eLFH - Vasodilators and Antihypertensives Flashcards
Methods of reducing MAP
Reduce SVR
Reduce HR
Reduce SV
Methods of reducing SVR
Vasodilatation
Methods of reducing SV
Reduce preload - venodilatation or reduce circulating volume
Reduce contractility
Reduce afterload - arteriolar vasodilatation
Pathway of adreno-receptor intracellular action
Adrenaline binds to e.g. beta 2 receptor
GDP replaces GTP in Gs protein causing conformational change
Alpha subunit of Gs protein activates Adenylate cyclase
Magnesium binds to Adenylate cyclase as co-factor
AC converts ATP to cAMP
cAMP activate Protein Kinase A
PKA inhibits myosin light chain kinase
Therefore unable to phosphorylate myosin light chain and results in smooth muscle relaxation
Gs protein structure
Alpha subunit with GDP/GTP binding site
Beta subunit
Gamma subunit
Action of Atrial Natriuretic peptide
ANP stimulates membrane bound cGMP
Guanylyl cyclase on smooth muscle membrane converts GTP to cGMP intracellularly (cyclic Guanosine monophosphate)
cGMP activates Protein Kinase G
PKG activates Myosin phosphatase and potassium channels (hyperpolarisation of cell) but inhibits calcium entry into cell
Results in smooth muscle relaxation
Classification of antihypertensives by site of action
Central nervous system
Peripheral autonomic nervous system
Direct action on vascular smooth muscle
Reducing blood volume (and direct action on smooth muscle)
Renin-angiotensin system
Antihypertensives which act via Central nervous system
Alpha 2 agonists
Examples of alpha 2 adrenergic receptor agonists (which also have some minimal alpha 1 agonism)
Clonidine
Methyldopa
Dexmedetomidine - more selective alpha 2 agonist
Routes of administration of clonidine
Epidural
Subarachnoid
IV
PO
Routes of administration of Methyldopa
PO
IV (rarely)
Mechanism of action of alpha 2 adrenergic receptor agonists
Alpha 2 receptor stimulation
Decreased noradrenaline release
Reduced alpha 1 receptor stimulation
Reduced sympathetic tone
Side effects of clonidine
Diuresis via inhibition of ADH release
Inhibits insulin release
Rebound hypertension post abrupt cessation
Sedation
Side effects of methyldopa
Sedation
Positive direct Coombs test in 10-20% cases
Antihypertensives which act on peripheral autonomic nervous system
Ganglion blocking agents
Adrenergic neurone blocking agents
Mechanism of action of Ganglion blocking agents
Non-depolarising competitive antagonist at ganglion type of nicotinic receptor of autonomic ganglia
Reduced sympathetic input to peripheral vasculature
Vasodilatation
Side effects of Ganglion blocking agents
Associated histamine release
Side effects mostly due to parasympathetic antagonism
Example of Ganglion blocking agent
Trimetaphan
Generally these agents aren’t used anymore
Mechanism of action of adrenergic neurone blocking agents
Enters adrenergic neurone via uptake 1 noradrenaline pathway
Displaces noradrenaline and prevents further norad release
Reduced alpha 1 receptor stimulation
Vasodilatation
Example of adrenergic neurone blocking agent
Gaunethidine
Route of administration of Guanethidine
PO
IV
Side effects of adrenergic neurone blocking agents
Diarrhoea
Postural hypotension
Use of adrenergic neurone blocking agents
Now only commonly used in chronic pain management
Antihypertensives which have direct action on vascular smooth muscle
Hydralazine
Nitrates
Sodium nitroprusside
Magnesium
Calcium channel blocking agents
Hydralazine mechanism of action
Hydralazine activates Guanylyl cyclase on smooth muscle cell membrane
(Also possible nitric oxide donor which also activates GC)
GC converts GTP to cGMP
cGMP decreases sensitivity to calcium and decreases calcium entry into cells
Vasodilatation - mainly acts on arterioles
Bioavailability of hydralazine
Affected by acetylator status
Side effects of hydralazine
Reflex tachycardia
Fluid retention
Increases cerebral blood flow
Nausea / Vomiting
Long term oral use can cause lupus like syndrome
Nitrates mechanism of action
Nitrate converts to Nitric Oxide (NO)
NO activates Guanylyl cyclase on smooth muscle cell membrane
GC converts GTP to cGMP
cGMP decreases sensitivity to calcium and decreases calcium entry into cells
Vasodilatation
Pharmacokinetics and pharmacodynamics of nitrates
Lower doses act on veins
Higher doses can act on arterioles
GTN (glyceryl trinitrate) highly lipid soluble so can be given transdermal route
Side effects of nitrates
Headache
Flushing
Postural hypotension
Tachycardia
Tolerance
Methemoglobinemia
GTN is absorbed by PVC plastic
Mechanism of tolerance to nitrates
Depletion of sulphydryl groups
Sodium Nitroprusside mechanism of action
Sodium Nitroprusside converts to Nitric Oxide (NO)
NO activates Guanylyl cyclase on smooth muscle cell membrane
GC converts GTP to cGMP
cGMP decreases sensitivity to calcium and decreases calcium entry into cells
Vasodilatation
Routes of administration of sodium nitroprusside
Only parenteral
Must cover syringes as can breakdown to form cyanide on light exposure
Pharmacokinetics and pharmacodynamics of sodium nitroprusside
Rapid onset and offset
Acts on arterioles and venules
Increases ICP but autoregulation maintained
Cautions with use of sodium nitroprusside
Can cause rebound hypertension if stopped abruptly as activates RAAS and increases plasma catecholamines
Inhibits hypoxic pulmonary vasoconstriction so can result in shunt
Side effects of sodium nitroprusside
Reacts with oxyhaemoglobin to form cyanide, nitric oxide and methaemoglobin
High infusion rates can cause cyanide accumulation
Methaemoglobin can react with cyanide to form cyanmethaemoglobin
How many cyanide ions form per molecule of sodium nitroprusside
5
Cyanide overdose treatment
Dicobalt edetate - chelates cyanide so can be excreted
Magnesium mechanism of action
1) Blocks alpha 1 receptors so less stimulation by catecholamines
2) Blocks L type calcium channels so less Ca2+ influx into smooth muscle cells
3) Generation of cAMP is magnesium dependent
Uses of magnesium
Severe pre-eclampsia - unknown mechanism but may prevent cerebral vasospasm
Acute asthma
Calcium channel blocking agents mechanism of action
Block L type Ca2+ channels, reducing Ca2+ influx into smooth muscle cells
Results in:
- Vasodilatation
- Reduced cardiac contractility
- Reduced propagation of cardiac depolarisation
Subgroups of calcium channel blockers
Phenylalkylamines
Dihydropyridines
Benzothiazepines
Examples of Phenylalkylamine calcium channel blockers
Verapamil
Examples of Dihydropyridine calcium channel blockers
Nifedipine
Amlodipine
Examples of Benzothiazepine calcium channel blockers
Diltiazem
Uses of Phenylalkylamine calcium channel blockers
Anti-arrhythmia
Uses of Dihydropyridine calcium channel blockers
Mainly cause arteriolar vasodilatation
Therefore used as antihypertensive and anti-anginal
Uses of Benzothiazepine calcium channel blockers
Affect peripheral and myocardial Ca2+ channels
Used more as anti-anginal
Side effects of calcium channel blockers
Headache
Flushing
Tachycardia
Postural hypotension
Ankle oedema
Antihypertensives which reduce blood volume (and have direct action on smooth muscle)
Diuretics - commonly thiazide diuretics
Thiazide diuretic mechanism of action
Lower dose - Activate potassium channels which cause hyperpolarisation and relaxation of smooth muscle cell
Higher dose - Inhibits Na+ and Cl- reabsorption in distal tubule of kidney
Initially CO drops but then recovers and SVR is reduced (possible due to low intracellular Na+)
Side effects of diuretics
Potassium depletion
Adverse effects on lipid metabolism
Antihypertensives affecting RAAS
ACE inhibitors
Angiotensin II receptor blockers
ACEi and ARB mechanism of action
Subgroups of ACEi / ARB and examples of each
Active drug - metabolised to active metabolites, e.g. Captopril
Pro drugs - activated in liver, e.g. Ramipril
Active drugs - excreted unchanged in urine, e.g. Lisinopril
Side effects of ACEi / ARB
Transient hypotension on initiation
Renal failure with renal artery stenosis +/- NSAIDs
Hyperkalaemia / Hyponatraemia with reduced aldosterone
Dry cough
Proteinuria
Angio-oedema
Bone marrow suppression - rare
Cause of dry cough with ACEi
Accumulation of bradykinin
Antihypertensives used for deliberate perioperative hypotension
GTN
Alpha 1 adrenoreceptor blockers
Beta adrenoreceptor blockers
Sodium nitroprusside - rare
Hydralazine - rare
Antihypertensives used for moderate hypertension in pregnancy
Oral treatment
Methyldopa
Labetalol
Nifedipine
Antihypertensives used for severe hypertension in pregnancy
Labetalol PO / IV
Nifedipine PO
Magnesium IV
Hydralazine IV
Antihypertensives used for essential hypertension
Potential anaesthetic side effect of nifedipine
Can reduce the MAC of volatile agents
