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
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:
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?
- 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
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.
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