Antihypertensives PDF

Objectives 1. List major groups of antihypertensive drugs and provide examples of drugs in each group. 2. Describe compensatory responses to each major type of antihypertensive drug. 3. Summarize major sites of action of sympatholytic drugs in clinical use and provide exa...

Objectives 1. List major groups of antihypertensive drugs and provide examples of drugs in each group. 2. Describe compensatory responses to each major type of antihypertensive drug. 3. Summarize major sites of action of sympatholytic drugs in clinical use and provide examples of drugs acting at each site. 4. Identify four mechanisms of action of vasodilator drugs. 5. Outline major antihypertensive vasodilator drugs and describe their effects. 6. Describe the differences between the two types of angiotensin antagonists. Supplemental Reading: The Pharmacological Basis of Therapeutics, 13th edition, Chapter 26 & Chapter 27. Katzung & Trevor’s Pharmacology Examination & Board Review, 13th ed., Chapter 11  Classification of Hypertension Table 27-4 Criteria for Hypertension in Adults BLOOD PRESSURE (mm Hg) CLASSIFICATION Systolic Diastolic Normal 100 Autonomic and Hormonal control of CV function  ANTIHYPERTENSIVE DRUGS: Mechanisms of Increased BP Heart or pump-based hypertension (HYPT) – more common in young with hyperkinetic circulation (inc SNS), inc. cardiac output (CO), PR normal Vascular-based HYPT – with age inc. peripheral resistance (PR)/ vasoconstriction, normal CO Renal/volume-based HYPT – inc. Na/H2O/fluid retention, inc. RAA/CO/PR Neuroendocrine dysfunction: hyperthyroidism, pheochromocytoma, hyperaldosteronism Sites controlling BP  Na and Smooth Muscle Increased conc of Na inside sm mus leads to increased Ca conc ‘s inside via Na/Ca exchange mechanism Sensitivity to NE/EPI/ang II increases as Ca conc increases inside sm muscle; causes increased vasoconstriction and PR As Na conc. is dec. (eg Na restriction/diuretics) inside smooth muscle, intracellular Ca conc. decs. > arteriolar relaxation/vasodilation and decreased PR  NONDRUG APPROACH Na restriction ~ diuretic therapy Weight loss Exercise Eliminate factors that ↑ BP – smoking, excess caffeine, stress/anxiety (stress relaxation techniques) Baroreceptor reflex arc  “Stepped Care” (method of treatment) Drugs are combined in certain sequences to reduce toxicity & compensatory mechanisms. Result in an additive hypotensive effect. Step One – Diuretic; Beta blocker; ACE inhibitor Step Two – other Sympathoplegic Agents Step Three - vasodilator Overview of Diuretic Agents  DIURETICS Mechanism of action and clinical indications Thiazides (preferred; mild to mod. HYPT) – e.g., Hydrochlorothiazide Loop diuretics (renal function significantly impaired; severe HYPT) – e.g., Furosemide Initial action: ↓ blood volume, but returns to almost predrug levels in week(s) Chronic effect (weeks): ↓ PR / vasodilation due to ↓ intracell. Na and Ca & less vasoconstriction to NE/ EPI & Angiotensin II Diuretics interfere w/ compensatory reflexes, baroreceptors & RAA Review adverse effects \ disadvantages, H’s of diuretics  Excessive Diuresis / Adverse H’s Hyponatremia - excessive diuretic effect Hypotension - loss of fluid volume Hypokalemia (except K+ sparing agents, e.g., sprinolactone) - cardiac arrhythmias Hypocalcemia (except thiazides) – muscle excitability/tetany(rare) Hypomagnesemia - twitching / convulsions Hypochloremic alkalosis – excessive loss Cl Hyperuricemia – compete with tubular secretion uric acid Hyperglycemia - interfere with release of insulin, related to hypokalemia  Loop/K-Sparing Diuretics Clinical indications Loops indication: CHF & decreased renal function (creatinine clearance < 50ml/min, normal 120ml/min) Would thiazides or loop diuretics help protect against osteoporosis? K-sparers usu. combined with thiazides/loops to even out & maintain normal K+ levels Spironolactone useful in CHF Aldosterone antagonist diuretic Compensatory responses to vasodilators  BETA BLOCKERS Mechanism of action, clinical indications and adverse effects Review cardioselectivity (eg., propanolol (NS), atenolol (B-1), metoprolol (B-1) MOA: ↓ CO (slow HR by ↑ P-R interval on ECG & force of myocardial contraction) & ↓ renin release (B-1); Negligible effect on venous tone and posture Esp. useful younger pts with hyperkinetic circulation and high sympathetic tone Interfere with both compensatory reflexes Reduce left ventricular hypertrophy ADRs: cardiac depression, bradycardia, bronchoconstriction (NS), CNS depression (lipid soluble)/vivid dreams, ↑ chol/ TGs, ↓ HDLs, impotence, ↓ insulin release / mask hypoglycemia, ↓ exercise tolerance / tiredness / fatigue  LABETALOL / CARVEDILOL Mechanism of action, clinical indications and adverse effects Alpha-1 and NS beta blocker (higher activity) ↓ PR & CO, more balanced SNS inhibitiion IV use in hypertensive emergencies/ pheochromocytoma and usu. as 2nd line drug in treatment moderate-severe hypertension Adverse effects combination of alpha / beta blockade (e.g., may precipitate asthma is selected patients)  SELECTIVE ALPHA -1 BLOCKERS Mechanism of action, clinical indications and adverse effects Competitive alpha-1 blockers (eg., prazosin) Balanced vasodilation; ↓ PR and both pre/ afterload, usu. maintain renal blood flow ↑ CO in CHF; ↓ LV hypertrophy Metabolically neutral with regard to insulin/ glucose/cholesterol/TG, may ↑ HDLs/ Na/H2O retention ADRs: dizziness, headache, postural hypotension (1st dose), reflex ↑ in HR if BP decs too much, blurred vision, nasal congestion, male: impotence (block vas deferens-ejaculation) or improve (↑ blood flow)  Alpha - 2 Adrenergic Receptors Mechanism of action Presynaptic receptors in periphery/CNS, binds to receptor to exert negative feedback and ↓ further NE release Postsynaptic alpha-2 receptors in CNS (brain stem) inhibit SNS outflow from vasomotor/ cardiac centers to ↓ vasomotor tone, BP & HR Mechanism of Action of alpha-2 receptors  CLONIDINE Mechanism of action, clinical indications and adverse effects CNS (medullary NTS): central α-2 agonist (pre/postsynaptic) = ↓ adrenergic outflow to SNS; also binds nonadrenergic-imidazole binding site that ↓ SNS outflow & BP ↓ BP/HR/CO/renin; ↑ PNS/vagal tone PO/BID or weekly transdermal patch IV only: transient ↑ BP – peripheral arteriolar α stimulation causing vasoconstriction ADRs: CNS sedation/depression, ↓ HR/ ↑ Na/H2O retention, dry mouth, post treatment syndrome (↑ SNS) with abrupt cessation (hypertensive crisis) Metabolism of Methyldopa  METHYLDOPA Mechanism of action, clinical indications and adverse effects CNS action (medullary NTS): converted to α-methyl- NE = central α-2 agonist = ↓ central adrenergic tone ↓ BP; less effect on HR & renin than clonidine PO, usu. w/ diuretic to prevent fluid retention, safe in pregnancy ADRs: ▪ CNS sedation, GI disturbances ▪ Autoimmune: hemolytic anemia + Coombs (20%); hemolysis rare (2%), liver jaundice / hepatitis; drug fever / lupus-like syndrome  HYDRALAZINE Mechanism of action, clinical indications and adverse effects Direct - acting arteriolar vasodilator Exact MOA unknown, may interfere with IP3 action to release Ca from SR ↓ diastolic > systolic; ↓ PR Activates baroreceptor \ RAA reflexes Usu. requires diuretic + β blocker or ACE inhibitor, used as triple therapy in severe hypertension High first-pass acetylation (fast/slow) ADRs: excessive vasodilation, edema flushing, headache, reflex HR, immune reaction: lupus syndrome/rash/ arthralgia Mechanism of Action of alpha 1 receptors  MINOXIDIL Mechanism of action, clinical indications and adverse effects Arteriolar dilator via K-channel opening & hyperpolarization of smooth muscle membrane Use: severe HPT when other drugs are ineffective / contraindicated, usu. requires β blocker + diuretic ADRs: reflex tachycardia & Na/H2O retention resulting in edema/CHF/pericardial tamponade; hirsutism DRUGS FOR HYPERTENSIVE CRISIS Nitroprusside & Diazoxide (infrequent use) Hypertensive crisis usu. caused by malignant HPT = severe ↑ BP, papilledema, acute renal insufficiency, encephalopathy & fibrinoid arterial necrosis Life-threatening; requires immediate therapy New: Fenolopam – Dopamine-1 agonist dilates renal/ mesenterics, also used in hypertensive crisis  NITROPRUSSIDE Mechanism of action, clinical indications and adverse effects Fe \ CN \ NO complex; NO inactivates MLCK/ MLC ; fast acting/potent, balanced vasodilator IV infusion in HPT emergency/ malignant hypertension; t1\2: 3-4 min Light sensitive/inactivation; wrap Al foil ADRs: hypotension, ↑ HR (baro-reflex), flushing/ headache CN → thiocyanate (toxic if it accumulates): weakness, spasms, convulsions, CNS disorientation/psychosis CN may accumulate in OD; antidote = sodium thiosulfate → forms thiocyanate Nitroprusside Mechanism of Action  DIAZOXIDE Mechanism of action, clinical indications and adverse effects Thiazide-like drug; no diuretic activity, K+ channel opening → hyperpolarizes arterial smooth muscle Potent arteriolar dilator Used IV bolus over 10 mins in hypertensive emergencies/ malignant hypertension; effect 3-12 hours, T1/2 – 24 hr Usu. requires concomitant use of beta blocker to control tachycardia /release of renin ADRs: excessive hypotension, tachycardia/ angina, Na/water retention  CA ANTAGONISTS Mechanism of action, clinical indications and adverse effects Block voltage-dependent slow Ca channel Block Ca @ SA / AV node / smooth muscle; phase 2 myocyte AP Verapamil & diltiazem affect both cardiac (↓ HR by inc. P-R interval on ECG, AV conduction, contraction) & smooth muscle (arteriolar dilators) Nifedipine & related drugs primarily affect only smooth muscle = more potent arteriolar dilators  VERAPAMIL\ DILTIAZEM Mechanism of action, clinical indications and adverse effects ↓ HR and AV conduction (V > D) Vasodilation less than nifedipine type ↓ myocardial contractility; usu. high doses / toxicity; may cause CHF Use: HPT, angina, & fast supra- ventricular arrhythmias Caution if used with β blockers, excessive depression of contractility (CHF) & AV conduction (heart block); constipation  Dihydropyridines: Nifedipine Class Mechanism of action, clinical indications and adverse effects Arteriolar dilators, no direct cardiac effects Nifedipine has fast onset/short duration, other longer-acting Ca blockers preferred for HPT Excessive dilation may trigger reflex HR and myocardial ischemia ADRs primarily related to excessive vasodilation: nausea, lightheadedness, dizziness, headache, tachycardia, peripheral edema (CHF, pulmonary) High doses/excessive vasodilation may ↑ MI risk in pts who also have CAD due to potential for myocardial ischemia MOA of ACEI’s & AII blockers  ACE INHIBITORS Mechanism of action, clinical indications and adverse effects ↓ angiotensin II = ↓ vasoconstriction/PR ↑ bradykinin = ↑ vasodilator PGs & NO = vasodilation Balanced vasodilation, ↓ pre-/afterload ↑ CO in CHF; maintains renal flow/function, improve renal function in diabetic nephropathy No metabolic disadvantages, or impotency ADRs: GI, hypotension, rash, cough/wheezing/angioedema, K+ retention/ hyperkalemia Contraindication: 2-3 trimester pregnancy, pts with bilateral renal stenosis  ACE Inhibitors pharmacokinetics Captopril: rapid onset; short duration (t1/2 = 3hr), usu. BID-TID ▪ Bioavailability ↓ by food, exc urine 50% unc ▪ Possesses SH- group, dysgeusia Enalapril: 1x/day advantage (t1\2 = 11hr); prodrug → active metabolite – enalaprilat Lisinopril: 1x/day (t1\2 = 12hr); slow onset, exc urine unchanged Most other drugs are prodrugs → active metabolite → “lat” eg. benazeprilat/fosinoprilat  Angiotensin II Inhibitors – Losartan Mechanism of action, clinical indications and adverse effects Active pro-drug: competitive AT1 blocker ▪ AT1 = AgII receptor (esp. arterial sm muscle, kidney, adrenal gland) Active metabolite: ↑ potency & t1/2; noncompetitive AT1 block No ↑ bradykinin or subsequent prostaglandin synthesis ADRs: similar to ACE inhibitors (< cough/ angioedema), excessive hypotension, dizziness, headache, fatigue, ↑ liver enz., hyperkalemia; contraindicated in pregnancy Other Angiotensin Receptor (AT1 Antagonists) Blockers Valsartan Irbesartan Candesartan Telmisartan Olmesartan Eprosartan  Selecting AHPT Drugs NOT Patient population Recommended Recommended Diuretics β blockers African-American Ca blockers ACEIs Diuretics Edema/CHF ACEIs Prostatic hypertrophy, CHF, α blockers peripheral vascular disease Asthma, sick sinus, brittle β blockers usu. not diabetes recommended Ca blockers Angina β blockers ACEIs CHF, diabetes, post MI AgII blockers Summary of Antihypertensive drugs Drugs used in hypertension Diuretics Sympathoplegics Vasodilators Angiotension Blockers of: antagonists Alpha or beta ACE Receptor blockers inhibitors blockers Nerve terminals CNS sympathetic Ganglia Calcium Parenteral outflow Older oral blockers vasodilators vasodilators Please review summary table on pages 187-188  Clinical Correlated Question 1. A friend has very severe hypertension and asks about a drug her doctor wishes to prescribe. Her physician has explained that this drug is associated with tachycardia and fluid retention (which may be marked) and increased hair growth. Which of the following is most likely to produce the effects that your friend has described? (A) Captopril (B) Guanethidine (C) Minoxidil (D) Prazosin (E) Propranolol  Clinical Correlated Question 2. A patient is admitted to the emergency department with severe bradycardia following a drug overdose. His family reports that he has been depressed about his hypertension. Which one of the following drugs slows the heart rate in a dose- dependent manner? (A) Captopril (B) Hydrochlorothiazide (C) Minoxidil (D) Prazosin (E) Verapamil  Basic Review Question 3. In comparing clonidine and prazosin, which one of the following is correct? A. Prazosin-but not clonidine-results in salt and water retention if used alone B. Prazosin causes fewer CNS adverse effects (such as sedation) than clonidine C. Clonidine like prazosin is a agonist of α2 receptor D. Clonidine causes more orthostatic hypotension than prazosin E. Clonidine like prazosin will result in the decrease in heart rate  Basic Review Question 4. Comparison of prazosin with atenolol shows that (A) Both decrease cardiac output (B) Both decrease renin secretion (C) Both increase heart rate (D) Both increase sympathetic outflow from CNS (E) Both produce orthostatic hypotension  Basic Review Question 5. A patient with hypertension and angina is referred for treatment. Metoprolol and verapamil are among the drugs considered. Both metoprolol and verapamil are associated with which one of the following? A. Diarrhea B. Hypoglycemia C. Increased PR interval D. Tachycardia E. Thyrotoxicosis  Clinical Correlation 6. A 32-year-old woman with hypertension wishes to become pregnant. Her physician informs her that she will have to switch to another antihypertensive drug. Which of the following drugs is absolutely contraindicated in pregnancy? (A) Atenolol (B) Losartan (C) Methyldopa (D) Prazosin (E) Propranolol  Basic Review Question 7. Which one of the following is a significant unwanted effect of the drug named? A. Constipation with verapamil B. Heart failure with hydralazine C. Hemolytic anemia with atenolol D. Hypokalemia with losartan E. Lupus-like syndrome with hydrochlorothiazide  Basic Review Question 8. Which one of the following is characteristic of enalapril treatment in patients with essential hypertension? A. Competitively blocks angiotensin II at its receptor B. Decreases angiotensin II concentration in the blood C. Decreases renin concentration in the blood D. Increases sodium and decreases potassium in the blood E. Decreases sodium and increases potassium in the urine  Clinical Correlated Question 9. A pregnant patient is admitted to the hematology service with moderately severe hemolytic anemia. After a thorough workup, the only positive finding is a history of treatment with an antihypertensive drug since 2 months after beginning the pregnancy. The most likely cause of the patient’s blood disorder is: (A) Atenolol (B) Captopril (C) Hydralazine (D) Methyldopa (E) Minoxidil  Clinical Correlated Question 10. A 73-year-old man with a history of a recent change in his treatment for moderately severe hypertension is brought to the emergency department because of a fall at home. Which of the following drug groups is most likely to cause postural hypotension and thus an increased risk of fall? A. ACE inhibitors B. Alpha1-selective receptor blockers C. Thiazides D. Beta1-selective receptor blockers E. Nonselective β-blockers  Clinical Correlated Question 11. A visitor from another city comes to your office complaining of incessant cough. He has diabetes and hypertension and has recently started taking a different antihypertensive medication. The most likely cause of his cough is (A) Captopril (B) Losartan (C) Minoxidil (D) Propranolol (E) Verapamil  Featured case in chapter 11 12. A 35-year-old man presents with a blood pressure of 150/95 mm Hg. He has been generally healthy, is sedentary, drinks several cocktails per day, and does not smoke cigarettes. He has a family history of hypertension, and his father died of a myocardial infarction at age 55. Physical examination is remarkable only for moderate obesity. Total cholesterol is 220 and high- density lipoprotein (HDL) cholesterol level is 40 mg/dL. Fasting glucose is 105 mg/dL. Chest x-ray is normal. Electrocardiogram shows left ventricular enlargement. How would you treat this patient? (A) Captopril (B) Hydrochlorothiazide (C) Minoxidil (D) Metoprolol (E) Verapamil  Bonus Diurectic Questions Clinical Correlated Question 13.A 70-year-old woman is admitted to the emergency department because of discomfort on urinating. She has had diabetes for 10 years and takes several oral medications. A finger-stick blood glucose determination is normal but urinalysis reveals white blood cells and gram-negative rods. Which of the following drugs is the most likely cause of her infection? (A) Acetazolamide (B) Dapagliflozan (C) Furosemide (D) Spironlactone (E) Conivaptan  Clinical Correlated Question 14. A 58-year-old woman with lung cancer has abnormally low osmolarity and hyponatremia. A drug that increases the formation of dilute urine and is used to treat SIADH is: A. Acetazolamide B. Amiloride C. Desmopressin D. Conivaptan E. Ethacrynic acid  Clinical Correlated Question 15. A graduate student is planning to make a high-altitude climb in South America while on vacation. He will not have time to acclimate slowly to altitude. A drug that is useful in preventing high-altitude sickness is: A. Acetazolamide B. Amiloride C. Demeclocycline D. Desmopressin E. Ethacrynic acid  Basic Review Question 16. Which one of the following diurectics would be most useful in the acute treatment of a comatose patient with traumatic brain injury and cerebral edema? A. Acetazolamide B. Amiloride C. Chlorthalidone D. Furosemide E. Mannitol