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BIOM 3090 > Unit 04: Antihypertensives > Flashcards

Unit 04: Antihypertensives Flashcards

1
Q

what is hypertension, what % of north americans require treatment?

A

most common cardiovascular disease

  • appox 15% of North Americans require treatment for high blood pressure
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2
Q

what are some contributing factors to hypertension?

A
  • genetics, environmental factors, physiological stress and diet
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3
Q

what happens if hypertension is left untreated? What does treatment do?

A
  • damage to blood vessels, renal failure, coronary disease and stroke
  • treatment flows down blood vessel damage and decreases morbidity and mortality associated with the disease
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4
Q

what is blood pressure and how is it calculated

A

pressure exterted by circulating blood upon the walls of blood vessels

  • can be calculated as teh CO x PVR (also called systemic vascular resistance SVR)
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5
Q

how is blood pressure expressed

A

systolic (maximum) pressure over diastolic (minimum) pressure

  • measured in mmHg
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6
Q

how is blood pressure controlled?

A

complex

  • product of cardiac output and systemic vasuclar resistance
  • various anatomic structures such as arterioles (resistance), venules (capacitance), heart (rate/cardiac output) and kidneys (blood volume)
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7
Q

BP = CO x SVR, how is CO controlled?

A
  • CO is the rpoduct of heart rate and stroke volume

HR

  • INC by SNS and catecholamines (epinephrine and NE)
  • DEC by PSNS

Stroke volume

  • increased by contractility
    • INC by SNS and catecholamines
  • Inc by preload and dec by afterload
    *
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8
Q

How is prelaod increased what does an increase in pre load do?

A
  • INC preload will inc stroke volume which INC cardiac output to inc BP
  • preload is altered by

Venus tone:

  • INC SNS
  • catecholamines increase

Intravasucalar volume

  • increases with thirst
  • inc with Na+/H2O retnetion
    • inc by SNS, aldosterone and ADH
    • DEC by natriuretic peptides
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9
Q

what is SVR and what is it a function of

A
  • systemic vascular resistance, CO x SVR = BP
  • controlled by direct inneration, circulating regualtors and local regulators

Direct innervation

  • α1-adrenergic receptors (α1-AR), which increase SVR

Circulating regulators

  • catecholamines and angiotensin II (AT II), both of which increase SVR.

Local regulators

  • endothelial-derived signaling molecules such as nitric oxide (NO), prostacyclin, H+ and adenosine DECREASE SVR
  • endothelin, AT II, local metabolic regulators such as O2 INC SVR
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10
Q

what is the major component of afterload?

A
  • SVR
  • inversely related to stroke volume

*The combination of a direct effect of SVR on blood pressure and an inverse effect of afterload on stroke volume illustrates the complexity of the system

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11
Q

what are Baroreceptors, what do they monitor and what are the effects when the detect

A

found on carotid artery and aorta

  • responsible for monitoring the stretch of blood vessels
  • monitor it on moment to moment basis to regulate blood pressure quickly
  • INC stretch will stim baroreceptors to decrease SNS activity
  • decrease stretch will dec baroreceptor activity resulting in INC in SNS activity
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12
Q

Role of renin-angiotensin - aldosterone in BP

A
  • kidneys control long term blood pressure by controlling blood volume
  • DEC in bp in renal arterioles will cause an INC in renin secretion -> INC angiotensin II
  • renin production can also be stimulated by SNS activation of B1 receptors
  • angiotensin II causes constriction of blood vessels and an inc in aldosterone
  • inc in aldersterone will inc Na+ and water retention which will inc blood volume
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13
Q

What is a healthy blood pressure, what is considered hypertensive? prehypertenive? hypotensive?

A

120/80 or less

  • if consistantly geater than 140/90 = hypertensive
  • pre-hypertension = systolic bp beterrn 120-140 and diastolic between 80-90
  • hypotensive = bp below 90/60 with presence of noticable systems
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14
Q

what are the two major types of sympatholytics

A
  • centrally acting and peripherally acting
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15
Q

describe centrally acting sympatholytics

A
  • medication that inhibits the activtiy of the sympathetic nervous sustem
  • in CNS adrenergic neruons regualte autonomic NS
  • increased CNS adrenergic activity results in an increased SNS and decrease PSNS activity
    ex: Clonidine
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16
Q

describe clonidine

A
  • centrally acting sympatholytic
  • a2 receptor agonist that lowers bp by acting in brainstem vasomotor centers to supress sympathetic outflow to periphery
  • will dec NE in the CNS which will dec SNS actiivity and inc PSNS activity
  • treats high BP bc end result is that it decreases CO and dec PVR which will lower blood pressure

adverse effect = light headedness, sedation and imparired concentration

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17
Q

describe Peripherally acting sympatholytics Beta (β) blockers

A

Beta (β) blockers or β-adrenergic antagonists have sympatholyic activity in the heart and kidney

  • block the actions of catecholamines (ep in NE) at β1 receptors resulting in decreased blood pressure
  • in heart they block β1 receptors decrease cardiac output
  • block β1 receptors in the juxtaglomerular region of the kidney decrease renin release which decreases PVR.

*decreases CP and PVR = antihypertensive effect

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18
Q

propranolol and metoprolol

A
  • both β blockers
  • propranolol blocks β1 and β2
  • metroprolol blocks only β1

*issues arise if patient has asthma

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19
Q

describe Alpha (α) blockers

A
  • peripherally acting sympatholytic
  • also α-adrenergic antagonists
  • block actions of catecholamines (ep and NE) at α1-receptors in arterioles and venules.
    ex: Prazoin, selectively blocks α1 resulting in decreased PVR and dilation of venous vessels
  • dilation causes dec venous return to the heart bc of reduction of cardiac preload
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20
Q

what is Prazoin

A

α1 blocker

  • blockers the receptors in arteroils and neules
  • DEC PVR and dilation of venus vessels
  • dilation causes reduction in cardiac preload - praazoin has little tendency to inc CO and HR
  • prescribed at vew low dose and titrated to higher doses depending on response
  • may cause water retention so diuretics and β-blockers might be administered in combination with α blockers.
21
Q

what are vasodilators, why are they prescribed?

A
  • relax vascular smooth muscle of arterioles and venuoles to decrease PVR and dec blood pressue
  • also ause responses from baroreceptors and the renin angiotensin system - work best in combination with otehr hypertensives that opose the compensatory responses
22
Q

What is sodium nitroprusside

A
  • SNP
  • vasodilator - nitric oxide donor
  • causes vasodilation of arterial and venous vessels by acting activating guanylyl cyclase, therby increasing dephosphrylation of myosin light chains which result in relaxation of smooth muscle cells
  • administered intravenously in cases of acute hypertensive emergency
  • release CN ions which can be detoxified to avoid reaching toxic levels
  • adverse effect = hypotension
23
Q

describe the chemical structure and metabolism of sodium nitroprusside

A
  • SNP is a complex of iron, cyanide and nitroso (NO) group
  • SNP spontaneously decomposes to release NO and cyanide
  • NO effects vasodilation; cyanide is metabolized in the liver to thiocyanate which undergoes renal excretion

*cyanide toxicity can result from prolonged administration of the drug or in presence of renal insufficiency

24
Q

What is verapamil

A
  • vasodilator used in long-term treatment of hypertension
  • Ca2+ channel blocker

– Ca2+ is involved in the electrical and mechanical events of the cardiac cycle and in vascular regulation

*Ca2+ activates myosin so it can bind to actin and cause muscle contraction

-SO dec Ca2+ will decrease contraction - blockers inhibit influex into arterial smooth muscle cells which causes them to relax resulting in vasodilation

*also dec Ca2+ levels in cardiac muscle cells

averse effects - associated w/ bradycardia

25
Q

sites of action of Ca2+ channel blockers

A
  • Ca2+ channel blockers dilate coronary arteries and peripheral arterioles but NOT veins
  • dec cardiac contractility, automaticity at the SA node and conduction at the AV node

*dec contractility and SA node automaticity can dec myocardial O2 demand

  • DIlation of coronary arteries increases myocardial O2 supply
  • dilation of systemic (peripheral) arterioles decreases afterload - dec myocardial O2 demand

*diagram rep effets of the class of drugs - individual agents are more or less selective for the effects

26
Q

Why are some Ca2+ channel blockers good antiarrhythmic agents

A
  • because they can inhibt of AV node conduction
27
Q

What can dihydropyridines cause?

*hint they re a calcium channel blocker

A
  • can cause reflex tachycardia which can paradoxically increase myocardial O2 demand
28
Q

what is angiotenin converting enzyme? what does it do

A

converts angiotensin I (AT I) to angiotensin II (AT II) -increases blood pressure by causing blood vessels to constrict

  • once AT I is cleaved by ACE to AT II, it can bind to its receptor subtypes AT1 and AT2
  • actions of AT II are best understood in vascular smooth muscle cells where it binds AT1 receptors on SNS nerve terminals to INC NR release
  • at AT I receptors on smooth muscle cells it inc IP3 resulting in an increase in intracellular calcium
29
Q

what is one of the most potent vasocontricters known?

A

AT II

  • following AT 1 binding AT II also stimulates aldosterone secretion by zona glomerulosa cells of the adrenal gland and antidiuretic hormone (ADH) secretion from the pituitary gland
  • INC Na+ reabsorption in distal tubules and collecting ducts in the kidney, resulting in increased water retention
  • ADH increases permeabiltiy of collecting ducts in the kidney which results in inc water reabsorption

**result is inc blood pressure

30
Q

describe the renin angiotensin aldosterone axis

A
  • angiotensin = prohormone that is secreted into circulation by hepatocytes
  • Renin = aspartyl protease - secreted by juxtaglomerular cells of kidneys to cleave angiotensin to angiotensin I
  • angiotenin converting enzyme (ACE) is a protease expressed on pulomary capillary edothelium and cleaves angiotensin I to angiotensin II
  • angiotensin II then has 4 actions that inc intravasucalr volume and maintain tissue perfusion
31
Q

describe the 4 actions of angiotensin II that inc intravascular volume and maintain tissue perfusion

A
  1. Stimulates zona glomerulosa cells of the adrenal cortex to secrete aldosterone (hormone that inc renal NaCl reabs at multiple segments in nephron
  2. directly stimulates renal rpoximal tubule reabsorption of NaCl
  3. causes efferent arteriolar vasoconstriction - an action that inc intraglomerular pressure and thereby increases GFR
  4. stimulates hypothalamic thirst centers and promotes ADH secretion
32
Q

what are angiotensin inhibitors

A
  • interuption of renin-angiotensin axid is usually via inhibition of ACE (bc AT II is the primary mediator of the activity of system)
  • dec concersation of AT I to AT II ihibits ateriolar vasoconstriction, decreases aldosterone synthesis, inhibits renal proximal tubule NaCl reabsorption and decreases ADH release

*all these result in DEC blood pressure

ex: enalapril, losartan

33
Q

describe enalapril

A

example of ACE inhibitor

  • ester prodrug that is converted in the plasma to an active metabolite
  • causes dec BP by the 4 ways in the pic
34
Q

what is losartan

A
  • angiotensin (AT1) receptor antagonist used to inhibit AT II actions
  • effectiveness of AT1 blockers is simlar to ACE inhibitors
35
Q

what are renin inhibitors?

what are ACE inhibitors?

A
  • prevent the conversion of angiotensinogen to angiotensin I
  • ACE inhibitors prevent the conversion of angiotensin I to angiotenin II (both in the lung and locally in blood vessels and tissues) - inhibit the inactivation of bradykinin

*both actions of ACE inhibitors lead to vasodilation

36
Q

describe the effects of the renin-agiotensin system inhibitors on blood pressure

A
  • inhibition of angiotensin I coversion decreases AT1 mediated vasoconstriction and decreases aldosterone secretion

*both effects act to decrease blood pressure

  • inhibtion of kininase Ii actvitiy results in higher bradykinin levels which promotes vasodilation
  • increased vasodilation decreases peripheral vascular resistance- this dec blood pressure

**in contrast

  • AT1 antagonists (aka angiotensin receptor blockers or ARBs) decrease aldosterone synthesis and interrupt AT-1 mediated vasocontriction but do not alter bradykinin levels

**bradykinin induced cough is a major side effect fo ACE inhibitiors but not AT1 antagonists

37
Q

what is a diuretic

what do they function to do

A
  • any substane that promotes the production of urine by increasing the excretion of water form the body
  • function to decrease blood pressure by inhibiting reabsorption of Na+ from the nephron which inc the renal excretion of water

* intial anti-hypertensive actions of some diuretics like loop diuretics and thiazides are due to this dec in intravascular volume - the sustained decrease in bp may be idependent of their diuretic effect

38
Q

why are mechanisms responseible for the long term reduction in bp using diuretics not well understood?

A
  • most liekly NOT due to diuresis
  • this is bc the body would be able to partially compensate for the decreased blood volume from inc urine production through activation of renin-angiotensin system
  • maximal antihypertensive effect of diuretics often occurs at lower doses then those requred to produce maximal diuresis
39
Q

what is hydrocholrothiazide?

A
  • thiazide diuretic used to treat mild to moderate hypertension
  • acts on distal convoluted tubule to inhibit the sodium-chloride sympoter which results in water secretion into urine
  • usually prescribed bc well absorbed orally, inexpensive and effective
  • toxicities associated = hypokalemia, acute myocardial infraction, gout, and hyponatremia and are hazardous for patients with arrhythmias
40
Q

what is furosemide

A
  • loop diuretic which inhibits the co-transport of Na+, K+ and Cl- in the ascending loop of lendle
  • elads to the inhibtion of NaCl reabsorption and excretion of water in urine
  • used for more severe hypertension that requires a more poerful diuretic
  • can be used alone or in combination with a sympatholytic or vasodilator

**rapid but short duration of action and toxicities are similar to those of thiazides (hypokalemia, acute myocardial infarction, gout, and hyponatremia)

41
Q

what can be used to enhance the efficact of diuretics

A

ACE inhibitors like enalapril

42
Q

describe the distal convoluted tubule cell

A
  • absorbes Na+ via an apical membrane NaCl cotransporter (NCC)
  • Na+ is then transported across the basolateral membrane into the interstitium ia the Na+/K+ ATPase

Cl- is transported from the cytosol into the interstitium via CL- channels (gCl-) and perhaps by K+ Cl- co transports (not in pic)

  • renal epithelial cells of the distal convoluted tubule also absorb Ca2+ via apical membrane, Ca2+ channels (TRPV5) and Ca2+ is transported across the basolateral membrane into the interstitium by Na+/Ca2+ excahnges NCX1 and by Na2+ ATPase PMCA

*thiazides inhibit NCC resulting in increased Na+ exretion, tehy also increase epithelial absorption of Ca2+ by an unknown mechanism

43
Q

how is hypertension monitored clinically

A
  • ltos of therapies and treatment depends on the blood pressue values and overall health of the aptient
  • patient is also advised to restrict their Na+ intake and reduce weight if either of those are issues

-

44
Q

initial monotherapy for hypertension

A
  • use thiazide diuretic which is useful in mild - moderate hypertension, an ACE inhibitor or AT1 receptor blocker (ARB), β blockers or Ca2+ channel blockers

*all have similar efficacy for lwoering blood rpessure

*many patients do well on monotherapy, it is more simple, has better complience and relatively low incidence of toxiciy

45
Q

what may be given to treat hypertension if typical monotherapies are not efefctive or caused adverse effects

A

α1 blocker or centrally acting sympatholytic

46
Q
A
47
Q

how is combination therapy used for treatment of hypertension

A
  • used in severe hypertension or if one group of drugs cannot control the hypertension
  • drugs added in stepwise fahsion until optimal blood pressure is acheived

*first step is to make lfiestyle changes then start adding drugs 1 by 1

  1. diuretics
  2. ACE inhibitors/ARB
  3. calcium channel blockers
  4. sympatholytics/vasodilators
48
Q

what are the problems with combination “stepped’ therapy

A
  • main complications are lack of patient compliance
  • may not want to take multiple emdications, disease is asymptomatic, drugs are expensive and side effects are common
  • tehre are fixed dose combinations available which increase compliance but the disadvantage is that you cannot titrate individual drug dosages
49
Q

complications of hypetension

A

hypertension is a risk factor for stroke, myocardial infarction (heart attacks), heart failure, aneurysms and even kidney failure.

BIOM 3090 (22 decks)

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