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Renal II Final > Intro To Antihypertensive Agents > Flashcards

Intro To Antihypertensive Agents Flashcards

1
Q

What is HP associated with?

A

Increased risk of myocardial infarction, heart failure, stroke, and kidney disease

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2
Q

What is the BP equation?

A

MAP=CO x TPR
Mean arterial pressure = cardiac output x total peripheral resistance
Cardiac output = HR x SV = volume of blood pumped through heart per minute

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3
Q

What are drug strategies to reduce blood pressure?

A

Reduce cardiac output

Reduce total peripheral resistance

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4
Q

What are compensatory responses to high blood pressure?

A 
Reflex tachycardia (increased sympathetic activity)
Edema (increased renin activity)
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5
Q

What are the 4 major categories of antihypertensive agents according to mechanism of action?

A
  1. Diuretics
  2. Agents that block production or action of angiotensin
  3. Direct vasodilators
  4. Sympathoplegic agents (those that alter sympathetic function)
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6
Q

Where do diuretics act? Example?

A

Kidney tubules

Thiazides

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7
Q

Where do agents that block production or action of angiotensin act? Examples?

A

Angiotensin receptors of vessels
-losartan and other angiotensin receptor blockers

Beta-receptors of juxtaglomerular cells that release renin
-propranolol and beta-blockers

ACE
-captopril and other ACEIs

Renin
-alskiren

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8
Q

Where do direct vasodilators work? Examples?

A

Vascular smooth muscle

Hydralazine, minoxidil, nitroprusside, diazoxide, verapamil and other CCBs, fendolapam

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9
Q

Where do sympathoplegic agents act? Examples?

A

Beta-receptors of heart and beta-receptors of juxtaglomerular cells that release renin
-propranolol and other beta-blockers

Alpha-receptors of vessels
-prazosin and other alpha1-blockers

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10
Q

What are diuretics used for?

A

Increase rate of urine flow and sodium excretion

Used to adjust volume and/or composition of body fluids in a variety of clinical situations including

  • edematous states: HF, kidney disease and renal failure, liver disease (cirrhosis)
  • nonedematous states: HTN, nephrolithiasis, hypercalcemia, diabetes insipidus
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11
Q

What are molecular targets of diuretics?

A

Specific membrane transport proteins

  • Na/K/Cl cotransporter (loop)
  • Na/Cl cotransporter (thiazide)
  • Na channels (K-sparing diuretics)

Enzymes
-Carbonic anhydrase (CA inhibitors)

Hormone receptors
-mineralocorticoid receptor (K-sparing diuretics)

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12
Q

What examples of carbonic anhydrase inhibitors? MOA and effects?

A

Prototypes: acetazolamide
Others: :brinzolamide, dorzolamide, methazolamide

MOA: inhibits membrane-bound and cytoplasmic forms of CA

Results in

  • decrease H formation inside PCT cell
  • decrease Na/H antiport
  • increase Na and HCO3 in lumen
  • increase diuresis

Urine pH is increased, and body pH is decreased

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13
Q

What are clinical indications and adverse effects of carbonic anhydrase inhibitors?

A

Rarely used as antihypertensives due to low efficacy as single agents and development of metabolic acidosis
Used for glaucoma, acute mountain sickness, and metabolic alkalosis

Adverse effects:
Acidosis, hypokalemia, renal stones, paresthesias (with high doses), sulfonamide hypersensitivity

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14
Q

What are prototypes of loop diuretics? MOA and effects?

A

Furosemide and ethacrynic acid

MOA: inhibit luminal Na/K/2Cl cotransporter (NKCC2) in TAL of loop of Henle

Results in

  • decreased intracellular Na, K, Cl in TAL
  • decreased back diffusion of K and positive potential
  • decreased reabsorption of Ca and Mg
  • increased diuresis

Ion transport is virtually nonexistent
Among most efficacious diuretics available

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15
Q

What are clinical uses and adverse effects of loop diuretics?

A

Used for edema, HF, HTN, acute renal failure, anion overdose, hypercalcemic states

Adverse effects: hypokalemia, alkalosis, hypocalcemia, hypomagnesemia, hyperuricemia, ototoxicity, sulfonamide hypersensitivity

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16
Q

Describe diuretic activity of loop diuretics and secretion rates

A

Act on luminal side of tubule
Half-life correlated to kidney function
0.5-2 hrs (healthy) vs 9 hrs (ESRD) for furosemide

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17
Q

What is the prototype of thiazide diuretics? MOA and effects?

A

Hydrochlorothiazide (HCTZ)
MOA: cause inhibition of Na/Cl cotransporter (NCC) and block NaCl reabsorption in DCT

Results in

  • increased luminal Na and Cl in DCT
  • increased diuresis
Enhance reabsorption of Ca in both DCT and PCT
Largest class of diuretic agents
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18
Q

Describe clinical uses and adverse effects of thiazide diuretics

A

Used for HTN, mild HF, nephrolithiasis, nephrogenic diabetes insipidus

Adverse effects: hypokalemia, alkalosis, hypercalcemia, hyperuricemia, *hyperglycemia, *hyperlipidemia, sulfonamide hypersensitivity
More hyponatremic effects than loop diuretics
Use with caution in pts with diabetes mellitus

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19
Q 
42 y/o weakness, dizziness, nausea after ascending moutains. Drug to prevent symptoms?
A. CA inhIbitors
B. Loop diuretics
C. Osmotic diuretics
D. potassium sparing
E. Thiazide
A

A. CA inhIbitors

Not used in treatment of HTN. Used in treatment of acute mountain sickness. Poor agent for increasing diuresis

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20
Q

What is the most important site of K secretion by kidney? What happens here?

A

Collecting tubule
Site at which all diuretic-induced changes in K balance occur. More Na delivered to collecting tubule leads to more K secretion

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21
Q

Describe mineralocorticoid receptor (MR) antagonists

A

Spironolactone and eplerenone

Uses include hyperaldosteronism, adjunct to K-wasting diuretics, antiandrogenic uses (female hirsutism), heart failure (reduces mortality)

Do not require access to tubular lumen to induce diuresis

Adverse effects: hyperkalemia, acidosis, and antiandrogenic effects

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22
Q

Describe Na channel (ENaC) inhibitors

A

Amiloride and triamterene

Uses include adjunct to K-wasting diuretics and lithium-induced nephrogenic diabetes insipidus (amiloride)

Adverse effects include hyperkalemia and acidosis

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23
Q

Describe mineralocorticoid receptor (MR)

A 
Also known as aldosterone receptor
Nuclear hormone receptor responsible for regulating expression of multiple gene products
Natural agonists include mineralocorticoids: class of steroid hormones that influence salt and water balance
-aldosterone, deoxycorticosterone, and glucocorticoids (cortisol)
24
Q 
54 yo M 2 month CHF and 10 yr HTN. Swollen painful big toe on L foot. SOme minor hearing loss. Gouty attack. Mild dehydartion. Agent acts where in the nephron to produce symptoms
A. collecting tubule
B. Distal convoluted tubule
C. Glomerulus
D. Loop of Henle 
E. Proximal convoluted tublule
A

*D. Loop of Henle - ototoxicity

25
Q

What are pharmaceutical strategies for inhibition of renin-angiotensin-aldosterone system?

A 
Aldosterone receptor (MR) antagonists
ACEIs
ARBs
Renin inhibitors
Beta-blockers
26
Q

What are the prototypes, MOA, and clinical indications of angiotensin converting enzyme (ACE) inhibitors?

A

Captopril and enalapril

MOA: inhibit conversion of angiotensin I to more active angiotensin II, also prevent degradation of bradykinin and other vasodilator peptides

Clinical indications: HTN, HF, left ventricular dysfunction, prophylaxis of future CV events (MI, CAD, stroke), and nephropathy (+/- diabetes)

27
Q

What are benefits of ACEIs in HTN?

A

Lowers TPR and mean, diastolic, and systolic BP

Cardiac functions in pts with uncomplicated HTN is little changed
-SV and CO may increase slightly with sustained treatment

Baroreceptor function and CV reflexes are not compromised
-responses to postural changes and exercise are little impaired

Evidence that ACEIs are superior in treating HTN in pts with diabetes
-improve endothelial function and reduce CV events moreso than CCBs or diuretic and beta-blocker combo

28
Q

What are adverse effects of ACEIs?

A

Hypotension

  • Cough
  • Angioedema
  • Hyperkalemia - avoid K-sparing diuretics
  • Acute renal failure - particularly in pts with renal artery stenosis
  • Fetopathic potential (teratogen) - *contraindicated in pregnancy

Drug interactions: antacids, capsaicin, NSAIDs, K-sparing diuretics, digoxin, lithium, allopurinol

29
Q

What are renal considerations with ACEIs?

A

They prevent/delay progression of renal disease in type I diabetics and in pts with nondiabetic nephropathies (results mixed in type II)

They vasodilate efferent arterioles>afferent arterioles
-reduces back pressure on glomerulus and reduces protein excretion

They usually improve renal blood flow and Na excretion rates in CHF

In rare cases, they can cause rapid decrease in GFR, leading to acute renal failure (ARF)
-can occur anytime during therapy, even after months or years of uneventful ACEI treatment

30
Q

What are risk factors for ACEI-induced acute renal failure?

A

MAP insufficient for adequate renal perfusion

  • poor cardiac output
  • low systemic vascular resistance

Volume depletion (diuretic use)

Renal vascular disease

  • bilateral renal artery stenosis
  • stenosis of dominant or single kidney
  • afferent arteriolar narrowing (HTN, cylcosporin A)
  • diffuse atherosclerosis in smaller renal vessels

Vasoconstrictor agents (NSAIDs, cylcosporine)

All cause renal hypoperfusion

31
Q 
52 yo F HTN and diabetes. 2 month cough. No cigarette, fevers, chills, sweats, or resp. Oral hypoglycemic agent and anti-HTN agent 3 months ago. Cough related to
A. Captopril
B. Clonidine
C. Hydrochlorothiazide
D. Losartan
E. Verapamil
A

Captopril

32
Q

Describe angiotensin II receptors

A

G-protein coupled receptors

Two receptor subtypes (AT1 and AT2)

33
Q

What are AT1 receptors?

A

Angiotensin II receptors
Major subtype in adults
Gq->PLC-> IP3 + DAG -> smooth muscle contraction

34
Q

Describe AT2 receptors

A

Angiotensin II receptors
Activation causes production of NO and bradykinin
Smooth muscle dilation

35
Q

What are the prototypes, MOA, and effects of angiotensin II receptor blockers (ARBs)

A

Prototypes: losartan and valsartan

MOA: selectivity block AT1 receptors, which leads to

  • decreased contraction of vascular smooth muscle
  • decreased aldosterone secretion
  • decreased pressor responses
  • decreased cardiac cellular hypertrophy and hyperplasia

No effect on bradykinin metabolism

36
Q

What are therapeutic uses and adverse effects of ARBs?

A

Uses: HTN, diabetic nephropathy, HF, HF or left ventricular dysfunction after AMI, and prophylaxis of CV events

Adverse: similar to ACEIs but less cough and edema. Contraindicated during pregnancy

37
Q

Compare ACEIs vs ARBs

A

ARBs reduce activation of AT1 receptors more effectively than do ACEIs
ARBs permit activation of AT2 receptors
ACEIs increase levels of a number of ACE substrates, including bradykinin
Unknown whether or not these pharmacological differences result in significant differences in therapeutic outcomes

38
Q

Describe aliskiren

A

Direct renin inhibitor
MOA: inhibits renin and blocks conversion of angiotensinogen to angiotensin I
Does not increase bradykinin
Rise in plasma renin levels but decreased plasma renin activity (ACEIs, ARBs, and diuretics raise plasma renin levels and activity via feedback loop)
Effectiveness comparable to ACEIs and ARBs
Adverse effects similar to ACEIs and ARBs. Contraindicated in pregnancy

39
Q

67 y/o HTN and diabetes. new onset CHF. BP 138/94. Angioedema when taking ACE inhibitor and is only taking hydroclorothiazide for BP. You want to add similar ACE inhibitor in that it affects angiotensisn II but not associaeted with edema. What do you give?

A

Bradykinin

40
Q

Describe calcium channel blockers (CCBs) and their subclasses

A

All CCBs bind to L-type Ca channels, but the 2 classes bind to different sites, resulting in different effects on vascular versus cardiac tissue

Non-dihydropyridines

  • prominent cardiac effects but also act at vascular tissues
  • *verapamil>diltiazem

Dihydropyridines (DHPs)

  • predominantly arteriolar vasodilation effects
  • *amlodipine, clevidipine, felodipine, isradipine, nicardipine, *nifedipine, nisoldipine
41
Q

What are adverse effects and toxicity of CCBs?

A

Generally very well tolerated

Excessive vasodilation: dizziness, hypotension, headache, flushing, nausea. Diminished by long-acting formulations and long half-life agents

*Constipation (esp verapamil), *peripheral edema, cough, wheezing, pulmonary edema

Use of verapamil/diltiazem with a beta-blocker is *contraindicated because of potential AV block

Verapamil/diltiazem should not be used in pts with ventricular dysfunction, SA or AV nodal conduction defects and systolic BP

42
Q

64 yo M palpitations. Given high BP and supraventricular tachycardia, start pt on drug to treat both. Which class

A

Calcium channel blocker

43
Q

What are the clinical uses of calcium channel blockers?

A

HTN: most useful when combined with another agent to counteract reflex cardiovascular responses

Hypertensive emergencies: parenteral formulations

Angina: reduction of O2 demand makes particularly useful

44
Q

Describe MOA of potassium channel openers

A

Increased potassium permeability stabilizes smooth muscle cell membrane at resting potential, reducing probability of contraction

45
Q

Describe diazoxide

A

Potassium channel opener
Arteriolar vasodilation

Diminishing use in hypertensive emergencies due to adverse effects:

  • excessive hypotension can cause stroke and MI
  • hyperglycemia
46
Q

Describe minoxidil

A

Potassium channel openers
Arteriolar vasodilation
Clinical uses: severe hypertension and baldness (topical)

Adverse effects

  • headache, sweating
  • hypertrichosis
  • reflex tachycardia and edema: must be used with beta-blocker and diuretic to avoid these effects
47
Q

Describe fenoldopam

A

D1 dopamine receptor agonist
Renal afferent arteries contain dopamine receptors: activation increases blood flow to kidneys
For HTN emergencies and post-operative HTN
Adverse effects include tachycardia, headache, and flushing
Should be avoided in pts with glaucoma due to increases in intraocular pressure

48
Q

Describe hydralazine

A

MOA: releases NO from endothelium
-dilates arterioles, but not veins

Clinical uses

  • first-line oral therapy for HTN in pregnancy, with methyldopa
  • combination with nitrates is effective in pts with HF
  • parenteral formulation useful in hypertensive emergencies

Adverse effects

  • can induce fluid and sodium retention
  • headache, nausea, anorexia, sweating, flushing, palpitations
  • reflex tachycardia can provoke angina in pts with ischemic heart disease
  • lupus-like syndrome (reversible on drug withdrawal)
49
Q

Describe nitroprusside and organic nitrates

A

Used to treat hypertensive emergencies, heart failure, and angina (nitrates)
Prototypes organic nitrate: nitroglycerin

Pharmacodynamic effects

  • dilates both arterial and venous vessels: decreases TPR and venous return
  • decreases both preload & afterload
  • mainly relaxation of large veins -> decreased venous return -> decreased preload -> decreased O2 demand (major effect), smaller decrease in afterload

Adverse effects

  • nitroprusside: excessive hypotension, cyanide poisoning
  • nitrates: orthostatic hypotension, syncope, throbbing headache
50
Q

Describe beta-blocker use in hypertension

A

No longer 1st line treatment for HTN, except when concomitant with a compelling indication

  • HF
  • recent MI
  • reduced left ventricular function

Predispose to diabetes, particularly when combined with thiazide

Relative contraindication: asthma

Less stroke protection than other antihypertensives

51
Q

Describe beta-blockers with vasodilating activity

A

Non-selective vasodilating beta blockers
-carteolol, carvedilol, labetalol

Beta1-selective vasodilating beta blockers
-betaxolol, nebivolol

These drugs produce peripheral vasodilation through a variety of mech

  1. Increase NO
  2. Activate beta2 receptors
  3. Block of alpha1 receptors
  4. Block Ca entry
  5. Open K channels
  6. Antioxidant activity
  7. Antiproliferative effects
52
Q

Describe esmolol (Brevibloc)

A

Very rapid onset & short duration of action
Beta1-selective
Used as IV infusion for peri-operative tachycardia and HTN, hypertensive emergencies, arrhythmias
Used in electroconvulsive therapy

53
Q

Describe alpha1-selective receptor blockers

A

Clinical use: 3rd or 4th line treatment of essential hypertension, added to other agents from different classes in refractory cases. Also used in men with concurrent HTN and BPH

Pharmacodynamic effects

  • prevent vasoconstriction of both arteries and veins
  • decreased TPR, decreased venous return, decreased preload
  • usually do not increase heart rate or cardiac output
  • do not increase NE release (no alpha2 block)
  • favorable effects on lipids (decreased LDL & triglycerides. Increased HDL)
  • relaxes smooth muscle in prostate

Adverse effects

  • postural hypotension & syncope, especially with initial doses
  • usually given at bedtime to minimize hypotensive effects
54
Q

Describe clonidine

A

Alpha2-adrenergic receptor agonist

  • IV: increase BP (peripheral alpha2b) followed by decreased BP (central alpha2a)
  • oral: decreased BP (decreased CO, preload)
  • patch: same as oral

Clinical use

  • *essential hypertension (rarely used)
  • adjunct for narcotic, alcohol, & tobacco withdrawal

Side effects

  • dry mouth, sedation, impotence, depression
  • *sudden withdrawal causes hypertensive crisis
55
Q

Describe methyldopa

A

False neurotransmitter concept

  • converted to methyl-NE
  • stored in vesicles instead of NE
  • released and acts as a centrally acting alpha2-agonist
  • decreases central sympathetic outflow & decreases BP

Many side effects: sedation, dry mouth, sexual dysfunction, postural hypotension, anemia

Now only used to *treat hypertension in pregnancy because of its safety

Renal II Final (8 decks)

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