04.15 - Anti-HTN Drugs

Question 1

What are the MOA, pharm effects, side effects, and clinical uses of the alpha-adrenergic receptor blockers?

Answer 1

• MOA: block alpha-adrenergic receptors in arteries AND veins
• Pharm effects: decrease TPR, reduce BP
  1. Relieve symptoms of BPH by relaxing mm of bladder, prostate
  2. INC HDL, lower LDL, and have beneficial effect on insulin resistance
• Side effects: first does hypotension, w/Prazosin (give at bedtime)
• Clinical uses: NOT recommended as monotherapy for HTN (ALLHAT study)

Question 2

Which 1st and 2nd gen beta-blockers have ISA, MSA, cardio-selectivity, and lipid solubility?

Answer 2

• ISA (binds and blocks beta receptor, but also a partial agonist): Timolol, Pindolol
• MSA (blocks heart conduction activity): Propranolol (anti-arrhythmic), Metoprolol, Pindolol
• Cardio-selectivity (B-1 selective): Metoprolol, Bisoprolol
• Lipid-solubility: all of these (esp. Propranolol, Metoprolol)

Question 3

What is the MOA of BB with no ISA? What are these drugs called?

Answer 3

• Pure beta-blockers
• Block myocardial ß1-adrenergic receptors (ß1-AR)
• DEC HR and contractility, thus, DEC cardiac output
• Block ß1-AR in the juxtaglomerular apparatus and thereby inhibit renin release
• Very useful in patients with high renin HTN, but work well in hypertensive patients with normal-low renin (do NOT cause salt, water retention)

Question 4

What are the clinical uses of pure beta-blockers?

Answer 4

• Effective therapy for all grades of hypertension
• Do NOT cause retention of salt and water and can be administered w/o a diuretic -> anti-HTN effect is additive with a diuretic
• Assoc w/definite mortality benefits (Bisoprolol)

Question 5

What are the three 3rd generation beta-blockers we covered?

Answer 5

• Labetalol: mixed A-1-ß-antagonist -> IV for HTN emergencies, i.e., pheochromocytoma, preeclampsia
• Carvedilol: mixed A1-ß antagonist
  1. Antioxidant; binds, scavenges ROS
  2. Protects membranes from lipid peroxidation
  3. Prevents LDL oxidation and LDL uptake into coronary blood vessels
  4. #1 drug for tx of CHF: biased agonism (blocks something, and activates something else)
• Nebivolol: #1 selective antagonist -> antioxidant activity; promotes endo NO-mediated vasodilation

Question 6

What are the additional uses of beta-blockers?

Answer 6

• CHF, MI, sinus and AV arrhythmias
• Open angle glaucoma: Timolol -> reduces production of aqueous humor
• Add’l off label uses: stage fright, altering memory
• Compelling indications for BB:
  1. Highly preferred in HTN pts with conditions such as MI, ischemic heart disease, or CHF
  2. Preferred in HTN pts who have hyper-thyroidism & migraines

Question 7

What are the side effects of the 1st- and 2nd-generation beta blockers?

Answer 7

• ~40-50% of patients on 1st-, 2nd-gen BB
• Cold extremities: worsens peripheral arterial insufficiency (due to reflex vasoconstriction)
• Bradycardia: DEC AV nodal conduction
• Bronchospasm: avoid w/asthma; ß1/3rd-gen ok in COPD
• CNS side effects: bad dreams, depression
• Metabolic effects:
  1. Block glycogenolysis, delaying recovery from hypoglycemia in T1D (not seen w/3rd-gen or selective ß1-blockers)
  2. Block hormone-sensitive lipase (HSL) in adipocytes; INC LDL, DEC HDL, and INC TG’s
• Drug withdrawal syndrome:
  1. WITHDRAW SLOWLY (10-14 days) -> prolonged use up-regulates #-receptors in heart, and abrupt withdrawal causes tachycardia

Question 8

What are the clinical uses and benefits of the 3rd generation beta-blockers?

Answer 8

• Primarily for CHF, HTN and reduce BP more than o/BB b/c of A-blockade (carvedilol) & NO (nebivolol)
• Reduce HR less than other BB; reduce mortality, morbidity in pts with mild to moderate CHF
• Not associated with changes in lipids & glucose, so preferred in metabolic syndrome
• NOT first-line treatment for HTN

Question 9

What are the drugs that affect the renin angiotensin system?

Answer 9

• Aliskerin: binds to renin, preventing conversion of angiotensinogen to angiotensin I (NOT used as an anti-HTN drug)
• ACE inhibitors
• ARB’s

Question 10

What are the MOA and pharmacological effects of the ACE inhibitors?

Answer 10

• MOA: inhibit conversion of Ang-I to Ang-II, and degradation of bradykinin (a potent vasodilator)
  1. Reduces secretion of aldosterone, but not seriously impaired
  2. INC renal blood flow without an INC in GFR
  3. Captopril: INC syn of renal PG’s; delays renal disease progression in diabetes (renoprotective)
• Pharmacological effects: inhibit all effects of Ang-II
  1. Dilate aa, vv (basis for use in CHF)
  2. DEC BP rarely followed by minor INC in HR
  3. Baroreceptor mechs remain intact; postural hypotension not seen
  4. Reduce Ang-II-mediated thickening of BV
  5. Positive impact on longevity in CHF

Question 11

What are the side effects of ACE-inhibitors?

Answer 11

• Hypotension: hypovolemic and/or Na+-depleted pts
• Hyperkalemia: esp. w/renal insufficiency, or pts receiving K+-sparing diuretics or K+ supplements
• Dry cough (most common), angioneurotic edema or angiodema; both related to bradykinin actions
  1. Bradykinin activates stretch receptors in the trachea, which might causes dry cough in ~10-15% of patients receiving ACEI
• Angioedema: infrequent but potentially fatal
  1. Rapid swelling of dermis, subcu tissue, mucosa, & submucosal tissues (like urticaria)
• Fetotoxicity: contraindicated in 2nd, 3rd trimesters

Question 12

How does Angiotensin-II cause cardiac and vascular hypertrophy?

Answer 12

By releasing PKC

Question 13

Why is Lisinopril unique among the ACE-inhibitors?

Answer 13

• # of properties distinguish it from o/ACE-inhibitors:
  1. Hydrophilic
  2. Long half-life and tissue penetration
  3. NOT metabolized by the liver

Question 14

What is the MOA of the ARB’s?

Answer 14

• Selectively block angiotensin-II type 1 receptors (AR-I), which are responsible for all of the effects of Ang-II
• Cause vasodilation, INC Na+ and water excretion, resulting in DEC TPR, plasma volume, CO, and BP
• No effect on bradykinin, so they are THE substitute when ACEI cause cough

Question 15

What is the pharmacological profile of the different ARB’s?

Answer 15

• Losartan: pro-drug metabolized to active product (not excreted by kidney; only taken once per day)
  1. Competitive antagonist of TXA2 receptor -> attenuates platelet aggregation
  2. Unique b/c it INC uric acid urinary excretion (uricosuric), so good for pts with gout
• Irbesartan, valsartan, and telmisartan: do NOT affect uric acid or CYP enzymes
• Fetotoxicity is main side effect of ALL of these

Question 16

What is the pharmacological profile of L-type Ca channel blockers (CCB)?

Answer 16

• 3 classes that differ in basic chemistry and relative selectivity for cardiac vs. vascular L-type Ca channels
• Phenylalkylamines: Verapamil (anti-arrhythmic)
  1. Relatively selective for myocardium; less effective as systemic vasodilator
• Benzothiazepines: Diltiazem (anti-arrhythmic)
  1. Intermediate b/t verapamil & dihydros in selectivity for vascular Ca2+ channels
• Dihydropyridines: selectively block L-type Ca2+ channels in blood vessels
  1. Used for HTN b/c DEC SVR & arterial pressure

Question 17

What are the pharmacology and clinical uses of the dihydropiridines?

Answer 17

• Relax arteriolar smooth muscles -> DEC BP, PVR
• Do NOT cause large baroreceptor-mediated SYM discharge; mild to non-existent changes in HR
• Clinical uses:
  1. More effective in DEC BP than other drugs in pts w/low renin HTN, i.e., elderly, AA (usually more difficult to treat)
  2. Preferred in older subjects w/systolic HTN
  3. First-line HTN tx; long-acting better than short
  4. No survival benefit in large cohort studies

Question 18

What are the actions, uses, and side effects of the centrally-acting alpha-2 agonists?

Answer 18

• Clonidine, Guanfacine, Guanabenz:
  1. Agonists of post-synaptic alpha-2A-adreno-ceptors in rostral ventrolateral medulla (RVLM)
  2. DEC SYM impulses from RVLM to heart, blood vessels
  3. DEC in PVR and HR
• Uses of specific agents:
  1. Clonidine: releases endogenous opiates (used as analgesic in neuropathic pain; patch), and approved for treatment of ADHD
  2. Tertiary use in HTN, i.e., used in triple combos
  3. Guanabenz: lowers chol in plasma (-5-10%)
• Side effects:
  1. Sedation (less w/Guanfa), drowsiness, fatigue
  2. Clonidine withdrawal -> HTN: DO IT SLOWLY

Question 19

What are Hydralazine and Fenoldopam?

Answer 19

• Hydralazine: arteriolar (not vv) smooth mm relaxer
  1. Strongly triggers reflex SYM stimulation, and renin/catecholamine secretion (so usually given w/BB and diuretic to manage compensatory response)
  2. Side effects: pronounced tachycardia and hemolytic anemia
• Fenoldopam: selective D1 partial agonist (can use in patients who may have renal failure)

Question 20

What is Minoxidil?

Answer 20

• Opens K+(ATP) channels & relaxes smooth muscles
• Dilates arterioles, but not veins, triggering reflex SYM stimulation -> catecholamine/renin secretion
• Hirsutism: male-pattern hair growth in women; a component of Rogaine
• Clinical uses: IV in hypertensive emergencies, preeclampsia
  1. Used with BB and diuretics to manage compensatory responses

Question 21

What are the MOA and pharmacological effects of Nitroprusside?

Answer 21

• MOA: mainly a pro-drug
  1. Forms NO, which stimulates smooth muscle guanylate cyclase -> INC levels of cGMP in vascular smooth muscle, causing relaxation
• Pharmacological effects: dilates both aa and vv
  1. Reduces TPR and induces venous pooling (increases preload)
  2. DEC CO in normal subjects, but INC CO in pts with LV failure b/c TPR (i.e. afterload) is reduced
  3. Very short half-life and given IV for HTN emergencies in pts with ventricular failure (or MI)

Question 22

Summary slide. Reflect.

Answer 22

Good job!

Question 23

How are diuretics used to treat HTN?

Answer 23

• Monotherapy or adjunctive with other anti-HTN b/c augments actions of all the others
• Alone, or with beta-blockers DEC mortality in pts with HTN
• Diuretics (esp. in low doses) and ACEI’s are best tolerated drugs for monotherapy of HTN
• Pts w/edematous conditions, like heart failure and renal insufficiency, freq require diuretic for optimal control of BP
• Pts w/volume-dependent HTN (w/low renin levels) show better responses -> poor response to thiazides may reflect overwhelming load of dietary Na or impaired renal capacity to secrete Na

Question 24

What are some of the advantages of BB therapy?

Answer 24

• Secondary protection in CAD, a characteristic not well established for other drugs
• Esp. useful in HTN’s w/tachycardia, high CO, and/or high renin -> less effective in AA, elderly
• Very useful in HTN’s w/hyperthyroidism, migraines, or glaucoma
• NOTE: 3rd-gen preferred over older b/c smoother clinical effect and substantially fewer side effects

Question 25

What is Bisoprolol?

Answer 25

• Considered as standard tx option w/ACEI’s and diuretics
• Associated with a 34% mortality benefit in Cardiac Insufficiency Bisoprolol Study

Question 26

What is first-line therapy for HTN?

Answer 26

ACEI, ARB, CCB +/- diuretic

Question 27

What are the highlights for ACEI’s and ARB’s?

Answer 27

• Useful in mgmt of all degrees of HTN, but superior in HTN’s w/high renin levels (young people & middle-aged Caucasians)
• INC efficacy of diuretics -> combo of thiazide & ACEIs necessary in pts w/low renin levels, AA, elderly
• Should be initial anti-HTN drug in diabetic pts with HTN, following which, it is appropriate to consider adding a CCB if 2nd drug needed
• May also preserve renal function in pts with non- diabetic nephropathies (Captopril -> INC renal PGs)
• Should be chosen as initial anti-HTN drug in pts prone to CHF
• Avoid in any condition that may cause hyperkalemia
• Contraindicated in pregnancy -> exposure to ACEI/ARB’s at conception appears to be safe

Question 28

What are the highlights for dihydropyridine CCB’s?

Answer 28

• Widely used in tx of HTN and other CV diseases, like CAD
• Some physicians (esp. in US) consider that CCBs should be reserved for pts who do not respond to, or cannot tolerate, diuretics, BB’s, or ACEI’s
  1. Recent meta-analyses have suggested risk of CAD and HF may be higher in pts treated with CCBs vs. those given ACEIs, BB’s and diuretics
• Wide efficacy profile; esp. useful in AA and groups with low-renin HTN (e.g., elderly)
• May be safely used in diabetics