04.15 - Anti-HTN Drugs Flashcards Preview

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Flashcards in 04.15 - Anti-HTN Drugs Deck (28)
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What are the MOA, pharm effects, side effects, and clinical uses of the alpha-adrenergic receptor blockers?

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) 


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

- 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) 


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

- 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)


What are the clinical uses of pure beta-blockers?

- 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) 


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

- 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


What are the additional uses of beta-blockers?

- 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


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

- ~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


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

- 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 


What are the drugs that affect the renin angiotensin system?

- Aliskerin: binds to renin, preventing conversion of angiotensinogen to angiotensin I (NOT used as an anti-HTN drug) 

- ACE inhibitors 

- ARB's 


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

- 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


What are the side effects of ACE-inhibitors?

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 


How does Angiotensin-II cause cardiac and vascular hypertrophy?

By releasing PKC


Why is Lisinopril unique among the ACE-inhibitors?

- # of properties distinguish it from o/ACE-inhibitors:

1. Hydrophilic

2. Long half-life and tissue penetration

3. NOT metabolized by the liver


What is the MOA of the ARB's?

- 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 


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

- 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 


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

- 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 


What are the pharmacology and clinical uses of the dihydropiridines?

- 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 


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

- ClonidineGuanfacineGuanabenz:

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


What are Hydralazine and Fenoldopam?

- 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)


What is Minoxidil?

- 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 


What are the MOA and pharmacological effects of Nitroprusside?

- 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)


Summary slide. Reflect.

Good job!


How are diuretics used to treat HTN?

- 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 


What are some of the advantages of BB therapy?

- 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 


What is Bisoprolol?

- Considered as standard tx option w/ACEI's and diuretics 

- Associated with a 34% mortality benefit in Cardiac Insufficiency Bisoprolol Study 



What is first-line therapy for HTN?

ACEI, ARB, CCB +/- diuretic


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

- 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


What are the highlights for dihydropyridine CCB's?

- 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