26. Antihypertensive Agents Flashcards
what is map
what is co
how do bp meds produce effects
MAP = CO × SVR
CO = SV × HR
(SV depends on preload, contractility and afterload)
Antihypertensive agents will produce their effect by modulating cardiac output (CO),
systemic vascular resistance (SVR) or both.
The easiest way to
categorise antihypertensive agents
is according to their site of action:
Heart:
1
> β-Blockers –
Competitive antagonists at β-adrenoceptors
with varying degrees of receptor selectivity.
Negative inotropic and chronotropic
effects reduce CO
while antagonism of the renal
β1 adrenoceptors reduces sympathetically
mediated release of renin.
• Atenolol, esmolol and metoprolol –
Cardioselective
(i.e. act only on β1 adrenoceptors at normal doses).
• Propranolol – Non-cardioselective
(i. e. acts at both β1 and β2
adrenoceptors) .
• Labetalol – Non-cardioselective and has antagonistic action at α1-adrenoceptors (ratio of α1: β blockade depends on the route of administration: oral = 1:3 and IV = 1:7).
Blood vessels:
> Directly acting vasodilators –
Produce NO, which acts on G-protein coupled receptors activating guanylate cyclase and increasing intracellular cGMP levels to cause vasodilatation.
• Sodium nitroprusside and hydralazine –
Produce vasodilatation of both arterial and venous vessels. Arterial vasodilatation reduces SVR while venous vasodilatation increases venous capacitance and reduces preload.
• Glyceryl trinitrate and isosorbide mononitrate –
Produce vasodilatation of primarily
the venous vessels.
This increases venous capacitance
and reduces preload.
> Indirectly acting vasodilators –
Reduce SVR and preload by various
mechanisms.
• Calcium channel blockers (e.g. amlodipine) – Antagonists at L-type calcium channel located in vascular smooth muscle.
• α-Blockers (e.g. prazosin) –
Antagonists at α1-adrenoceptors
causing vasodilatation of
both arterial and venous vessels.
• Potassium channel activators (e.g. nicorandil) – Activators of AT P-sensitive K+ channels within arterioles causing hyperpolarisation, reduced intracellular Ca2+ levels and hence arteriolar vasodilatation.
Venous vessels are also relaxed by
activation of guanylate cyclase by
the nitrate moiety within nicorandil.
• Magnesium – This is a natural antagonist to calcium.
Kidney
Kidney:
> Diuretics –
Reduce plasma volume
(which reduces preload and CO)
and some produce arteriolar vasodilatation reducing SVR ( e.g. thiazide and loop diuretics). See Chapter 27, ‘Diuretics’.
> Agents affecting the renin–angiotensin–aldosterone system
(See later)
• Angiotensin-converting enzyme inhibitors,
ACEI (e.g. ramipril)
• Angiotensin II receptor antagonists (e.g. losartan)
Central nervous system:
> Centrally acting drugs
(e.g. clonidine and methyldopa) –
Stimulate central inhibitory presynaptic
α2-adrenoceptors causing reduced
noradrenaline release
and hence
reduced centrally mediated sympathetic outflow.
> Ganglion blockers (e.g. trimetaphan) –
Competitive antagonists at
nACh receptors located in
parasympathetic and sympathetic ganglia.
Briefly explain the renin–angiotensin–aldosterone
system (RAAS).
RAAS system is intricately
involved in the regulation of blood pressure.
Renin is released from the
juxtaglomerular apparatus
in response to
low renal perfusion,
reduced Na+ at the macula densa
or sympathetic stimulation
via renal β1 adrenoceptors.
Renin converts angiotensinogen,
which is produced by the liver,
into angiotensin I.
Angiotensin I is then
converted into angiotensin II
in the lung via the action of
angiotensin-converting enzyme (ACE).
Angiotensin II produces a multitude of effects including peripheral vasoconstriction, aldosterone release from the adrenal cortex, increased thirst sensation, and increased ADH (also known as vasopressin) and ACTH release from the hypothalamo–pituitary axis.
What are some of the more
common side effects of
antihypertensive agents
> β-Blockers – Unwanted side effects come from antagonism of β2 adrenoceptors, which may cause bronchospasm and peripheral vasoconstriction. Hence these agents are best avoided in patients with COPD and peripheral vascular disease.
> Vasodilators –
Vasodilatation of the
capacitance vessels can cause
postural hypotension while
vasodilatation of
cerebral vessels
can lead to headaches.
> Diuretics – Loop and thiazide diuretics can both lead to hyponatraemia, hypokalaemia, hypomagnesaemia and hypochloraemic alkalosis due
to their action on renal electrolyte reabsorption.
Loop diuretics can also cause ototoxity
leading to deafness
while thiazide diuretics can
cause hyperuricaemia
and precipitate gout.
Owing to the risk of hypokalaemia,
these agents should be used cautiously with digoxin.
> ACEI –
Under normal conditions angiotensin II maintains renal perfusion by altering the calibre of the efferent arteriole at the glomerulus.
However, in the presence of an
ACEI this mechanism is lost
and renal perfusion
pressure may fall,
leading to renal failure in those individuals
who already have impaired renal circulation.
Hence these agents are contraindicated
in renal artery stenosis.
Some patients may experience a persistent
cough due to
increased bradykinin,
which is normally degraded by ACE.
NIMODIPINE
NIMODIPINE Dihydropyridine calcium channel antagonist • Tablets: 30 mg • Solution: 200 μg/mL
DOSE
• Oral: 60 mg 6x/day for SAH
• IV: 1–2mg/hr
MOA • Competitive antagonist at slow calcium channels causing decreased influx of Ca2+ into cells • Relatively selective for cerebral arterioles
METABOLISM
AND EXCRETION
• Hepatic metabolism
• Excreted in urine
ABSORPTION/ DISTRIBUTION • Well absorbed orally • Significant fist-pass metabolism
- Oral bioavailability up to 28%
- Protein binding 98%
- VD 0.94–2.3 L/kg
USES
• Reduction of vasospasm following subarachnoid
haemorrhage (SAH)
• Migraine
EFFECTS
CVS
• ↓ SVR and BP at > 2 mg/hr
CNS
• Increased cerebral blood
flow secondary to
vasodilatation
- Headache
- Vertigo
NIFEDIPINE
prep
dose
uses
MOA
ADME
NIFEDIPINE Calcium channel antagonist • Capsules: 5–10 mg • Tablets: 10–60 mg • Onset in: 15–20 min
DOSE
• 10–20 mg 8 hourly
USES • Angina • Hypertension • Reduction of vasospasm during coronary angiography • Raynaud’s phenomenon
MOA • Competitive antagonist at slow calcium channels causing decreased influx of Ca2+ into cells
ABSORPTION/
DISTRIBUTION
- Well absorbed orally
- Oral bioavailability 60%
- Protein binding 95%
- t½ 5 hours
METABOLISM
AND EXCRETION
• Hepatic metabolism
• Excreted in urine
EFFECTS
Nifedipine
EFFECTS CVS • ↓ SVR and BP • ↑ HR and ↓ contractility • ↑ CO • ↑ Coronary oxygen requirements • Sublingual administration can cause precipitous fall in BP
• Flushing
CNS
• Small increased cerebral
blood flow secondary to
vasodilatation
- Headache
- Vertigo
RS
• Inhibits hypoxic pulmonary
vasoconstriction
OTHER • Negatively inotropic effects of nifedipine are additive with those of the volatiles, especially isoflurane. Use together with caution • ↓ MAC • Prolong effects of neuromuscular blocking drugs
CAPTOPRIL
CAPTOPRIL
ACE Inhibitor
• Tablets: 12.5/25/50 mg
DOSE
• Oral: 12–50 mg/day,
starting
at 6.25 mg and titrating up
MOA
• Angiotensin converting enzyme
(ACEI)
preventing conversion of
angiotensin I to II
USES
• Hypertension
- Reduction of progression of diabetic nephropathy
- Post MI, to improve ventricular remodelling
ABSORPTION/
DISTRIBUTION
- Well absorbed orally
- Oral bioavailability 75%
- Protein binding 30%
- VD 0.61–0.79 L/kg
- t½ 1.9 hours
METABOLISM
AND EXCRETION
- Hepatic metabolism
- Excreted in urine, 50% unchanged
Captopril effects
EFFECTS
CVS
• ↓ SVR and BP
- Afterload ↓ > preload
- First-dose hypotension – give test dose at night
RENAL
• Angiotensin II (AII) autoregulates renal
perfusion pressure by altering arteriolar tone.
ACEI reduce plasma AII,
which can cause ↓ perfusion
and = renal failure
• So, contraindicated in renal
artery stenosis
METABOLISM
• ↓ Aldosterone leads to
↑ renin secretion
• ↑ K+ (as less exchanged for Na+) so avoid using with K+ sparing diuretics
OTHER
• Can cause refractory hypotension with anaesthesia – some advise omitting for 24 hours prior to surgery
• Dry cough results from ↑
serum bradykinin
• Angio-oedema (more
common in Afro-Caribbean
patients)
- Agranulocytosis
- Thrombocytopenia
- Rash, ulcers
• Caution with NSAIDs –
increase chance of renal
failure
LOSARTAN
LOSARTAN
Substituted imidazole AII receptor antagonist
• Tablets: 25/50 mg
DOSE
• 50–100 mg/day
MOA
• Antagonist at angiotensin II
receptors
USES
• Hypertension
• To reduce progression of
diabetic nephropathy,
independent of its
antihypertensive effect
• Used when dry cough of
ACE inhibitors unacceptable
• Not usually first line,
as more expensive than ACE inhibitor
METABOLISM
AND EXCRETION
- Hepatic metabolism
- Excreted in urineand bile
ABSORPTION/
DISTRIBUTION
• Well absorbed orally
• Significant first-pass metabolism
- Oral bioavailability 30%
- Protein binding 99%
- VD 0.61–0.79 L/kg
- t½ 2 hours
LOSARTAN
effects
EFFECTS
CVS
• ↓SVR and BP
• Afterload ↓ > preload
• first-dose hypotension –
give test dose at night
RENAL • Angiotensin II (AII) autoregulates renal perfusion pressure by altering arteriolar tone and so antagonists can cause ↓ perfusion and renal failure
• So, contraindicated in
renal artery stenosis
OTHER • Can cause refractory hypotension with anaesthesia – some advise omitting for 24 hours prior to surgery
• Does not block actions of
ACE, therefore no increase
in bradykinins and no
cough
• Caution with NSAIDs –
increased chance of renal
failure
NICORANDIL
Nicotinamidoethyl nitrate
K+ channel activator
• Tablets: 10/20 mg
DOSE
• 10–30 mg 12 hourly
MOA
• Activates K+ channels, i.e. opens them. K+ flows out of cell hyperpolarising the membrane
• This closes Ca2+ channels, reducing Ca2+ concentration and decreasing contractility and cardiac work
• Causes venous relaxation and reduction of preload by donating nitric oxide to cells. This increases cGMP and reduces Ca2+
(see GTN, next page, for
full explanation)
METABOLISM AND EXCRETION • Hepatic metabolism • Excreted in urine and bile
ABSORPTION/ DISTRIBUTION • Well absorbed orally • Protein binding 0% • t½ 1 hour
USES
• Angina – treatment
and prophylaxis
EFFECTS CVS • ↓Preload • ↓ LVEDP • ↓ Cardiac work • Flushing
CNS
• Vertigo
• Headache
OTHER
• Nausea and vomiting
• Angio-oedema
• Hepatic dysfunction
GLYCERYL TRINITRATE (GTN)
GLYCERYL TRINITRATE (GTN)
Organic Nitrate
- Tablets: 300/600 μg S/L
- Buccal: 2/5 mg prn
- Spray: 400 μg/spray S/L prn
- Patch: 5–10 mg/24 hours
• Solution: 5 mg/mL infused
at 1–10 mg/hr titrated to BP
• Sublingually – effective in
3 min lasts 1 hour
MOA
• GTN broken down to
liberate nitric oxide (NO)
• NO increases cGMP,
so Ca2+ uptake into smooth
muscle is reduced
leading to vasodilation
CHEMICAL PROPERTIES
• Explosive, so remove
patches before
cardioversion
METABOLISM
AND EXCRETION
• Hepatic metabolism
to di/mononitrites
• Excreted in urine
ABSORPTION/ DISTRIBUTION • Well absorbed orally • Significant first-pass metabolism • Oral bioavailability 5% • Protein binding 60% • VD 0.04–2.9 L/kg
USES
• Prophylaxis/treatment of
angina
• CCF and pulmonary
oedema
- MI, ACS
- Hypertension
• Patch over vein to
maintain dilation, e.g. for
peripheral feeding
EFFECTS
CVS
• ↓ SVR and BP
• Predominantly venodilatation so ↓ preload CNS • ↑ ICP causing headache
OTHER • Tolerance develops to patches, so have ‘patch-free period’ each day
• No significant tolerance
develops to IV infusion
• Methaemoglobinaemia
(rare)
CLONIDINE
Tablets: 100/250/300 μg
• Solution: 150 μg/mL
DOSE
- Oral: 50–600 μg 8 hourly
- IV: 75–300 μg 8 hourly
MOA
• Agonist at presynaptic a2
receptors,
so decreasing
sympathetic tone
• In spinal cord they
increase release of
endogenous opiates
• Effective within 10 min
METABOLISM
AND EXCRETION
- Hepatic metabolism
- Excreted in urine, 50% unchanged
ABSORPTION/
DISTRIBUTION
- Well absorbed orally
- Oral bioavailability 100%
- Protein binding 20%
- VD 2l L/kg
- t½ 9–18 hours
USES
• Hypertension
• Agitation and anxiety
on ICU
• Adjunct in neuroaxial
anaesthesia
- Migraine
- Analgesia
EFFECTS
CVS
• ↓ SVR and BP
• Rebound hypertension if
stopped suddenly
CNS
• Sedation, anxiolysis
• ↓ MAC
RENAL
• Diuresis?
result of ADH
inhibition
HAEMATOLOGICAL • No increase in platelet aggregation, despite their surface a2 receptors
OTHER
• ↓ Post-operative
analgesia requirements
SODIUM NITROPRUSSIDE
SODIUM NITROPRUSSIDE
• Red/brown powder
50 mg/vial
• Reconstitute with 5%
dextrose
DOSE
• 0.5–6 μg/kg/min titrate
to effect
CHEMICAL PROPERTIES • Biodegrades in sunlight so use opaque giving sets or wrap normal ones in tin foil
MOA
• Broken down to
liberate nitric oxide (NO)
• NO increases cGMP,
so Ca2+ uptake into smooth
muscle is reduced leading
to vasodilation
USES
• Hypertension
SNP
ADME
EFFECTS
METABOLISM
AND EXCRETION
• Metabolised two ways:
1 Reacts with sulfhydryl
groups on plasma proteins
2 Hydrolysis in red blood
cells to liberate NO +
5 cyanide (CN– ) ions +
methaemoglobin.
• Of the 5 CN-s:
• 1 CN– reacts with Hb
-> cyanomethaemoglobin
• 4 CN– enter plasma,
and of these:
• 3 CN– react with
thiosulphate ->
thiocyanate
• 1 CN– reacts with
hydroxy-cobalamin ->
cyanocobalamin
ABSORPTION/
DISTRIBUTION
• Not absorbed orally
• t½ 10 min
EFFECTS
CVS
• Arteriolar dilation,
↓ SVR and BP
- Venodilatation, ↓preload
- ↓ LVEDP
- ↓ Myocardial O2 consumption
RS
• ↓ Hypoxic pulmonary
vasoconstriction,
so give O2 to reduce shunt
CNS
• ↑ ICP
• Dizziness
ENDOCRINE
• ↑ Catecholamines
• ↑Renin
TOXICITY
• Cyanide irreversibly inhibits
respiration by binding to
cytochrome oxidase
- Signs:
- Tachycardia, arrhythmias
- Hyperventilation
- Sweating
- Rising SVO2
- Metabolic acidosis
- More common in
- Liver/renal failure
- Vit B12 deficiency
OTHER
• Nausea and vomiting
• Muscle twitching
• Tachyphylaxis
METHYLDOPA
Phenylalanine derivative
- Tablets: 125/250/500 mg
- Solution: 50 mg/mL
DOSE
• 0.5–3 g/day
in 2–3 doses
MOA
• Metabolised to a -methyl
noradrenaline,
which is an
a2 agonist
• This is taken up into
nerve terminals in CNS,
and when released decreases sympathetic tone
METABOLISM AND EXCRETION • Hepatic metabolism • Excreted in urine, 50% unchanged
ABSORPTION/ DISTRIBUTION • Variable oral absorption • Undergoes first-pass metabolism • Variable oral bioavailability 8–60% • Protein binding < 20%
USES • Hypertension • Pregnancy induced hypertension and pre-eclampsia
METHYLDOPA
EFFECTS
CVS
• ↓ SVR and BP
• Postural hypotension
(rare)
• Rebound hypertension if
stopped suddenly
CNS • Sedation • Vertigo • Depression, nightmares (uncommon)
RENAL • Urine darkens on standing due to oxidation of methyldopa and its metabolites
GI • Constipation • Impaired liver function with long-term use • Hepatic necrosis reported
HAEMATOLOGICAL • Direct Coombe’s test + in 10–20% • Haemolytic anaemia • Thrombocytopenia (rare) • Leucopenia (rare)
OTHER • Decreases MAC • Hypersensitivity to drug can cause myocarditis • Gynaecomastia
PRAZOSIN
PRAZOSIN
Quinazoline derivative
• Tablets:
0.5/1/2/5 mg
DOSE
• 0.5 mg t.d.s.
increasing to
max of 20 mg/day
MOA
• Highly selective a1
competitive antagonist
ABSORPTION/ DISTRIBUTION • Oral bioavailability 50–80% • Protein binding 92% • VD 0.5–0.89 L/kg
METABOLISM
AND EXCRETION
• Hepatic metabolism
• Excreted in bile
USES • Hypertension • Benign prostatic hypertrophy • Raynaud’s phenomenon • Treatment of nightmares associated with posttraumatic stress disorder
EFFECTS CVS • a1 blockade • Vasodilation and ↓ BP • Little reflex tachycardia
GU
• Relaxes bladder
sphincters
SIDE-EFFECTS • Profound orthostatic hypotension • Syncope • Nasal congestion • Fatigue • Headache • Vertigo
• Nausea and vomiting These side-effects may be pronounced after the first dose (‘first-dose effect’), but may resolve with continued use
PHENOXYBENZAMINE
PHENOXYBENZAMINE
a-blocker
- Capsules: 10 mg
- Solution: 50 mg/mL
DOSE
• Oral: 10–60 mg per day
in divided doses
• IV: 10–40 mg over
1 hour Lasts for 3–4 days
MOA
• Non-selective irreversible
a-blocker
• New receptors must be
synthesised to overcome
drug effect
• Blockade of a2 receptors
increases the amount of
noradrenaline released
• Partial agonist at 5-HT2
receptors
ABSORPTION/
DISTRIBUTION
• Oral bioavailability
25%
- Protein binding 50%
- t½ 24 hours
USES
• Hypertensive emergencies,
especially caused by
- Phaeochromocytoma
- Cocaine
• Reynaud’s phenomenon
• Complex regional pain syndrome,
because it modulates the
sympathetic nervous system
PHENOXYBENZAMINE
ME
EFFECTS
METABOLISM AND EXCRETION • Hepatic metabolism • Excreted in urine and bile
EFFECTS
CVS
• a1 blockade
• Vasodilation and ↓BP
• Reflex tachycardia
causes ↑ CO
• a2 blockade enhances
noradrenaline release
causing ↑ HR and ↑ CO
CNS • Sedation • Meiosis • Convulsions with rapid infusion • Dizziness
OTHER • Little effect on GI/renal blood flow • Dry mouth • Impotence • Contact dermatitis
PHENTOLAMINE
PHENTOLAMINE
Imidazoline
• Pale yellow solution:
10 mg/mL
DOSE
• 1–5 mg titrate to effect
- Onset in 1–2 min
- Offset in 5–20 min
MOA
• Competitive a blocker
• 3x higher affinity for a1
than a2
- b receptor agonist activity
- Anti-serotonergic activity
USES
• Hypertensive emergencies, especially caused by:
- Phaeochromocytoma
- Cocaine
- MAOI reactions with tyramine
- Inject into corpus callosum to facilitate erection in impotence
• Used in diagnosis and treatment of
complex regional pain syndrome as this
has an element of sympathetic mediation
PHENTOLAMINE
METABOLISM
AND EXCRETION
• Extensively
metabolised
• 10% excreted
unchanged in urine
ABSORPTION/ DISTRIBUTION • Oral bioavailability 20% • Protein binding 50% • t½ 15 min
EFFECTS
CVS
• a1 blockade
• Vasodilation and ↓ BP
• ↑ Coronary artery
perfusion
• ↓ Pulmonary artery
pressure
• a2 blockade
• Enhances noradrenaline
release causing ↑ HR and
↑ CO
• Marked nasal congestion,
use topical vasoconstrictors
if planning nasal instrumentation
RS
• ↑ VC and ↑ FEV1
• ↑ Secretions
• Prevents bronchospasm
caused by histamine release
GI
• GI motility
• Salivation
• Gastric acid secretions
OTHER
• Insulin secretion
B BLOCKERS
Class II antiarrhythmic
B BLOCKERS
(Class II antiarrhythmic)
MOA
• All competitive
antagonists at b adrenoreceptor
• Some have intrinsic
sympathomimetic activity
• Varying receptor affinity
(see box below)
RECEPTOR SELECTIVITY
Aim to block b1 but not
b2 receptors
‘Cardioselective’ drugs: • Atenolol • Esmolol (ultra-short acting) • Metoprolol (short acting) • Bisoprolol • Carvedilol NB all will act on b2 if dose high enough USES • Hypertension • Angina and MI • Tachycardias • Obtund reflex hypertension during laryngoscopy, e.g. esmolol • In phaeochromocytoma – pre-op stabilisation • HOCM • Anxiety • Glaucoma • Migraine prophylaxis
