Antihypertensives Flashcards

Question

Why shouldn't short half life DHP CCBs be used for hypertension?

Answer 1

They can cause: Rapid drop in blood pressure Oscillations in blood pressure control Concurrent surges in sympathetic reflex activity.

Answer 2

Normal: L-type Ca2+ channels have long, large, high threshold Dominant type in vascular smooth muscle, cardiac myocytes, SA and AV nodal tissue They mediate entry of EC Ca2+ and induce Ca2+-induced Ca2+ release → contraction of smooth muscle and cardiac muscle and stimulate SA node conduction Drug Action: CCBs bind to a site on the main poreforming (α1) subunit of the Ca2+ channel → block Ca2+ entry Blocks smooth muscle contraction and drug binding reduces frequency of opening in response to depolarization and a decrease in transmembrane calcium current: long-lasting smooth muscle relaxation, reduction in contractility through the heart and decreases SA node pacemaker rate and AV cconduction velocity. CCBs bind more effectively to open channels and inactivated channels

Answer 3

Verapamil / Diltiazem: => Decrease the channel’s rate of recovery =>channel block is enhances as the frequency of stimulation increases => Depress rate of the sinus node pacemaker (automaticity) => Slow AV conduction Dihydropyridines (DHPs) => potent vasodilators with reflex tachy and positive iontropy => does not affect the channels rate of recovery => does not affect conduction through the AV node

Answer 4

Slow heart rate, Slow AV conduction and Reduce myocardial contractility ↓ peripheral arterial resistance => ↓ afterload => ↓O2 consumption

Answer 5

Hypertension => used for initial or add-on therapy; decrease BP by relaxation of arterioles and decreased SVR Hypertensive emergency => DHP CCB plus labetalol or esmolol to prevent reflex tachycardia => Nicardipine: potent, long acting → duration ≤8 hours => Clevidipine: 1-minute t½ → duration 5-15 min Angina - initial or add-on therapy - decreased PVR increases coronary blood flow and increases O2 delevery to myocardium. Supraventricular tachyarrhythmias => verapamil/diltiazem, slow automaticity & slow conduction through AV node Raynaud phenomenon => Long-acting DHP CCB may reduce intensity of attacks Subarachnoid hemorrhage => to reduce incidence and severity of ischemic deficits Migraine => Verapamil may prevent migraine Tocolytic => Nifedipine (for 48 hours only) to suppress premature contractions in preterm labor (24-34 weeks)

Answer 6

Variant angina => CCBs first line Exertional angina => BB plus DHP and CCB => Non-DHP act on the double product (HR x SBP) →↓ O2 demand Unstable angina /acute coronary syndrome: => DHP CCB when combined with BB => Non-DHP only for paitents who do not tolerate BB

Answer 7

non-DHP: bradycardia and worsening cardiac output, constipation (especially verapamil) DHP: peripheral edema caused by vasodilation which increased capillary pressure and permeability leading to the edema. Both -- GERD aggravation

Answer 8

Increased risk of AV block and/or severe depression of ventricular function => I.V. verapamil + I.V. beta blocker verapamil or diltiazem in patients with ventricular dysfunction,. SA or AV nodal conduction disturbances and SBP below 90 mm Hg

Answer 9

immediate-release is not for use in patients with acute or unstable angina and STEMI because it may precipitate or aggravate myocardial infarction short-acting formulations are not appropriate in the long-term treatment of angina or hypertension

Answer 10

Verapamil + digoxin → digoxin toxicity => verapamil blocks P-gp Verapamil + quinidine → excessive hypotension => CYP3A4, P-gp inhibition, PD effects CYP- and P-gp mediated interactions

Answer 11

Non-DHP CCB In addition to hypertension and angina: Supraventricular tachyarrhythmias and migrane when given with digotoxin can lead to digitoxin toxicity and given with quinidine can cause hypotension Diltiazem - also a Non-DHP CCB that is used for Supraventricular Tachyarrhythmias

Answer 12

competitive antagonists of norepinephrine and epinephrine (or inverse agonists) the amino nitrogen favors interaction with β receptors βArs regulate numerous functional responses, including heart rate and contractility, smooth muscle relaxation and multiple metabolic events β-Adrenergic receptors (β1β2β3) are GsPCRs which means they activate adenylyl cyclase and increase cAMP and PKA

Answer 13

SA node - increased HR; in atria, AV node, his-purkinje system all increase automaticity and conduction velocity and in the ventricles contractility, conduction, automaticity and rate of idioventricular pacemakers. All Beta1 Skeletal muscle and hepatic vasculature beta 2 vasodilation predominates Renal jextaglomerular apparatus => beta receptor activation induces renin release causing activation of RAAS system Blocking cardiac β1 adrenergic receptors → slows heart rate and AV conduction Blocking renal β1 adrenergic receptors → inhibits renin release BBs reduce cardiac output and lower blood pressure in patients with hypertension

Answer 14

non-selective beta blocker - first gen (also, nadolol, penbutolol, pindolol, pimolol) (not starred) highly lipid soluble and plasma protein binding, halflife 3-5 hours and <90 absorption

Answer 15

Esmolol and Metaprolol (also acebutolol, atenolol, bisoprolol -- not starred) esmolol - low lipid solubility, 9 minute halflife, 55% protein binding metaprolol - moderate lipid solubility, 100% absorbed, 3 to 7 hour halflife with low protein binding.

Answer 16

Carteolol -- highly intrinsic agonist activity, Low lipid solubility, and 85% absorption, 85 % bioavil, 6 hr halflife, and 23-30% protein binding. Carvedilol -- ++ membrane stabilizing, Moderate lipid solubility, >90 absorption, ~30 bioavil, 7-10 half-life, 98% protein binding Labetalol -- has membrane stabalizing and intrinsic agonist activity, Low lipid solubility, >90 extent of absorption, ~33% bioavail, ~5 hr halflife, and ~50 protein binding

Answer 17

Nitric oxide production and beta2 receptor agonism

Answer 18

alpha 1 receptor antadonism

Answer 19

alpha 1 receptor antagonism, Ca2+ entry blockade, antioxidant activity

Answer 20

Hypertension Hypertensive emergencies - labetalol, esmolol (other classes of vasodilators) Intraoperative tachy, hypertension - propranolol, metoprolol, esmolol Ischemic heart disease (angina) Congestive heart failure Certain arrhythmias Hyperthyroidism Glaucoma

Answer 21

β receptor blockade has relatively little effect on the normal heart of an individual at rest but has profound effect during exercise or stress At these points sympathetic control of the heart is dominant. They do not usually cause hypotension in health peeps with normal BP

Answer 22

they reduce myocardial O2 consumption in ischemia heart disease, such as for the treatment of exertional angina Shown to improve survival in patients who have had an MI

Answer 23

↑End-diastolic volume and ↑Ejection time which tend to increase myocardial O2 requirement Use nitrates to counterbalance

Answer 24

Thought to decrease unstable tachyarrhythmias and reduce remodeling (decrease LV chamber size and increase LV EF, and decrease stress in the myocardium) attenuation of sustained sympathetic activation => inhibit maladaptive proliferative cell signaling in the myocardium, reduce catecholamine-induced cardiomyocyte toxicity and decrease myocyte apoptosis. most patients respond favorly to BB but they can precipitate acute decompensation of cardiac function. bisoprolol, carvedilol, metoprolol and nebivolol >>> shown to reduce mortality

Answer 25

Class II antiarrhythmics Reduce HR and decrease intracellular Ca2+ overload which inhibit afterdepolarization-mediated automaticity increase AV nodal conduction time (PR interval) and prolong AV nodal refractoriness BBs are useful in terminating re-entrant arrhythmias involving the AV node and in controlling ventricular response in atrial fibrillation or flutter. BBs can prevent recurrent infarction and sudden death in patients recovering from acute myocardial infarction propranolol - some Na+ channel blocking effects at high concentrations

Answer 26

Hyperthyroidism increases the basal metabolic rate and enhanced organ sensitivity to catecholamines BBs ameliorate symptoms -- palpitations, tachycardia, tremulousness, anxiety, heat intolerance Controll pulse rate, hypertension and atrial fibrillation thyroid storm can cause SVT and sudden death => thyrotoxicosis

Answer 27

beta 2 receptors in eye - ciliary body, epithelium and blood vessels decrease intraocular pressure by decreasing production of aqueous humor and decreasing ocular blood flow (decrease ultrafilatration) Nasolacrimal drainage ⇒ BBs potentially can cause adverse cardiovascular and pulmonary effects in susceptible patients little to no effect on pupil size or accommodation, no blurred vision or night blindness.

Answer 28

Sympathetic manifestations may include palpitations, tightness in the chest, breathlessness, muscular tension, trembling, flushing, sweating, dry mouth Low dose of propranolol taken an hour before decreases somatic manifestations of anxiety

Answer 29

Excessive bradycardia peripheral vascular insufficiency => Block β2-mediated peripheral vasodilation asthma/copd exacerbation => Block β2-mediated bronchodilation delayed recovery from insulin-induced hypoglycemia => Inhibit β2-mediated hepatic glycogenolysis / gluconeogenesis and blunt perception of symptoms (beta1 may be less likely to do this) Decrease insulin sensitivity and Increase plasma VLDL and agents decrease HDL => both selective and non-selective BB Decrease release of free fatty acids from adipose tissue (an exercising muscles energy source) => Block β-mediated activation of hormone-sensitive lipase in fat cells Fatigue; insomnia; nightmares and decreased libido

Answer 30

Nervousness, tachycardia, increased BP, increased intensity of angina, and increased risk of sudden cardiac death may be because of upregulation or supersensitivity of beta adrenoceptors

Answer 31

Prazosin Terazosin Doxazosin

Answer 32

phenoxybenzamine phentolamine

Answer 33

Terazosin and Doxazosin have largely replaces prazosin because they can be given once daily while prazosin is given 2-3 times daily. P/T undergo hepatic metabolism, Dox is hepatic CYP3A4, 2D6 and 2C19 All have high bioavil, terazosin is 100%

Answer 34

"-osin" Block the activation of GqPCR and the activation of PLC metabolic pathway. predominant receptor subtype in most arteries and veins with the effect of vasoconstriction. Selective competitive antagonists of α1 ARs: reduce arteriolar resistance and increases venous capacitance which decreases preload

Answer 35

* Phenoxybenzamine: irreversible αAR block * Phentolamine: competitive αAR antagonist reduce arteriolar resistance and increases venous capacitance which decreases preload

Answer 36

Reduction of blood pressure by reduces PVR Orthostatic hypotension "first dose effect" by blocking contraction of veins and arterioles in the legs which enhances venous pooling and inability to maintain BP in upright position. Tachycardia - low in alpha 1 selective, reflex event through the a2R block of nonselective alpha blockers

Answer 37

Miosis (unopposed muscarinic effect) Nasal stuffiness (blcoked vasoconstriction of nasal mucosa vasculature) decreases resistance to urine flow - because of smooth muscle relaxation

Answer 38

Persistence of vasodilation and retention of salt and water some patient may continue to experience orthostatic hypotension

Answer 39

"-osin" Hypertension (mild-moderate) refractory to first-line agents -- as an add on to diuretic, BB etc.. => less protective in reducing CV morbidity/mortality Urinary retention due to benign prostatic hyperplasia =>blocking α1 receptors relaxes smooth muscle of the bladder neck and prostate, which improves urine flow

Answer 40

Hypertension / sweating treatment in pheochromocytoma => BB may be added (after alpha blocker) to reverse the cardiac effects of excessive catecholamines

Answer 41

• Diagnosis of pheochromocytoma => historic use • Extravasation management => pressor, blocks local blood flow around injection site, this reverses it. • Local anesthesia reversal (dental use) => reversal of the vasocontrictive effect

Answer 42

1. Orthostatic hypotension / syncope: first dose effect => Reflex increase in PVR is blocked; venous return and cardiac output are reduced 2. Mild, infrequent AEs: dizziness, palpitations, headache, tiredness, 3. Intraoperative floppy iris syndrome • no benefit in discontinuing a-blocker before surgery 4. Nasal congestion, rhinorrhea Drug interactions: Sympathomimetic agents; other alpha blockers; other drugs affecting blood pressure

Answer 43

nonselective alpha blockers Orthstatic hypotension with reflex tachy, cardiac arrhythmias, or ischemic cardiac events => Slow titration Reversible ejaculation impairment Cancer risk with Phenoxybenzamine so long term use is not recommended GI effects in phentolamine include upper abdominal pain, nausea, vomiting, diarrhea => stimulates GI smooth muscle (muscarinic) and acid secretion (histamine release)

Answer 44

Use with caution in patients with CV disease and renal impairment Drug Interactions - high potential so avoid drugs that enhance hypotensive effects or increase BP

Answer 45

CENTRALLY ACTING SYMPATHOLYTICS Clonidine Methyldopa

Answer 46

70-80% bioavailability with low plasma protein binding hepatic metabolism with enterohepatic circulation with renal excretion half life is 12-16 hours, 30 min to 1 hr onset and twice daily dosing

Answer 47

~42% bioavailability due to being a substrate of COMT and metabolism in gut and liver. low protein binding Renal excretion, half life about 2 hours, onset 4-6 hours. 2-3 times dosing

Answer 48

Alpha-2 agonists reduce sympathetic outflow from CNS activate alpha 2 adrenergic R in brainstem act on postsynaptic α2 adrenoceptors, inhibiting the activity of those neurons, and / or act on postsynaptic α2 reducing norepinephrine release α2-Adrenergic receptors are GiPCRs which inhibit adenylyl cyclase and decrease cAMP and activity levels of PKA. located on presynaptic and potsynaptic sites centrally and located peripherally.

Answer 49

Directly activates α2 receptors Alpha-2 agonists lower BP by decreasing heart rate, relaxing capacitance vessels, and reducing peripheral vascular resistance

Answer 50

Taken up into presynaptic vesicles =. Converted to active methylnorepinephrine => Replaces NE in secretory vesicle false transmitter Alpha-2 agonists lower BP by decreasing heart rate, relaxing capacitance vessels, and reducing peripheral vascular resistance

Answer 51

Sympatholytic effects => reduce sympathetic outflow to hear and vasculature and stimulate parasympathetic outflow Does not effect sensitivity to baroreceptor or the baroreceptor effect or renal blood flow/ GFR ↓ PVR ↓ HR, myocardial contractility ↓ renal vascular resistance ↑vagal tone Spinal effect for pain relief => epidural clonidine patient supine - ↓ heart rate and ↓ stroke volume patient upright - ↓ vascular resistance

Answer 52

Refractory hypertension => add-on after ACEI/ARB, diuretic and CCB ADHD with 12-hour extended release Pain management - epidural Glaucoma - topical off-label use for menopausal hot flashes, substance withdrawal (opioids, alcohol, smoking) and reduction of catecholamine-induced symptoms

Answer 53

Management of hypertension in pregnancy What else can you give to a hypertensive pregnant patient?

Answer 54

Most commonly are sedation and dry mouth => dose dependent others => bradycardia, orthostatic hypotension, sexual dysfunction, CNS depression, and vivid drease

Answer 55

Parkinsonism, hyperprolactinemia Hepatotoxicity Hemolytic anemia => autoimmune Abs to Rh antigen Lupus-like syndrome

Answer 56

Cardiovascular disease like bradycardia, coronary insufficiency, recent MI or conduction disturbances Severe bradycardia or sinus arrest can occur in patients with SA nodal dysfunction or AV nodal block Epidural clonidine should be avoided in patients with predisposition for hypotension or respiratory depression

Answer 57

Because of withdrawal syndrome sudden discontinuation of alpha 2 agonist leads to a catecholamine surge => headache, apprehension, tremors, abdominal pain, sweating, and tachycardia and Rebound hypertension => BP could rise to levels higher than warranted treatment in the first plase => typically 18-36 hours after discontinuation CLONIDINE SHOULD BE GRADUALLY TAPERED

Answer 58

Yes, alpha 2 agonists may enhance AV blocking effects of BB but BB may enhance rebound hypertension effect of alpha 2 agonist withdrawal Withdraw the beta blocker several days before clonidine withdrawal => both drugs need to be tapered down, starting with BB and then clonidine => BP should be monitored.

Answer 59

Direct vasodilator - decrease BP by decreasing systemic vascular resistance ``` Can be IV or Oral, high protein binding with extensive first pass effect and excretion in the urine. t½: 2-8 h (oral) O: 20-30 min D: 8 h (oral) D: 1-4 h (I.V.) ``` Relaxes vascular smooth muscle (mechanism not defined) Dilates arterioles but not veins add-on drug for refractory hypertension

Answer 60

N-Acetyltransferase 2 (NAT2) Slow acetylators may be more subject to adverse effects and are at risk of developing antinuclear antibodies and lupus-like syndrome Fast acetylators have greater first-pass metabolism and may be prone to inaduate therapeutic response to standard doses

Answer 61

Heart failure with reduced ejection fraction − Hydralazine + isosorbide dinitrate => patients unresponsive to ACEI and BB => evidence of benefit in African-Americans Hypertensive emergency in pregnancy and postpartum Also - Lebetolol or methyldopa Hypertension

Answer 62

Relaxing the smooth muscle of arterioles => ↓ SVR and ↓ MAP => Compensatory responses => mediated by baroreceptors, SNS, renin, ANG II, and aldosterone works best when given with other anti-HTN to oppose cardiovascular responses (reflex tachy and/or salt and water retention) does not cause orthostatic hypotension or sexual dysfunction

Answer 63

Diuretics to counter salt and water retention Beta blockers to counter reflex tachycardia

Answer 64

Vasodilator - oral, decrease SVR and BP add-on drugs for refractory hypertension Oral, 90% bioavail, hepatic meta by glucuronidation and excreted in the urine half life 4 hours, onset 30 min and duration is 3 days MOA - Active metabolite mediates opening of KATP channels in smooth muscle membranes of arterioles → hyperpolarization → relaxation of smooth muscle => dilates arterioles but not veins

Answer 65

Reflex tachycardia and fluid retention can be severe Hypertrichosis - because of this it is also used as a stimulant for hair growth

Answer 66

Lupus-like syndrome -- high dose, prolonged time, slow acetylators => arthralgia, myalgia, skin, rashes, fever Rare: Peripheral Neuropathy Drug fever

Answer 67

Headache, nausea, anorexia, palpitations, sweating, flushing Reflex tachycardia Salt / fluid retention Angina exacerbation in patients with ischemic heart disease Development of congestive heart failure Beta blocker and diuretic should be co-administered to counteract these compensatory effects

Answer 68

Parenteral Vasodilator nitroprusside is taken up by red blood cells => NO + cyanide cyanide is detoxified by way of sulfur in the mitochondria. This process is saturable and too much cyanide => toxicity t½ elimination: Nitroprusside, circulatory: ~2 min Thiocyanate, renal elimination: ~3 days t½ elimination: Nitroprusside, circulatory: ~2 min Thiocyanate, renal elimination: ~3 days Activates guanylyl cyclase, either via release of nitric oxide or by direct stimulation of the enzyme → ↑ intracellular cGMP → vascular smooth muscle relaxation Dilates arterial and venous vessels

Answer 69

Parenteral Vasodilator Acute hypertension Acute decompensated heart failure Controlled hypotension during surgery

Answer 70

Parenteral Vasodilator Excessive blood pressure lowering Cyanide accumulation => Metabolic acidosis, arrhythmias, excessive hypotension, death Methemoglobinemia reported ANtidote: 1. Sod. nitrite f/b sod. thiosulfate → sulfur donor → cyanide metabolism 2. Hydroxycobalamin → cyanocobalamin (nontoxic vitamin B12)

Answer 71

Fenoldopam - Parenteral Vasodilator Hepatic methylation, glucuronidation, sulfation; renal excretion t½: ~5 minutes; O: 10 min; D: 1 hour Vasodilators decrease BP by decreasing systemic vascular resistance Dopamine D1 agonist → relaxation of vascular smooth muscle + natriuresis / diuresis => GsPCR → ↑ cAMP Dilates peripheral arterioles

Answer 72

Severe hypertension - Rx up to 48 hours short-term use in patients with renal compromise and pediatric patients => because D1 agonism increases renal blood flow

Answer 73

parental vasodilator hypotension reflex tachy headache and flushing increases intraocular pressure >> contraindication in glaucoma patients

Answer 74

Sympathetic nerve terminal blockers Oral, crosses BBB, hepatic metabolism with half-life 50 to 100 hours and duration of several weeks MOA - blocks VMAT 2 irreversibly => depletion of neurotransmitter centrally and peripherally (degraded in the cytoplasm on account of being unable to be stored in vesicles) Put simple - blocks neutrotransmitter reuptake Effects => ↓ cardiac output + ↓ peripheral vascular resistance

Answer 75

AEs => orthostatic hypotension, sexual dysfunction, dyspepsia, depression, sedation and Parkinsonism Contraindicated in patients with history of depression, active peptic ulcer, ulcerative colitis, cardiac arrhythmias, bradycardia and parkinson's disease

Answer 76

No longer used clinically due to intolerable toxicities Mecamylamine and Trimethaphan competitively block nicotinic cholinoceptors on postganglionic neurons in both sympathetic and parasympathetic ganglia Reduce blood pressure by decreasing cardiac output and peripheral resistance

Answer 77

Trimethaphan and Mecamylamine Adverse effects: − Sympathoplegia: excessive orthostatic hypotension − Parasympathoplegia: constipation, urinary retention, precipitation of glaucoma, blurred vision / mydriasis, dry mouth − Sexual dysfunction: and decreased libido, impotence (both erection and ejaculation) − CNS: altered mental status, choreiform movements, convulsions, fatigue, orthostatic dizziness, paresthesia, sedation