 60-80 90 1.5-2.0 11-15 80/20 Losartan 33 99 1 1.5-2.0 60/35 Olmesartan Medoxomil 26 99 1.5-3.0 10-15 40/60 Telmisartan 42-58 100 5 24 97/3 Valsartan 25 95 2-4 6 83/13  All of the compounds have similar onset of action (Except, Candesartan, Telmisartan), and are highly protein bound  Elimination half life is significantly high to allow once or twice-daily dose  Except Olmesartan, all of them are mainly cleared through fecal route.  Telmisartan requires dose adjustment for hepatic impairment 20 3/22/2024 ARBs Oral availability is low (≈30%) Protein binding is high (>90%) Do not cause cough Should be discontinued before pregnancy Adverse reactions equal to placebo Enhance BP lowering effects of other drugs Hyperkalemia in at risk pts Caution in pts with renal function dependent on RAS (volume depleted) Therapeutic Uses All for Hypertension Ibersartan and Losartan for diabetic nephropathy Losartan for stroke prevention Valsartan, Candesartan over Losartan for HF pts intolerant to ACEIs Though in general, first line trt of HF with ACEI then use ARB if intolerant or unsatisfactory response. 21 3/22/2024 Caution To minimize hypotension in diuretic treated pts who are elderly, volume depleted, hyponatremic or have CHF exacerbation , hold diuretic dose (if possible) for 2-3 days before starting an ARB and use low dose. Warning: Olmesartan can cause sprue-like enteropathy Direct Renin Inhibitors 22 3/22/2024 MOA: blocks conversion of Angiotensinogen(AGT) to angiotensin I (AngI) Aliskiren (Tekturna) First of class to directly inhibit Renin Adverse Effects: Hypotension Angioedema GI(diarrhea at high doses) URI HA Dizziness fatigue 23 3/22/2024 Aliskiren (Tekturna) BBW: Do Not use in Pregnancy esp 2-3 trimesters Not approved for children < 6 yo Decreases effects of furosemide by 50% May ↑ K+, CK and Uric acid Levels increased by atorvastatin & ketoconazole & cyclosporine Low bioavailability, Cmax 3-6 hrs, t1/2 2045 h, avoid high fat foods. Fixed dose combos with HCTZ – (Tekturna HCT), amlodipine (Tekamlo), and both – (Amturnide). 24 3/22/2024 April 20th, 2012 FDA Warning Concomitant use of aliskiren with ARBs or ACE inhibitors in patients with diabetes is contraindicated because of the risk of renal impairment, hypotension, and hyperkalemia. Avoid use of aliskiren with ARBs or ACE inhibitors in patients with renal impairment where GFR < 60 mL/min. Calcium Channel Blockers (CCB’s) 25 3/22/2024 Calcium Channel Blockers Dihydropyridines (DHPs) Amlodipine (Norvasc) & Katerzia(oral suspension) Nimodipine (Nimotop): subarachnoid H. Nifedipine ER (Procardia XL), preterm labor, ureteral calculi. (Adalat CC)& Procardia IR Felodipine (Plendil), Isradipine- preeclampsia Nicardipine (Cardene), Nisoldipine (Sular)…impaired hepatic function Clevidipine (Cleviprex) IV only Calcium Channel Blockers cont’d NON-Dihydropyridines Diltiazem (Cardizem) Verapamil (Isopten) Combo drugs Benazapril/Amlodipine (Lotrel) Trandolapril/Verapamil (Tarka) Valsartan, Olmesartan, Telmisartan + Amlodipine = (Exforge, Azor & Twynsta) Aliskiren/Amlodipine = (Tekamlo) 26 3/22/2024 Mechanism and Effectors CCBs inhibit voltage-gated L-type Ca2+ channels → ↓ Ca2+ influx in vascular and cardiac cells. Major effectors: VSMCs: Relaxation Heart: ↓ HR and contractility Lowering BP may stimulate compensatory mechanisms leading to net ↑ HR. 27 3/22/2024 Cardiac Muscle Cells Vascular Effects VSMCs express L-type Ca2+ channels Blockade of Ca2+ channels → vasodilation Affects arteries > veins Peripheral vasculature: ↓ PVR Dihydropyridines > Diltiazem > Verapamil Coronary arteries: ↑ coronary blood flow Diltiazem, nicardipine > others Cerebral ↑ cerebral blood flow Nimodipine > others 28 3/22/2024 Effects on the Heart L-type Ca2+ channels are expressed in the SA and AV node and myocardium SA and AV: Phase 0 depolarization Muscle: Phase 2 of AP Inhibition of L-type Ca2+ channels: ↓ firing rate of SA node → ↓ HR & CO ↓ contractility of atrial & ventricular muscles → ↓ CO Verapamil > diltiazem > Dihydropyridines 29 3/22/2024 30 3/22/2024 Therapeutic Uses Angina: ↑ coronary blood flow (all) Prinzmetal’s (DHPs) ↓ O2 demand (verapamil, diltiazem) Hypertension ↓ PVR (all) ↓ CO verapamil, diltiazem Supraventricular tachyarrhythmias ↓ AV nodal conduction (verapamil) Controls ventricular rate in atrial flut & fib Subarachnoid Hemorrhage Cerebral vasodilation (nimodipine) Therapeutic Uses cont’d Generates various compensatory mechanisms and not commonly used as monotherapy Very effective when combined with αblockers or diuretics May have favorable effects in: Migraine (non-DHP) Diabetes 31 3/22/2024 Contraindications & Precautions Short-acting agents may ↑ mortality (esp Nifedipine IR) Hepatic dysfunction (all CYP3A4), avoid grapefruit, reduce doses of simva or lovastatin. AV block & LV dysfunction (Verapamil, Diltiazem) Nicardipine not in advanced aortic stenosis Drug interactions: Concurrent β-Blockers Digoxin (Verapamil) Antiarrhythmic drugs 32 3/22/2024 CCB’s When patient on carbamazepine, phenobarbital, phenytoin, rifampin or St John’s wort…use alternative as they significantly reduce nifedipine Clevidipine (Cleviprex) CI w/egg or soy allergy, severe aortic stenosis or defective lipid metabolism Rarely gingival hyperplasia & hypertrigylceridemia. There are many long acting forms be sure to check orange book regarding generic substitutions. Category C in pregnancy, but nifedipine (ER not sublingual form) can be used as DOC for hypertensive pre-eclampsia or eclampsia. Questions 1.Which CCB should not be used for acute BP reduction? 2. Which CCBs require light protection? 3. What are ghost shells? 4. What is frequency dependent affinity? 5. Which CCBs are best with Heart failure and reduced EF? 33 3/22/2024 Question Clevidipine lipid emulision for injection contains 2 kcals/mL. If a patient is receiving 50mg/100mL at a rate of 5 mg/hr then how many kcals per day is the patient receiving? 5mg/hr x 24hrs/day x 100 mL/50mg x2kcal/mL = 480 kcal/day 34 3/22/2024 Centrally Acting α2 adrenergic Agonists Methyldopa Clonidine (Catapres) GuanFacine (Tenex) Centrally Acting α2 -Agonists Mechanisms of Action: Bind to α2 receptors on presynaptic nerve terminals and inhibits the release of neurotransmitters into the synaptic cleft. CNS: ↓ Sympathetic outflow Periphery: ↓ PVR and ↓ renin secretion Few compensatory mechanisms activated No adverse effects on blood lipids (↓ LDL) 35 3/22/2024 Methyldopa (Aldomet) Converted to α-methyl NE: agonist of presynaptic α2 receptors ↓ PVR without much change in CO ↓ renin secretion One of Drugs of Choice for hypertension crisis & in pregnancy. Others include Labetalol, Hydralazine & Nifedipine ER. Methyldopa Adverse Effects CNS sedation Dry mouth, somnolence, fatigue Hemolytic anemia (pos Coombs test) Withdrawal rebound hypertension Hyperprolactinemia, sexual dysfunction Drug induced lupus erythematosus 36 3/22/2024 Methyldopa Contraindications Avoid in active liver disease and concurrent use of MAOIs Avoid in SA node dysfunction: severe bradycardia Clonidine (Catapres), & Guanfacine (Tenex) Stimulates α2 and reduces sympathetic outflow and increases vagal tone Lower PVR and CO Insufficient information showing these drugs reduce the risk of cardiovascular consequences of hypertension Used in resistant hypertension or those who cannot swallow due to dysphagia or dementia. 37 3/22/2024 Clonidine & GuanFacine Clonidine comes in tablet (Catapres), patch* (Catapres-TTS) or injection (Duraclon) Apply weekly to different spot of hairless skin on upper outer arm or chest *Remove patch prior to MRI Can also be used in menopausal flushing. GuanFacine IR or known as Tenex, use lower dose with CrCl 180/120-130 mmHg with no end organ damage. Example drugs used: Labetolol (DOC) 20-80 mg IV q5-10 min, onset 5-10 min Captopril (agent of choice), 25-50 mg orally at 1-2 hr intervals w/ onset of action 15-30 min. Amlodipine 2.5 to 5 mg orally at 1-2 hr intervals Hypertensive Emergencies Defined as: systolic BP typically exceeding 180 and diastolic > 120 presenting with end organ damage such as headaches (encephalopathy), AKI, blurred vision (papilledema) or focal neurologic symptoms (stroke), aortic dissection, pulmonary edema. Goal is to decrease BP by not > 25% within first hr. If stable, decrease to 160/100 43 3/22/2024 Na+ Nitroprusside Na+ Nitroprusside (Nipride) Non-selective vasodilator that relaxes VSMCs of all regions Unstable molecule , light sensitive, IV only Onset of action within seconds, peaks in 2 min and effects disappear in 3 min Adverse Effects: Sudden hypotension, worsen hypoxemia in COPD Metabolized to cyanide & thiocyanate by liver and excreted in the urine. (lactic acidosis)Na thiosulfate Toxicity: anorexia, nausea, fatigue, disorientation 44 3/22/2024 Organic Nitrates Nitroglycerin Longer acting nitrates: Isosorbide dinitrate (Isordil) Isosorbide mononitrate (ISMO) Vendodilation >> Arteriodilation Effects are dose related Organic Nitrates Low dose : Venodilation → ↓ CO Compensatory reflexes: ↑ HR, ↑ PVR, ± BP High Dose: Venodilation → ↓ CO Arteriodilation → ↓ PVR → ↓ BP resulting ↓ preload and after load reduce oxygen demand Compensatory reflexes: ↑ HR Overall: ↓ CO, ↓ PVR, ↓ BP, ↑ HR 45 3/22/2024 Organic Nitrates Also used in Angina, CHF & acute MI Excessive hypotension: HA (dilation) Tachycardia Orthostatic hypotension Angina Tolerance in 24-48 hrs K+ Channel Opener: Minoxidil Mechanism: ↑ K+ efflux from (arterial only)vascular smooth muscle causing relaxation and hyperpolarization → ↓ TPR Compensatory mechanisms include: ↑ HR, ↑ CO, ↑ contractility ,↑ fluid retention due to potent sympathetic stimulation of renin secretion. Very effective in severe resistant hypertension 46 3/22/2024 Minoxidil (Loniten) Increases blood flow to skin, muscle, GI and heart more than the CNS Well absorbed from GI, peak in 1 hour Metabolized 20% K and 80% L Averse effects: Marked fluid retention (must use diuretic) BBW: potent vasodilator, reflex tachycardia (use β-blockers)—similar to hydralazine, avoid in LVH & Diastolic dysfunction, flattened & inverted T waves and pheochromocytoma. Hypertrichosis Other Agents Fenoldopam (Corlopam): Dopamine-1 Agonist Especially useful when hypertensive emergencies are accompanied by acute or chronic renal failure. Nicardipine hydrochloride (Cardene) Intermediate onset Side Effects: Tachycardia, HA, flushing & local phlebitis 47 3/22/2024 IV Hypertension MEDs Chlorothiazide Clevidipine Diltiazem Enalaprilat Esmolol Fenolodopam Hydralazine Labetalol Metoprolol tartate Nicardipine Nitroprusside Propanolol Verapamil 48 3/22/2024 Sympatholytics: β-blockers Normally not a first line agent Excellent medication for initial therapy if treating for angina, MI, HF or LV dysfunction Normally do not cause water retention Less effective in African Americans Compelling indication: Post MI or Pregnancy! Subtypes of β-adrenergic receptors β1- adrenergic effects β2-adrenergic effects Eye: increased aqueous humor Kidney: increased renin production Heart: increased chronotropy, lipolysis, gluconeogenesis, inotropy, glycogenolysis, automaticity and lactic acid production Lung: bronchodilation Vascular: arterial dilation Metabolic: increased insulin production, glucagon release and hepatic glycogenolysis Other: movement of potassium into cells BETA BLOCKERS DO THE OPPOSITE!!! 49 3/22/2024 Fig 26.2 G & G β-Blockers May have favorable effects: Chronic stable angina Atrial tachyarrhythmias Essential tremor Hyperthyroidism Migraine Anxiety 50 3/22/2024 β-Blockers (olols) Propanolol (Inderal) Metoprolol IR (Lopressor) Metoprolol ER(Toprol XL) Nadolol (Corgard) Atenolol (Tenormin) Timolol (Blocadren) Pindolol (Visken) Labetalol (Trandate) Acebutolol (Sectral) Esmolol (Brevibloc)* Penbutolol (Levatol) Bisoprolol (Zebeta) Carvedilol (Coreg) Nebivolol (Bystolic) Betaxolol (Kerlone) ISA nebivolol 51 3/22/2024 Alpha -1 inhibition on blood vessels Nebivolol also produces NO dependent vasodilation in addition to beta-1 activity… Take all oral agents without regard to food except Lopressor, Toprol XL and carvedilol. 52 3/22/2024 β-Blocker Adverse Effects Avoid in Asthma & bronchospasm Cardioselective drugs preferred (AMEBBA) ↓ myocardial contractility Caution in CHF ↓ AV conduction: avoid in AV block Receptor upregulation Sudden discontinuation can cause withdrawl syndrome (BBW) Adverse Effects cont’d ↓ HDL, ↑ triglycerides Avoid in hyperlipidemia Diabetes ↓ insulin secretion Mask symptoms of hypoglycemia Avoid non-selective ones in diabetes Depression: Avoid…esp Inderal Fatigue: avoid in active patients Sexual Dysfunction Avoid in vulnerable patients 53 3/22/2024 Potential Advantages Review Katzung ch 10 summary & table 10.2 Cardioselective agents: Diabetes and asthma Those with ISA: no effect on lipids or increase in HDL Agents with α1 blocking activity: Excellent synergy Labetolol (Trandate) good for use in pregnancy, Carvedilol (Coreg) Cocaine use complications Drug Interactions Propanolol: more CNS penetration… NSAIDS: Blunt antihypertensive effects of β-Blockers Verapamil, diltiazem: Severe decrease in heart rate and CO Coreg IR and Coreg CR are not equivalent, CR has less bioavailability, therefore dose conversions are not 1:1, Also Metoprolol tartrate IV and PO are not equivalent. 54 3/22/2024 Pregnancy with Hypertension Avoid or stop immediately drugs with BBWs: ACEIs, ARBs, direct renin inhibitor aliskiren. Preeclampsia is elevated BP and proteinuria beyond 20 wks gestation. Eclampsia: is above + seizures Pre-existing or chronic hypertension should only receive treatment when SBP > 160 mmHg or DBP > 105/110. First line DOCs are labatelol and nifedipine ER or methyldopa. Summary 55 3/22/2024 1. A 45-year-old man has recently been diagnosed with hypertension and started on monotherapy designed to reduce peripheral resistance and prevent NaCl and water retention. He has developed a persistent cough. Which of the following drugs would have the same benefits but would not cause cough? A. Losartan. B. Nifedipine. C. Prazosin. D. Propranolol. 2. Which one of the following drugs may cause a precipitous fall in blood pressure and fainting on initial administration? A. Atenolol. B. Hydrochlorothiazide. C. Nifedipine. D. Prazosin. E. Verapamil. 56 3/22/2024 3. Which one of the following antihypertensive drugs can precipitate a hypertensive crisis following abrupt cessation of therapy? A. Clonidine. B. Diltiazem. C. Enalapril. D. Losartan. E. Hydrochlorothiazide. 4. A 48-year-old hypertensive patient has been successfully treated with a thiazide diuretic for the last 5 years. Over the last 3 months, his diastolic pressure has steadily increased, and he has been started on an additional antihypertensive medication. He complains of several instances of being unable to achieve an erection and that he is no longer able to complete three sets of tennis. The second antihypertensive medication is most likely which one of the following? A. Captopril. B. Losartan. C. Minoxidil. D. Metoprolol. E. Nifedipine. 57 3/22/2024 5. Which antihypertensives could cause an increase in lithium levels? Thiazide, Loop & K+ sparing diuretics ACEIs ARBs Direct renin inhibitors 58 3/22/2024 59