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ACEM Primary Written > Cardiovascular: Pharmacology - Antihypertensives > Flashcards

Cardiovascular: Pharmacology - Antihypertensives Flashcards

1
Q

Outline 6 main classes of antihypertensives and briefly describe what physiological determinants of HTN they target

A

AABCDN
1. ACEIs: inhibits ACE to decrease angiotensin II -> decreased TPR and preload
2. ARBs: block AT1 receptors -> decreased TPR and preload
3. B-blockers: decreased HR, TPR and preload (via increased venous pooling)
4. CCBs: decreased TPR
5. Diuretics: decrease preload
6. Nitrates: decreased preload (via venodilation) and TPR (via arterial vasodilation)

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2
Q

Outline five classes of anti-anginal drugs

A

B-blockers
CCBs
Nitrates
Vasodilators (nicorandil)
If inhibitor (ivabradine)

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3
Q

What is the formula for BP? What is the formula for CO?

A

BP = CO x TPR
CO = HR x SV

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4
Q

Give a brief overview of RAAS

A

(there is a better diagram in your paper notes)

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5
Q

Describe in detail the mechanism of ACEIs. What is the effect on TPR, CO and HR?

A

Inhibits ACE to prevent hydrolysis of angiotensin I to angiotensin II and inactivation of bradykinin (ACE called “plasma kinanase” in this latter reaction)
Decreases TPR
CO and HR unchanged

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6
Q

What is the advantage of ACEIs over direct vasodilators?

A

Do not induce reflex sympathetic activation (can be used safely in IHD)

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7
Q

Why are ACEIs used in CKD and in DM?

A

Shown to reduce proteinuria and stabilise renal function independent of BP-lowering effect

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8
Q

Name three long-acting ACEIs

A

Lisinopril
Ramipril
Perindopril

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9
Q

Which ACEIs are prodrugs converted to active metabolites via hydrolysis in the liver?

A

Enalapril
Lisinopril
Ramipril
Perindopril

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10
Q

Captopril half-life and bioavailability

A

t1/2 = 2.2hrs
Bioavailability = 65%

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11
Q

Give two examples of ACEIs which are primarily renally excreted and must be dose-reduced in renal impairment

A

Captopril
Lisinopril

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12
Q

Lisinopril half-life and bioavailability

A

t1/2 = 12hrs
Bioavailability = 25%

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13
Q

Enalapril half-life

A

t1/2 = 11hrs

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14
Q

List five adverse effects of ACEIs

A
  1. First dose hypotension in hypovolaemic patients
  2. AKI (especially in setting of bilat renal artery stenosis)
  3. Hyperkalaemia
  4. Effects due to increased bradykinin and substance P: dry cough, wheeze, angioedema
  5. Contraindicated in pregnancy (increased risk stillbirth, prematurity, IUGR)
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15
Q

Identify some specific adverse effects of captopril

A

Neutropenia
Proteinuria
Allergic skin rash
Drug fever

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16
Q

Give four examples of ARBs

A

Losartan
Candesartan
Telmisartan
Valsartan

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17
Q

What is the mechanism of action of ARBs?

A

Block AT1 receptors (decreased TPR, CO and HR unchanged)
No effect on bradykinin

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18
Q

List three adverse effects of ARBs

A

Similar to ACEIs but without bradykinin/substance P effects:
1. First dose hypotension in hypovolaemic patients
2. AKI (especially in setting of bilat renal artery stenosis)
3. Hyperkalaemia

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19
Q

Outline the pharmacokinetics of losartan. Is dose reduction required in renal impairment?

A

t1/2 = 1-2hrs
Bioavailability = 36%
No dose reduction required in renal impairment

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20
Q

Which B-blockers have been shown to decrease mortality from HF and post-MI?

A

Bisoprolol
Metoprolol
Carvedilol

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21
Q

Which B-blockers have a use in hypertensive emergencies?

A

Labetalol
Esmolol

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22
Q

Is propranolol a selective or non-selective B-blocker?

A

Non-selective

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23
Q

Give four examples of cardioselective B-blockers

A

Metoprolol
Atenolol
Bisoprolol
Esmolol

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24
Q

Which B-blocker undergoes high first-pass metabolism?

A

Metoprolol

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25
Q

Give three examples of B-blockers which additionally have vasodilator activity. Explain how this occurs

A

Labetalol: a-blocker activity
Carvedilol: a-blocker activity
Nebivolol: increases endothelial NO

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26
Q

Carvedilol half-life

A

7-10hrs

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27
Q

Nebivolol half-life

A

10-12hrs

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28
Q

Esmolol half-life and typical clinical application

A

t1/2 = 9-10mins
Used to treat peri-op HTN

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29
Q

What type of Ca2+ channel do CCBs act on?

A

L-type

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30
Q

What four common features are shared by all CCBs?

A

Orally active
High first-pass metabolism
High plasma protein binding
Extensively metabolised

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31
Q

Which two CCBs can be administered IV?

A

Verapamil
Diltiazem

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32
Q

What is the difference between dihydropyridines and other CCBs?

A

Dihydropyridines: bind to same site on a1 subunit of L-type Ca2+ channels
Other: bind to different receptors in another region of a1 subunit

Dihydropyridines have higher ratio of vascular:cardiac effects

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33
Q

What is unique about the mechanism of verapamil?

A

In addition to inhibiting L-type Ca2+ channels, also inhibits K+ channels
This means it is less vasodilatory than other CCBs

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34
Q

Describe in detail the mechanism of action of CCBs

A

Block L-type Ca2+ channels by binding at inner side of membrane (therefore bind more effectively to open and inactive channels rather than closed channels)
Decreases transmembrane Ca2+ current to induce smooth muscle relaxation (decreased TPR), and negative inotropy, chronotropy and dromotropy

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35
Q

Outline the organ effects of CCBs on smooth, cardiac and skeletal muscle

A

Smooth muscle: vasodilation, bronchodilation, decreased GI motility, uterine relaxation
Cardiac muscle: negative inotropy, reduced HR (due to decreased SA node pacemaker rate and decreased AV conduction velocity)
Skeletal muscle: no effect

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36
Q

Why are CCBs less likely to cause orthostatic hypotension?

A

Arteriolar vasodilation > venodilation

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37
Q

Why do CCBs have no effect on skeletal muscle?

A

Skeletal muscle uses intracellular pools of Ca2+ so does not require as much transmembrane flux to produce contraction

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38
Q

Which CCBs are used to prevent cerebral vasospasm/infarct following SAH?

A

Nimodipine and nicardipine (have high affinity for cerebral blood vessels)

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39
Q

What are the most important adverse effects of CCBs?

A

Related to cardiac depression: bradycardia, AV block, cardiac arrest, HF

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40
Q

Amlodipine half-life and bioavailability

A

t1/2 = 30-50hrs
Bioavailability: 65-90%

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41
Q

Felodipine half-life and bioavailability

A

t1/2 = 11-16hrs
Bioavailability = 15-20%

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42
Q

Nifedipine half-life and bioavailability

A

t1/2 = 4hrs
Bioavailability = 45-70%

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43
Q

Verapamil half-life and bioavailability

A

t1/2 = 6hrs
Bioavailability = 20-35%

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44
Q

Diltiazem half-life and bioavailability

A

t1/2 = 3-4hrs
Bioavailability = 40-65%

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45
Q

Mechanism of action of diuretics in treatment of HTN

A

Initial: decreased blood volume to decrease CO (may transiently increase TPR)
After 6-8 weeks: CO back to baseline, decreased TPR

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46
Q

How many mmHg do diuretics lower BP by?

A

10-15mmHg

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47
Q

How does Na+ affect TPR?

A

Increases by increasing vessel stiffness and neural reactivity

48
Q

Chlorthalidone half-life and bioavailability

A

t1/2 = 40-60hrs
Bioavailability = 65%

49
Q

HCT half-life and bioavailability

A

t1/2 = 12hrs
Bioavailability = 70%

50
Q

List six adverse effects of diuretics

A
  1. Hypo- (except K+-sparing) or hyper- (K+-sparing) kalaemia
  2. HypoMg
  3. Impaired glucose tolerance
  4. Hyperlipidaemia0
  5. Gout (may precipitate flare due to increased uric acid)
51
Q

Describe the difference in bioavailability and duration of action of sublingual vs oral preparations of nitrates

A

Oral: GTN has low bioavailability (<10-20%) due to action of hepatic nitrate reductase, ISMN used instead which is an activate metabolite with bioavailability of 100%, has longer duration of action than sublingual preparations
Sublingual: efficiently absorbed, dose limited to prevent excessive effect and so duration is brief (10-15mins)

52
Q

How are nitrates excreted?

A

Primarily renal in form of glucuronide derivatives of denitrated metabolites

53
Q

Describe in detail the mechanism of action of nitrates

A

Drug must be bioactivated with subsequent release of NO
NO activates guanyl cyclase -> increased cGMP -> decreased Ca2+ -> dephosphorylation of myosin light chain -> prevents actin-myosin interaction and therefore smooth muscle contraction

54
Q

What is the effect of nitrates on cardiac and skeletal muscle?

A

None

55
Q

What are the organ effects of nitrates’ action on vascular smooth muscle?

A

Decreased preload due to marked venodilation (may cause orthostatic hypotension)
Decreased pulmonary vascular pressure
Decreased heart size
Decreased CO in absence of HF (in HF CO may increase in response to decreased preload)
Coronary artery dilation improves O2 delivery to myocardium

56
Q

What are the indirect effects of nitrates’ action on vascular smooth muscle?

A

Reflex tachycardia
Positive inotropy
Na+/H2O retention

57
Q

What effects do nitrates have on platelets?

A

Decrease platelet aggregation

58
Q

Outline seven adverse effects of nitrates

A
  1. Orthostatic hypotension due to increased venous capitance
  2. Reflex tachycardia
  3. Headache due to meningeal artery pulsations
  4. “Coronary steal syndrome”
  5. Risk of severe hypotension and MI if taken with sildenafil
  6. Methaemoglobinaemia (pseudocyanosis, tissue hypoxia, death)
  7. Tachyphylaxis/tolerance
59
Q

What is the mechanism of action of sildenafil?

A

Inhibits PDE to reduce breakdown of cGMP, potentiating effects of NO

60
Q

What is the clinical significance of tachyphylaxis in nitrate administration?

A

Develops with continuous exposure of more than a few hours of uninterrupted infusion, or with long-acting preparations
Long-acting preparations therefore need a nitrate-free period of 8hrs between doses

61
Q

What is the likely mechanism of tachyphylaxis to nitrates?

A

Depletion of sulfhydryl donors

62
Q

What is coronary steal syndrome?

A

Stenosed coronary vessels are already maximally dilated, so dilated of all coronary vessels results in blood being shunted away from ischaemic areas

63
Q

Describe the four beneficial and two deleterious effects of nitrates on the heart

A

Beneficial:
1. Decreased work and myocardial O2 demand: via decreased ventricular volume, atrial pressure and ejection time
2. Relief of coronary spasm: via coronary artery dilation
3. Increased perfusion of ischaemic areas due to increased collateral flow
4. Increased subendocardial perfusion due to decreased LV disastolic pressure
Deleterious:
1. Increased myocardial O2 demand and decreased disastolic and coronary perfusion time: due to reflex tachycardia
2. Increased myocardial O2 demand: due to reflex positive inotropy

64
Q

What other three classes of antihypertensives are there (outside of AABCDN)? Give examples of each

A
  1. Centrally acting sympathoplegics (e.g. methyldopa, clonidine)
  2. Adrenergic neuron-blocking drugs (e.g. guanethidine, reserpine)
  3. Vasodilators (e.g. hydralazine, sodium nitroprusside)
65
Q

Describe the pharmacodynamics of methyldopa

A

Stimulates central a-adrenoceptors to decrease TPR via decreased sympathetic outflow from vasomotor centres, also decreases renal vascular resistance

66
Q

Describe the pharmacokinetics of methyldopa

A

Enters brain via aromatic amino acid transporter
Max effect at 4-6hrs (but can persist up to 24hrs)
t1/2 = 2hrs
Bioavailability 25%

67
Q

What is the starting dose of methyldopa?

A

1g/day

68
Q

Does methyldopa need to be dose reduced in renal impairment?

A

No

69
Q

Clinical applications of methyldopa

A

HTN of pregnancy and pre-eclampsia

70
Q

List five features of methyldopa toxicity

A
  1. Sedation
  2. Hyperprolactinaemia
  3. Positive Coombs’ test (rarely causes haemolytic anaemia)
  4. Hepatitis
  5. Drug fever
71
Q

Describe the pharmacodynamics of clonidine

A

Partial agonist of a-adrenoceptors (including centrally in medulla where it induces hypotension and bradycardia)
Decreased CO due to decreased HR and TPR
Decreased renal vascular resistance

72
Q

What is the immediate vs sustained effect of clonidine on BP? What is the mechanism?

A

Immediate increase in BP due to agonist action at arterioles
Longterm blocks other agonists to reduce BP

73
Q

What are four features of clonidine toxicity?

A
  1. Dry mouth
  2. Sedation
  3. Depression (absolute CI)
  4. Withdrawal syndrome with long term use
74
Q

Describe the effects of TCAs on clonidine action

A

Blocks antihypertensive effects

75
Q

Describe the withdrawal syndrome seen with long term clonidine use

A

Seen after long term use, particularly if high-dose >1mg/day
Results in hypertensive crisis
Presentation with anxiety, tachycardia, diaphoresis and headache
Onset after missing as few as 1-2doses

76
Q

Describe the pharmacodynamics and pharmacokinetics of guanethidine

A

Pharmacodynamics: replaces NA in nerve terminal vesicles causing gradual depletion of stores
Pharmacokinetics: t1/2 = 5 days, maximal effect after 1-2 weeks and persists similarly post cessation

77
Q

Does clonidine cause postural hypotension?

A

Rarely

78
Q

What drugs block the effect of guanethidine?

A

Drugs which block guanethidine uptake into nerve terminals by NET (e.g. cocaine, amphetamines, TCA)

79
Q

What are the adverse effects of guanethidine?

A

Postural hypotension
Can cause hypertensive crisis in phaeochromocytoma

80
Q

Describe the pharmacodynamics of reserpine

A

Blocks VMAT to deplete stores of NA, dopamine and serotonin in central and peripheral neurons
Also depletes catecholamines in adrenal medulla

81
Q

What is the effect of reserpine on CO and TPR?

A

Reduces

82
Q

Describe the pharmacokinetics of reserpine?

A

t1/2 = 24-48hrs
Bioavailability = 50%

83
Q

Describe the adverse effects of reserpine

A

CNS: sedation, nightmares, depression
GI: diarrhoea, cramps, reflux

84
Q

List 7 types of vasodilators used in the management of HTN

A
  1. Nitrates
  2. CCBs
  3. Hydralazine
  4. Minoxidil
  5. Sodium nitroprusside
  6. Diazoxide
  7. Fenoldopam
85
Q

Describe the pharmacokinetics of hydralazine

A

Absorption: well-absorbed
Metabolism: rapidly metabolised by liver, partly by acetylation (portion of the population are rapid acetylators)
Bioavailability = 25%
t1/2 = 1.5-3hrs

86
Q

Describe the pharmacodynamics of hydralazine

A

Induces NO release and causes arteriolar (but not venous) dilation

87
Q

What are the clinical applications of hydralazine?

A

Severe HTN
In HF in combination with nitrates

88
Q

List 6 common side effects of hydralazine

A
  1. Headache
  2. Nausea
  3. Anorexia
  4. Palpitations
  5. Sweats
  6. Flushing
89
Q

What are three other features of hydralazine toxicity?

A
  1. Reflex tachycardia
  2. Rapid tachyphylaxis
  3. Lupus-like syndrome with doses >400mg/day (arthralgia, myalgia, fever, rash)
90
Q

Minoxidil half-life and bioavailability

A

t1/2 = 4hrs
Bioavailability = 90%

91
Q

Describe the pharmacodynamics of minoxidil

A

Mechanism of action as for diazoxide
Membrane stabilisation via hyperpolarisation through increase K+ channel opening in smooth muscles
Results in arteriolar (not venous) dilation

92
Q

Which is more efficacious: minoxidil or hydralazine?

A

Minoxidil

93
Q

What drugs must be given in conjunction with minoxidil?

A

B-blocker
Diuretic

94
Q

List 3 side effects of minoxidil

A
  1. Reflex sympathetic stimulation
  2. Na+/H2O retention
  3. Hypertrichosis (used to treat baldness)
95
Q

Describe the chemical structure of sodium nitroprusside

A

Complex of iron, cyanide groups and nitroso moiety

96
Q

Describe the pharmacokinetics of sodium nitroprusside

A

Metabolism: rapidly metabolised by uptake into RBCs with release of NO and cyanide, cyanide then metabolised in mitochondria and renally excreted
Rapid onset of effect, disappears within 1-10mins of cessation: given as IV infusion

97
Q

Why does sodium nitroprusside need to be kept covered?

A

Photosensitive

98
Q

Describe the pharmacodynamics of sodium nitroprusside

A

Activation of guanylyl cyclase (either direct or via NO) causes increased cGMP which results in vascular smooth muscle relaxation (both arteriolar and venous)

99
Q

What is the effect of sodium nitroprusside on TPR, VR and CO?

A

Decreases TPR and VR
In HF: causes increased CO due to decreased afterload
In absence of HF: same or slightly reduced CO

100
Q

Describe two possible adverse effects of sodium nitroprusside?

A
  1. Cyanide toxicity: metabolic acidosis, arrhythmias, excessive HTN, death
  2. Thiocyanate accumulation: weakness, disorientation, psychosis, seizure, muscle spasm (increased risk in renal failure)
101
Q

What is used to treat cyanide poisoning?

A

Sodium thiosulphate
Hydroxocobalamin

102
Q

Describe the pharmacokinetics of diazoxide

A

Distribution: bound to serum albumin and to vascular tissue
Metabolism: t1/2 = 24hrs, effect within 5mins

103
Q

Describe the pharmacodynamics of diazoxide

A

Mechanism of action as for minoxidil
Membrane stabilisation via hyperpolarisation through increase K+ channel opening in smooth muscles
Results in arteriolar (not venous) dilation

Also active in pancreatic B cells where it inhibits insulin release

104
Q

What is another clinical application of diazoxide apart from the management of HTN?

A

Hypoglycaemia in hyperinsulinism
Through action on pancreatic B cells (inhibits insulin release)

105
Q

List 4 adverse effects of diazoxide

A
  1. Excessive hypotension
  2. Reflex sympathetic response
  3. Hyperglycaemia
  4. Na+/H2O retention (in contrast to structurally related thiazides)
106
Q

What is the mechanism of action of fenoldopam?

A

D1 agonist
Causes arteriolar dilation and natriuresis

107
Q

Fenoldopam half-life

A

t1/2 = 10mins (administered via IV infusion)
Rapidly metabolised

108
Q

What are the clinical applications of fenoldopam?

A

Hypertensive emergencies
Peri-op HTN

109
Q

What are 4 adverse effects of fenoldopam?

A
  1. Tachycardia
  2. Headache
  3. Flushing
  4. Raised IOP
110
Q

Define malignant HTN

A

SBP >200 and DBP >120 with evidence of end-organ failure (e.g. AKI, encephalopathy)

111
Q

What are 6 symptoms of hypertensive encephalopathy?

A
  1. Headache
  2. Confusion
  3. Apprehension
  4. Blurred vision
  5. N+V
  6. Focal neurologic deficits
112
Q

Describe the underlying pathology in malignant HTN

A

Progressive arteriopathy with inflammation and necrosis of arterioles
Vascular lesions in kidney cause activation of RAAS which further increases BP

113
Q

List two hypertensive emergencies

A
  1. Malignant HTN
  2. HTN with haemodynamic complications (e.g. in HF, CVA, dissecting aortic aneurysm)
114
Q

What are the treatment aims in malignant HTN?

A

Aim to lower BP by 25% and maintain DBP >/= 100-110mmHg within first hours/days
Initially IV then transition to PO and aim to normalise BP over several weeks

115
Q

What are the risks of rapid normalisation of BP in hypertensive emergencies?

A

Rapid normalisation may cause cerebral hypoperfusion due to autoregulatory changes in chronic HTN

116
Q

What drugs are used in the management of hypertensive emergencies? What additional class of drug is used to prevent volume expansion caused by vasodilators?

A
  1. Sodium nitroprusside
  2. GTN
  3. Labetalol
  4. CCBs
  5. Fenoldopam
  6. Hydralazine
  7. Esmolol

Diuretics used concurrently to prevent volume expansion

117
Q
A

ACEM Primary Written (150 decks)

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