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Drug Mech Final > Anti-hypertensives > Flashcards

Anti-hypertensives Flashcards

1
Q

How do diuretics work?

A

reduce blood pressure by depleting the body of sodium and decreasing blood volume

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2
Q

How do sympathoplegic agents work?

A

lower blood pressure by inhibiting the function of the sympathetic nervous system. As a result, they reduce PVR, inhibit cardiac function (which reduces CO), and increases venous pooling in capacitance vessels (which reduces CO)

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3
Q

How do vasodilators work?

A

reduce blood pressure by relaxing vascular smooth muscle; this leads to dilating vessels and increasing capacitance

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4
Q

How do inhibitors of angiotensin work?

A

lower blood pressure by inihibiting the renin-angiotensin-aldosterone pathway in the kidneys. As a result, they reduce PVR and blood volume

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5
Q

Sodium contributes to PVR by (increasing or decreasing?) vessel stiffness and neural activity?

A

increasing

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6
Q

Increasing vessel stiffness by sodium leads to ______

A

an increase in intracellular calcium

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7
Q

What drugs are used in combination with diuretics in patients with severe hypertension?

A

sympathoplegic and vasodilator drugs

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8
Q

What do sympathoplegic drugs inhibit the function of?

A

the sympathetic nervous system

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9
Q

What happens if you use a sympathplegic drug alone?

A

may cause retention of sodium and water by the kidneys and expansion of blood volume (via the RAAS pathway)

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10
Q

Which drug type should be used in combination with a sympathoplegic drug to make its effects more beneficial?

A

diuretic

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11
Q

Name the central alpha-2 adrenergic agonists

A

Methyldopa
Clonidine
Guanabenz
Guanfacine

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12
Q

Where do the central alpha-2 adrenergic agonists act on?

A

the central sympathetic neurons in the brain

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13
Q

What is the MOA for the central alpha-2 adrenergic agonists?

A

Work on sympathetic neurons in the brain stimulating central alpha-adrenoceptors to reduce sympathetic outflow from vasopressor centers in the brain

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14
Q

Are toxicities dependent on posture?

A

no, because they work on central neurons

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15
Q

Name the adrenergic neuron-blocking agents

A

Reserpine

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16
Q

How do the adrenergic neuron-blocking agents work?

A

reduce blood pressure by preventing normal physiologic release of norepinephrine from prostaganglionic sympathetic neurons

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17
Q

Where is Reserpine derived from?

A

it is a natural alkaloid derived from the roots of the plant Rauwolfia serpentine

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18
Q

What Reserpine cause in higher doses?

A

severe depression

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19
Q

What is Reserpine’s MOA?

A

Binds irreversibly and blocks the uptake and storage of biogenic amines in throughout the body inhibiting the uptake mechanism that depends on Mg and ATP resulting in a depletion of NE, dopamine, and serotonin in BOTH central and peripheral neurons

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20
Q

Name the beta-adrenoceptor antagonists (beta-blocker) discussed in the notes

A

Propanolol

Nebivolol

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21
Q

Where does Beta-1 act on?

A

Heart
Brain
Kidney

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22
Q

Where does Beta-2 act on?

A

Heart
Smooth muscle
Liver

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23
Q

Where does Beta-3 act on?

A

Heart

Lipocytes

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24
Q

What are the toxicities for the central alpha-2 adrenergic agonists?

A
  • Sedation
  • Mental Depression
  • Sleep disturbances (nightmares)
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25
Q

Name the toxicities of Reserpine

A
  • Mild postural HTN
  • Sedation
  • Nightmares
  • Mental depression
  • Extrapyramidal effects resembling Parkinson’s as a result of dopamine depletion in the corpus striatum
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26
Q

Beta-blockers antagonize the effects of ________ at the Beta-adrenergic receptors

A

catecholamines

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27
Q

How does Propanolol work?

A

lower blood pressure by decreasing CO

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28
Q

Which beta-blocker exhibits nitric oxide-mediated vasodilating activity?

A

Nebivolol

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29
Q

Is Propanolol selective or non-selective? If selective, which beta-adrenergic subtype is selective to?

A

nonselective

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30
Q

Is Nebivolol selective or non-selective? If selective, which beta-adrenergic subtype is selective to?

A

Beta-1 selective

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31
Q

What is the beta-blockers MOA?

A

Blocks beta-1 and beta-2 receptors inhibiting the stimulation of renin production by the catecholamines

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32
Q

Name some toxicities of Propanolol

A
  • Asthma
  • Sedation
  • Sleep disturbances
  • Depression
  • Caution in patients with bradycardia or cardiac conduction disease
  • Bronchospasm (at very high doses, non-selective)
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33
Q

What can patients experience if they abruptly discontinue the use of beta-blocker therapy after chronic use/

A

withdrawal symptoms such as nervousness, tachycardia, HTN, and/or MI

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34
Q

Name the alpha-adrenoceptor antagonist discussed in the notes

A

Prazosin

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35
Q

Where does alpha-1 act on?

A

Heart
Smooth muscle
Prostate

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36
Q

Where does alpha-2 act on?

A

Lipocytes
Smooth muscle
Platelets

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37
Q

Is Prazosin selective or non-selective? If selective, which receptor subtype is selective towards?

A

alpha-1 selective

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38
Q

What is the MOA of alpha blockers?

A

Antagonizes (blocks) the effects of catecholamines causing dilation in BOTH resistance (arterioles) and capacitance (venules) vessels thus causing vasodilation thereby reducing BP

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39
Q

Which class of drugs are used in combination with alpha blockers to make them more effective?

A

Beta-blockers

Diuretics

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40
Q

Name the toxicities of Prazosin

A

Little postural hypotension (especially after the first dose)

First-dose phenomenon occurs in salt and volume depleted patients—first dose should be given at bedtime

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41
Q

True or False: Blood pressure is reduced more in the upright position?

A

True

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42
Q

Name the non-dihydropyridine CCBs

A

Verapamil

Diltiazem

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43
Q

Name the dihydropyrimidn CCBs discussed in the notes

A

Nifedipine

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44
Q

What is the MOA of the CCBs?

A

Block calcium channels in:

  1. Arteriole smooth muscle cells resulting in inhibition of calcium influx
  2. Cardiac muscle cells inhibiting calcium influx which will reduce contractility, decrease SA pacemaker rate and AV conduction
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45
Q

What is the function of CCBs?

A

dilate peripheral arterioles and reduce blood pressure

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46
Q

Which CCB is the more selective vasodilator and has a less cardiac depressant effect than the others?

A

Nifedipine

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47
Q

Which CCB has the greatest depressant effect?

A

Verapamil

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48
Q

Which CCB has intermediate effects?

A

Diltiazem

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49
Q

Name the oral vasodilator

A

Minoxidil

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50
Q

Name the parenteral vasodilators

A

Nitroprusside

Fenoldopam

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51
Q

Which type of vasodilator is used for long-term outpatient therapy?

A

oral vasodilators

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52
Q

Which type of vasodilator is used to treat hypertensive emergencies?

A

parenteral vasodilators

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53
Q

What is the function of vasodilators?

A

effective in treating HTN because they relax smooth muscle of arterioles, which leads to a decrease in systemic vascular resistance

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54
Q

Which vasodilator dilates both arterial and venous vessels, resulting in reduced PVR and venous return?

A

Sodium Nitroprusside

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55
Q

What is the MOA of Minoxidil?

A

Lowers BP by activating the ATP-modulated K channels opening them and allowing K efflux causing hyperpolarization making contraction less likely resulting in an overall relaxation of vascular smooth muscle

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56
Q

What is the MOA of Nitropursside?

A

Activates guanylyl cyclase enzyme increasing intracellular cGMP which relaxes vascular smooth muscle. It is then metabolized by RBCs into cyanide which is then metabolized by mitochondrial rhodanase along with sulfur to create the less toxic thiocyanate

57
Q

What is the MOA of Fenoldopam?

A

Agonist of dopamine D1 receptor causing a dilation of peripheral arteries

58
Q

Name the toxicities of Minoxidil

A

Headaches
Sweating
Hirsutism (hair growth)

59
Q

Name the toxicities of Nitroprusside

A
  • Excessive hypotension
  • Accumulation of thiocyanate (especially in renal insufficiency)—leads to disorientation, psychosis, muscle spasms, and convultions
60
Q

Name the toxicities of Fenolopam

A
  • Reflex tachycardia
  • Headache
  • Flushing
  • Increased intraocular pressure (contradicted in patients with glaucoma)
61
Q

Which vasodilator causes compensatory effects and is used topically as Rogaine?

A

Minoxidil

62
Q

Minoxidil should be used in combination with ___________

A

beta-blockers

diuretics

63
Q

Which vasodilator is a complex of iron, cyanide groups, and nitroso moiety?

A

Nitroprusside

64
Q

Which vasodilator dilates arterioles but not veins?

A

Minoxidil

65
Q

Which vasodilator dilates both arteriol and venous vessels, resulting in reduced PVR and venous return?

A

Nitroprusside

66
Q

Name the Endothelin receptor antagonists (ERA)

A

Macitentan
Ambrisentan
Macitentan

67
Q

What is Macitentan’s approved use?

A

oral treatment of pulmonary arterial HTN (PAH)

68
Q

Which ERAs are nonselective endothelin antagonists?

A

Macitentan

Bosentan

69
Q

Which ERAs are selective endothelin receptor subtype A antagonist?

A

Ambrisentan

70
Q

Name the 3 isoforms of endothelin

A

ET-1
ET-2
ET-3

71
Q

Each endothelin is a ____ amino-acid peptide containing _____ disulfide bridges

A

21; 2

72
Q

What is the enzyme that processes propeptide to a mature peptide?

A

Endothelin-converting enzyme (ECE)

73
Q

Which endothelin isoform is the predominant endothelin secreted by the vascualr endothelium?

A

ET-1

74
Q

Which endothelin isoform is produced predominantly in the kidneys and intestine?

A

ET-2

75
Q

Which endothelin isoform is found in highest level in the brain but is also present in the GIT, lungs, and kidneys?

A

ET-3

76
Q

Expression of the ET-1 gene is increased by:

A
  • Growth factors
  • Cytokines
  • Vasoactive substances
  • Mechanical stress
77
Q

Expression of the ET-1 gene is inhibited by:

A
  • Nitric oxide
  • Prostacyclin
  • Atrial natriuretic peptide (ANP)
78
Q

Which endothelin isoform(s) are present in the blood but in low concentrations?

A

All of them (ET-1, ET-2, and ET-3)

79
Q

How do endothelins exert their actions in the body?

A

binding to and activating the endothelin receptor

80
Q

Where are ETA receptors located?

A

on vascular smooth muscle cells where they mediate vasoconstriction

81
Q

Where are ETB receptors located?

A

on vascular endothelin cells, where they mediate the release of PGI2 and nitric oxide. Some ETB receptors are also present on vascular smooth muscle cells and mediate vasoconstriction

82
Q

In blood vessels, endothelins cause potent dose-dependent ____________ in most vascular beds

A

vasoconstriction

83
Q

How does IV-administered ET-1 affect arterial blood pressure?

A

IV-administered ET-1 causes a rapid and transient decrease in arterial blood pressure followed by a sustained increase

84
Q

The signal transduction mechanisms triggered by binding of ET-1 to its vascular receptors include:

A
  • Stimulation of Phospholipase C
  • Formation of inositol triphosphate
  • Release of calcium form the ER (results in vasoconstriction)

Stimulation of PGI2 and nitric oxide synthesis results in decreased intracellular calcium concentration and vasodilation

85
Q

How do endothelins effect the heart?

A

exert direct positive inotropic and chronotropic actions and are potent coronary vasoconstrictors

86
Q

How do endothelins effect the kidneys?

A

cause vasoconstriction and a decrease in GFR and sodium and water excretion. They interact with several endocrine systems, increasing the secretion of renin, aldosterone, and ANP

87
Q

How do endothelins effect the respiratory system?

A

cause potent contraction of tracheal and bronchial smooth muscle

88
Q

What blocks the effects of the endothelin system?

A
  • Endothelin receptor antagonists

- Endothelin-converting enzyme inhibitors

89
Q

What two factors contribute to the pathophysiology of PAH?

A

increased levels of ET-1 and decreased levels of vasodilators such as nitric oxide and PGI2

90
Q

What is Macitentan’s MOA?

A

 Macitentan is a nonselective antagonist for both ETA and ETB. It blocks both subtypes of the endothelin receptor and prevents the binding of ET-1. As a result, macitentan is able to inhibit ET-1-induced calcium release in pulmonary arterial smooth muscle cells and prevent ET-1-induced pulmonary vasoconstriction. This leads to relaxation of pulmonary arterial smooth muscle and vasodilation.

91
Q

Name the toxicities of Macitentan

A
  • Headache
  • Nasopharyngitits
  • Bronchitis
  • Anemia
  • Elevated aminotransferases
  • Systemic hypotension
  • Tachycardia
  • Facial flushing/edema
  • Decrease in sperm count
  • N/V, constipation
92
Q

When should Macitentan be discontinued?

A

when aminotransferase elevations are clinically significant, accompanied by an increase in bilirubin, or accompanied by symptoms of hepatotoxicity

93
Q

Is Macitentan teratogenic in animals?

A

yes

94
Q

What patients is Macitentan contraindicated in?

A

use during pregnancy and is available for women of reproductive age only through a restricted access program

95
Q

What is Macitentan a substrate for?

A

CYP3A4 and should be avoided with potent inducers and inhibitors of CYP3A4

96
Q

Name the Phosphodiesterase 5 (PDE5) Inhibitors

A

Tadalafil

Sildenafil

97
Q

What are the uses of the PDE5 inhibitors?

A

used for the treatment of pulmonary arterial hypertension (PAH) and their brand names (Cialis and Viagra) and used for the treatment of erectile dysfunction

98
Q

Which PDE5 inhibitor is more convenient to take because it is taken once daily and has a half-life of 35 hours?

A

Tadalafil

99
Q

What is the MOA of PDE5 inhibitors?

A

Inhibits PDE5 (main PDE in lungs) causing an increase in cGMP in vascular smooth muscle resulting in vasodilation

100
Q

Name the toxicities of the PDE5 inhibitors

A
  • Headache
  • Flushing
  • Myalgia
  • Transient disturbances of vision (rarely occurs with Tadalafil)
101
Q

Which PDE5 is more selective?

A

Tadalafil

102
Q

What occurs if PDE5 inhibitors are taken with nitrates and alpha-blockers?

A

severe hypotension

103
Q

Name the Soluble Guanylate Cyclase (sGC) Stimulators

A

Riociguat

104
Q

What are the approved used for Riociguat?

A

PAH and chronic thromboembolic pulmonary hypertension (CTEPH)

105
Q

Soluble guanylate cyclase is the receptor for?

A

Nitric oxide

106
Q

What is the function of guanylate cyclase?

A

it is an important cardiovascular/pulmonary enzyme that catalyzes the synthesis of cyclic guanosine monophosphate (cGMP)

107
Q

In vascular smooth muscle cells, sGC converts ____ to ____

A

GTP; cGMP

108
Q

True or False: sGC is a heterodimer composed of alpha and beta subunits?

A

True

109
Q

Where does NO bind and what effect does it produce?

A

NO binds to the protoporphyrin-IX heme domain of sGC (located at the N-terminal end of the sGC molecule) at low nM concentrations and produces a 200- to 400-fold increase in the Vmax of the enzyme, leading to a marked increase in intracellular levels of cGMP.

110
Q

What is the MOA of Riociguat?

A

Acts through complementary NO-depdendent/independent mechanisms:

  1. acts as an allosteric agonist for sGC. Binds to and directly stimulates/activates sGC independently of NO through a NO-independent binding site. This leads to an increase in the catalytic activty of sGC and increase in cGMP levels in the cell (NO-independent mechanism)
  2. Binding of Riociguat to sGC stabilizes the endogenous NO-sGC binding, leading to further increase in intracellular levels of cGMP (NO-dependent mechanism)
111
Q

Name the toxicities of Riociguat

A
  • Headache
  • Dyspepsia
  • Gastritis
  • Gastroesophageal reflux
  • Dizziness
  • Hypotension
  • Peripheral edema
  • Anemia
112
Q

True or False: Riociguat is teratogenic and contraindicated during pregnancy?

A

True

113
Q

What drugs is Riociguat contraindicated for use with?

A

other drugs that can affect the NO-sGC-cGMP pathway including NO donors, PDE5 inhibitors, and nonspecific PDE inhibitors

114
Q

Name the Direct Renin Inhibitors (DRIs)

A

Aliskiren

115
Q

What is the MOA of Aliskiren?

A

High affinity binding to the catalytic site of renin resulting in inhibition of renin release blocking the conversion of angiotensinogen to angiotensin I—this leads to overall reduced levels of angiotensin I and II and aldosterone

116
Q

Name the toxicities of Aliskiren

A
  • Dizziness
  • Diarrhea
  • Nasopharyngitis
  • Hypotension (even when the drug is discontinued)
117
Q

True of False: Aliskiren is the first DRI approved for HTN?

A

True

118
Q

What drugs can be used in combination with Aliskiren?

A

other anti-HTN agents

119
Q

True or False: Large compensatory increases in plasma renin concentrations (PRC) may surpass the renin-binding capacity of Aliskiren and decrease its antihypertensive effect?

A

True

120
Q

True of False: Aliskiren has a short half-life?

A

False

121
Q

True or False: Aliskiren has a low binding affinity for binding to renin

A

False

122
Q

Name the ACE inhibitor discussed in the notes

A

Captopril

123
Q

What is the function of ACE inhibitors?

A

they inhibit the converting enzyme peptidyl dipeptidase

124
Q

What is the function of the enzyme peptidyl dipeptidase (ACE)?

A
  1. hydrolyzes angiotensin I to angiotensin II

2. responsible for inactivating the potent vasodilator bradykinin

125
Q

The antihypertensive activity of the ACE inhibitors is attributed to both:

A
  1. inhibition of the renin-angiotensin system

2. activation of kallikrein-bradykinin system

126
Q

ACE inhibitors reduce BP mainly by decreasing ____

A

PVR

127
Q

What are the two disadvantages of using ACE inhibitors?

A
  1. ACE inhibitory therapy causes a compensatory increase in both plasma renin concentrations (PRC) and plasma renin activity (PRA) due to suppression of the negative feedback loop in the renin-angiotensin pathway. This leads to increased levels of angiotensin I.
  2. ACE inhibitory therapy does not completely terminate the pharmacological effects of angiotensin II because other non-ACE pathways are still able to convert angiotensin I to angiotensin II in the body
128
Q

Name the toxicities of ACE inhibitors

A
  • Severe hypotension (after initial doses in patients who are hypovolemic)
  • Hyperkalemia
  • Dry cough
  • Angioedema (due to activation of bradykinin)
129
Q

ACE inhibitors are contraindicated:

A

Contraindicated during the second and third trimester of pregnancy due to fetal hypotension and renal failure which can lead to malformations or death

130
Q

Which drugs do ACE inhibitors interact with that results in hyperkalemia?

A
  • Potassium supplements

- Potassium-sparing diuretics

131
Q

Which drugs do ACE inhibitors interact with that inhibit the hypotensive effects of the ACE inhibitors by blocking bradykinin-mediated vasodilation?

A

NSAIDs

132
Q

ACE inhibitors are also useful in the treatment of: __________

A

HF and treatment following MI

133
Q

Name the Angiotensin Receptor Blockers (ARBs) discussed in the notes

A

Losartan

134
Q

What is the function of ARBs?

A

block the angiotensin II type 1 (AT1) receptor. As a result, they are able to prevent angiotensin II from exerting its pharmacological effects in the body.

135
Q

Since ARBs have NO effect on bradykinin metabolism, what is the result?

A

they are more selective than the ACE inhibitors in blocking the effects of angiotensin II

136
Q

ARBs cause a compensatory (increase or decrease?) in both plasma renin concentrations (PRC) in blocking the effects of angiotensin II

A

increase

137
Q

True of False: ARBs are capable of providing complete inhibition of the effects of angiotensin II?

A

True

138
Q

Name the toxicities of ARBs

A

Same as ACE inhibitors but less likely to cause cough and angioedema

Drug Mech Final (7 decks)

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