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
