Cardiovascular: Pharmacology - Antihypertensives Flashcards
Outline 6 main classes of antihypertensives and briefly describe what physiological determinants of HTN they target
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)
Outline five classes of anti-anginal drugs
B-blockers
CCBs
Nitrates
Vasodilators (nicorandil)
If inhibitor (ivabradine)
What is the formula for BP? What is the formula for CO?
BP = CO x TPR
CO = HR x SV
Give a brief overview of RAAS
(there is a better diagram in your paper notes)
Describe in detail the mechanism of ACEIs. What is the effect on TPR, CO and HR?
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
What is the advantage of ACEIs over direct vasodilators?
Do not induce reflex sympathetic activation (can be used safely in IHD)
Why are ACEIs used in CKD and in DM?
Shown to reduce proteinuria and stabilise renal function independent of BP-lowering effect
Name three long-acting ACEIs
Lisinopril
Ramipril
Perindopril
Which ACEIs are prodrugs converted to active metabolites via hydrolysis in the liver?
Enalapril
Lisinopril
Ramipril
Perindopril
Captopril half-life and bioavailability
t1/2 = 2.2hrs
Bioavailability = 65%
Give two examples of ACEIs which are primarily renally excreted and must be dose-reduced in renal impairment
Captopril
Lisinopril
Lisinopril half-life and bioavailability
t1/2 = 12hrs
Bioavailability = 25%
Enalapril half-life
t1/2 = 11hrs
List five adverse effects of ACEIs
- First dose hypotension in hypovolaemic patients
- AKI (especially in setting of bilat renal artery stenosis)
- Hyperkalaemia
- Effects due to increased bradykinin and substance P: dry cough, wheeze, angioedema
- Contraindicated in pregnancy (increased risk stillbirth, prematurity, IUGR)
Identify some specific adverse effects of captopril
Neutropenia
Proteinuria
Allergic skin rash
Drug fever
Give four examples of ARBs
Losartan
Candesartan
Telmisartan
Valsartan
What is the mechanism of action of ARBs?
Block AT1 receptors (decreased TPR, CO and HR unchanged)
No effect on bradykinin
List three adverse effects of ARBs
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
Outline the pharmacokinetics of losartan. Is dose reduction required in renal impairment?
t1/2 = 1-2hrs
Bioavailability = 36%
No dose reduction required in renal impairment
Which B-blockers have been shown to decrease mortality from HF and post-MI?
Bisoprolol
Metoprolol
Carvedilol
Which B-blockers have a use in hypertensive emergencies?
Labetalol
Esmolol
Is propranolol a selective or non-selective B-blocker?
Non-selective
Give four examples of cardioselective B-blockers
Metoprolol
Atenolol
Bisoprolol
Esmolol
Which B-blocker undergoes high first-pass metabolism?
Metoprolol
Give three examples of B-blockers which additionally have vasodilator activity. Explain how this occurs
Labetalol: a-blocker activity
Carvedilol: a-blocker activity
Nebivolol: increases endothelial NO
Carvedilol half-life
7-10hrs
Nebivolol half-life
10-12hrs
Esmolol half-life and typical clinical application
t1/2 = 9-10mins
Used to treat peri-op HTN
What type of Ca2+ channel do CCBs act on?
L-type
What four common features are shared by all CCBs?
Orally active
High first-pass metabolism
High plasma protein binding
Extensively metabolised
Which two CCBs can be administered IV?
Verapamil
Diltiazem
What is the difference between dihydropyridines and other CCBs?
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
What is unique about the mechanism of verapamil?
In addition to inhibiting L-type Ca2+ channels, also inhibits K+ channels
This means it is less vasodilatory than other CCBs
Describe in detail the mechanism of action of CCBs
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
Outline the organ effects of CCBs on smooth, cardiac and skeletal muscle
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
Why are CCBs less likely to cause orthostatic hypotension?
Arteriolar vasodilation > venodilation
Why do CCBs have no effect on skeletal muscle?
Skeletal muscle uses intracellular pools of Ca2+ so does not require as much transmembrane flux to produce contraction
Which CCBs are used to prevent cerebral vasospasm/infarct following SAH?
Nimodipine and nicardipine (have high affinity for cerebral blood vessels)
What are the most important adverse effects of CCBs?
Related to cardiac depression: bradycardia, AV block, cardiac arrest, HF
Amlodipine half-life and bioavailability
t1/2 = 30-50hrs
Bioavailability: 65-90%
Felodipine half-life and bioavailability
t1/2 = 11-16hrs
Bioavailability = 15-20%
Nifedipine half-life and bioavailability
t1/2 = 4hrs
Bioavailability = 45-70%
Verapamil half-life and bioavailability
t1/2 = 6hrs
Bioavailability = 20-35%
Diltiazem half-life and bioavailability
t1/2 = 3-4hrs
Bioavailability = 40-65%
Mechanism of action of diuretics in treatment of HTN
Initial: decreased blood volume to decrease CO (may transiently increase TPR)
After 6-8 weeks: CO back to baseline, decreased TPR
How many mmHg do diuretics lower BP by?
10-15mmHg
How does Na+ affect TPR?
Increases by increasing vessel stiffness and neural reactivity
Chlorthalidone half-life and bioavailability
t1/2 = 40-60hrs
Bioavailability = 65%
HCT half-life and bioavailability
t1/2 = 12hrs
Bioavailability = 70%
List six adverse effects of diuretics
- Hypo- (except K+-sparing) or hyper- (K+-sparing) kalaemia
- HypoMg
- Impaired glucose tolerance
- Hyperlipidaemia0
- Gout (may precipitate flare due to increased uric acid)
Describe the difference in bioavailability and duration of action of sublingual vs oral preparations of nitrates
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)
How are nitrates excreted?
Primarily renal in form of glucuronide derivatives of denitrated metabolites
Describe in detail the mechanism of action of nitrates
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
What is the effect of nitrates on cardiac and skeletal muscle?
None
What are the organ effects of nitrates’ action on vascular smooth muscle?
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
What are the indirect effects of nitrates’ action on vascular smooth muscle?
Reflex tachycardia
Positive inotropy
Na+/H2O retention
What effects do nitrates have on platelets?
Decrease platelet aggregation
Outline seven adverse effects of nitrates
- Orthostatic hypotension due to increased venous capitance
- Reflex tachycardia
- Headache due to meningeal artery pulsations
- “Coronary steal syndrome”
- Risk of severe hypotension and MI if taken with sildenafil
- Methaemoglobinaemia (pseudocyanosis, tissue hypoxia, death)
- Tachyphylaxis/tolerance
What is the mechanism of action of sildenafil?
Inhibits PDE to reduce breakdown of cGMP, potentiating effects of NO
What is the clinical significance of tachyphylaxis in nitrate administration?
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
What is the likely mechanism of tachyphylaxis to nitrates?
Depletion of sulfhydryl donors
What is coronary steal syndrome?
Stenosed coronary vessels are already maximally dilated, so dilated of all coronary vessels results in blood being shunted away from ischaemic areas
Describe the four beneficial and two deleterious effects of nitrates on the heart
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
What other three classes of antihypertensives are there (outside of AABCDN)? Give examples of each
- Centrally acting sympathoplegics (e.g. methyldopa, clonidine)
- Adrenergic neuron-blocking drugs (e.g. guanethidine, reserpine)
- Vasodilators (e.g. hydralazine, sodium nitroprusside)
Describe the pharmacodynamics of methyldopa
Stimulates central a-adrenoceptors to decrease TPR via decreased sympathetic outflow from vasomotor centres, also decreases renal vascular resistance
Describe the pharmacokinetics of methyldopa
Enters brain via aromatic amino acid transporter
Max effect at 4-6hrs (but can persist up to 24hrs)
t1/2 = 2hrs
Bioavailability 25%
What is the starting dose of methyldopa?
1g/day
Does methyldopa need to be dose reduced in renal impairment?
No
Clinical applications of methyldopa
HTN of pregnancy and pre-eclampsia
List five features of methyldopa toxicity
- Sedation
- Hyperprolactinaemia
- Positive Coombs’ test (rarely causes haemolytic anaemia)
- Hepatitis
- Drug fever
Describe the pharmacodynamics of clonidine
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
What is the immediate vs sustained effect of clonidine on BP? What is the mechanism?
Immediate increase in BP due to agonist action at arterioles
Longterm blocks other agonists to reduce BP
What are four features of clonidine toxicity?
- Dry mouth
- Sedation
- Depression (absolute CI)
- Withdrawal syndrome with long term use
Describe the effects of TCAs on clonidine action
Blocks antihypertensive effects
Describe the withdrawal syndrome seen with long term clonidine use
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
Describe the pharmacodynamics and pharmacokinetics of guanethidine
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
Does clonidine cause postural hypotension?
Rarely
What drugs block the effect of guanethidine?
Drugs which block guanethidine uptake into nerve terminals by NET (e.g. cocaine, amphetamines, TCA)
What are the adverse effects of guanethidine?
Postural hypotension
Can cause hypertensive crisis in phaeochromocytoma
Describe the pharmacodynamics of reserpine
Blocks VMAT to deplete stores of NA, dopamine and serotonin in central and peripheral neurons
Also depletes catecholamines in adrenal medulla
What is the effect of reserpine on CO and TPR?
Reduces
Describe the pharmacokinetics of reserpine?
t1/2 = 24-48hrs
Bioavailability = 50%
Describe the adverse effects of reserpine
CNS: sedation, nightmares, depression
GI: diarrhoea, cramps, reflux
List 7 types of vasodilators used in the management of HTN
- Nitrates
- CCBs
- Hydralazine
- Minoxidil
- Sodium nitroprusside
- Diazoxide
- Fenoldopam
Describe the pharmacokinetics of hydralazine
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
Describe the pharmacodynamics of hydralazine
Induces NO release and causes arteriolar (but not venous) dilation
What are the clinical applications of hydralazine?
Severe HTN
In HF in combination with nitrates
List 6 common side effects of hydralazine
- Headache
- Nausea
- Anorexia
- Palpitations
- Sweats
- Flushing
What are three other features of hydralazine toxicity?
- Reflex tachycardia
- Rapid tachyphylaxis
- Lupus-like syndrome with doses >400mg/day (arthralgia, myalgia, fever, rash)
Minoxidil half-life and bioavailability
t1/2 = 4hrs
Bioavailability = 90%
Describe the pharmacodynamics of minoxidil
Mechanism of action as for diazoxide
Membrane stabilisation via hyperpolarisation through increase K+ channel opening in smooth muscles
Results in arteriolar (not venous) dilation
Which is more efficacious: minoxidil or hydralazine?
Minoxidil
What drugs must be given in conjunction with minoxidil?
B-blocker
Diuretic
List 3 side effects of minoxidil
- Reflex sympathetic stimulation
- Na+/H2O retention
- Hypertrichosis (used to treat baldness)
Describe the chemical structure of sodium nitroprusside
Complex of iron, cyanide groups and nitroso moiety
Describe the pharmacokinetics of sodium nitroprusside
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
Why does sodium nitroprusside need to be kept covered?
Photosensitive
Describe the pharmacodynamics of sodium nitroprusside
Activation of guanylyl cyclase (either direct or via NO) causes increased cGMP which results in vascular smooth muscle relaxation (both arteriolar and venous)
What is the effect of sodium nitroprusside on TPR, VR and CO?
Decreases TPR and VR
In HF: causes increased CO due to decreased afterload
In absence of HF: same or slightly reduced CO
Describe two possible adverse effects of sodium nitroprusside?
- Cyanide toxicity: metabolic acidosis, arrhythmias, excessive HTN, death
- Thiocyanate accumulation: weakness, disorientation, psychosis, seizure, muscle spasm (increased risk in renal failure)
What is used to treat cyanide poisoning?
Sodium thiosulphate
Hydroxocobalamin
Describe the pharmacokinetics of diazoxide
Distribution: bound to serum albumin and to vascular tissue
Metabolism: t1/2 = 24hrs, effect within 5mins
Describe the pharmacodynamics of diazoxide
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
What is another clinical application of diazoxide apart from the management of HTN?
Hypoglycaemia in hyperinsulinism
Through action on pancreatic B cells (inhibits insulin release)
List 4 adverse effects of diazoxide
- Excessive hypotension
- Reflex sympathetic response
- Hyperglycaemia
- Na+/H2O retention (in contrast to structurally related thiazides)
What is the mechanism of action of fenoldopam?
D1 agonist
Causes arteriolar dilation and natriuresis
Fenoldopam half-life
t1/2 = 10mins (administered via IV infusion)
Rapidly metabolised
What are the clinical applications of fenoldopam?
Hypertensive emergencies
Peri-op HTN
What are 4 adverse effects of fenoldopam?
- Tachycardia
- Headache
- Flushing
- Raised IOP
Define malignant HTN
SBP >200 and DBP >120 with evidence of end-organ failure (e.g. AKI, encephalopathy)
What are 6 symptoms of hypertensive encephalopathy?
- Headache
- Confusion
- Apprehension
- Blurred vision
- N+V
- Focal neurologic deficits
Describe the underlying pathology in malignant HTN
Progressive arteriopathy with inflammation and necrosis of arterioles
Vascular lesions in kidney cause activation of RAAS which further increases BP
List two hypertensive emergencies
- Malignant HTN
- HTN with haemodynamic complications (e.g. in HF, CVA, dissecting aortic aneurysm)
What are the treatment aims in malignant HTN?
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
What are the risks of rapid normalisation of BP in hypertensive emergencies?
Rapid normalisation may cause cerebral hypoperfusion due to autoregulatory changes in chronic HTN
What drugs are used in the management of hypertensive emergencies? What additional class of drug is used to prevent volume expansion caused by vasodilators?
- Sodium nitroprusside
- GTN
- Labetalol
- CCBs
- Fenoldopam
- Hydralazine
- Esmolol
Diuretics used concurrently to prevent volume expansion
