Alpha Blockers And Other Sympatholytics Flashcards
What are sympatholytics
All drugs that reduce ability of sympathetic nervous system to raise blood pressure
Examples of sympatholytics
Alpha 1 adrenoreceptor antagonists
Alpha 2 adrenoreceptor agonists (acting in CNS?)
Beta adrenoreceptor antagonists (beta blockers)
what is the definition of adrenoreceptor antagonists
Drugs which occupy adrenoreceptors and prevent the cation of endogenous catecholamines - adrenaline and noradrenaline
Describe alpha adrenoreceptor antagonists
Non-selective (alpha 1 and alpha 2) - phentolaamine (competitive reversible); phenoxybenzamine (competitive irreversible)
Alpha 1 adrenoreceptor selective - prazosin, doxazosin; tamsulosin (alpha 1A selective)
Alpha 1 adrenoreceptors prevent….
Vasoconstriction by noradrenaline
Effects of noradrenaline are…..
Further reduced by negative feedback since pre-synaptic a2 adrenoreceptors are not blocked and can still be occupied by noradrenaline to activate a negative feedback pathway
Describe the cardiovascular effects of alpha adrenoreceptor antagonists
Reduce peripheral vascular resistance - postsynaptic a1 adrenoreceptors especially on smaller arteries/arterioles
Rebound increase in HR, cardiac work and oxygen demand - due to sympathetic activation and beta adrenoreceptor stimulation; less marked for a1-selective antagonists since -ve feedback (a2-mediated action) on noradrenaline release intact
Describe the role of alpha1-adrenoreceptor antagonists in treatment of hypertension
> / efficacy to other classes as 1st line mono therapy?
Decreased LV hypertrophy and target organ damage?
Favourable effects on plasma lipid profile - decreased coronary atherosclerotic risk - minor clinical benefit?
Little long term outcome data available - ALLHAT doxazosin raises new onset heart failure? Recent studies support safety of a blockers
Describe the clinical uses of alpha 1 adrenoreceptor antagonists
Not routinely used for management of hypertension - clinical use limited de to adverse effects, poor tolerability
For hypertension secondary to pheochromocytoma
Relieve urinary retention in prostate hyperplasia - blockade of alpha 1A adrenoreceptor-mediated contraction of bladder sphincter
Adverse effects of alpha1 adrenoreceptor antagonists
Postural hypotension, dizziness and fainting
Headache (dilation of meninges vessels)
Nasal congestion (due to dilation of nasal mucosal arterioles and venous capacitance vessels)
Stress incontinence (relaxation of bladder sphincter due t alpha 1A blockade)
Describe why postural hypotension occurs after use of a1 adrenoreceptor antagonists
Loss of reflex activation of a1 adrenoreceptor mediated venoconstriction (needed to ensure adequate return of blood to heart to maintain CO)
Loss of reflex vasoconstriction of arteries (needed to maintain BP and blood flow to cerebral arteries)
Especially in elderly and in combination with other vasodilators
Give first dose in evening
Describe non-selective alpha-adrenoreceptor antagonists and examples
Phenoxybenzamine, phentolamine
Often used (with beta blockers) in treatment of secondary hypertension due to pheochromocytoma prior to and during surgery or if surgery not possible
Non-selective antagonists more likely to cause reflex tachycardia
Non-selective antagonists more likely to cause ….
Reflex tachycardia
Describe a2 adrenoreceptor agonists and examples
Clonidine; alpha-methyldopa
Mimic auto-inhibitory effects of noradrenaline on sympathetic activity (stimulation of alpha 2 adrenoreceptor?)
Action predominantly in CNS?
Do not produce sympathomimetic effects (selective for a2 adrenoreceptor relative to a1, b)
Describe the action of a2 adrenoreceptor agonists
Decrease activity of CNS vasomotor centre (a2 adrenoreceptor or imidazoline receptor?)
Decreases sympathetic nerve activity
Decrease peripheral vascular resistance, lower HR, decreasing CO
Pre-synaptic a2 adrenoreceptor agonist do what??
Prevent release of noradrenaline from nerve terminals resulting in reduced stimulation of post-synaptic adrenoreceptors (a1 which mediates vasoconstriction of BVs and B1 which mediates tachycardia in the heart)
When to give clonidine?
Reserve treatment for hypertension if other drug combinations not tolerated or ineffective
Adverse effects of clonidine
Dry mouth
Nausea
Constipation
postural hypotension and dizziness (elderly)
bradycardia
drowsiness (impairs driving)
short-duration of action, rapid rebound hypertension on sudden withdrawal (accompanied by tachycardia, restlessness, sweating)
Describe alpha methyldopa and when it is useful
Undergoes conversion to alpha methylnoradrenaline (a2 selective adrenoreceptor agonist)
Less widely used than previously
Useful for: hypertension with renal insufficiency; hypertension with cerebrovascular disease; hypertension in pregnancy (relatively safe)
Describe the adverse effects of a-methyldopa
• sedation
• bradycardia
• postural hypotension (in elderly)
• dry mouth
• gastrointestinal disturbance
• myalgia
• depression
• liver damage (monitor)
• blood disorders (monitor)
• fever?
Describe an overview of Imidazoline I1receptor agonists and examples
Moxonidine, rilmenidine
I1 receptors present in rostral ventrolateral medulla of brainstem (also adrenal medulla, kidney)
- decrease sympathetic outflow from the brain; decrease peripheral vascular resistance and heart rate
Imidazoline favourable side effect profile?
I1 to a2 selectivity>clonidine
Decr a2 mediated side effects - sedation, dry mouth
Lowered risk of rebound hypertension on withdrawal
Low incidence of idiosyncratic side effects
Awaiting prospective morbidity/mortality data
Imidazoline additional benefits ?
• ↓ BP efficacy = ACE inhibitors
• effect persists > than predicted by T½ (2 hours) – retention of drug in CNS?
• ↓ renin levels (↓ sympathetic input)
• ↓insulin resistance ↓ blood glucose
• protect against cardiac/renal damage, remodelling
Currently for mild/moderate hypertension if other drugs not tolerated, contra-indicated or ineffective
Noradrenaline store-depleters and example
Reserpine
• transported into sympathetic nerve terminal via noradrenaline uptake 1
• inhibits Mg-ATP-dependent noradrenaline pump on storage vesicles in neuronal cytoplasm
• slowly depletes noradrenaline content of storage vesicles, decrease noradrenaline release
• lower cardiac output , lower peripheral vascular resistance
Adrenergic neurone blockers and example
Guanethidine
• transported into sympathetic nerve terminal via noradrenaline uptake 1
– competes for uptake into storage vesicles
– binds to neurolemma, decr fusion between storage vesicles / membrane surface
• decr release of noradrenaline
• decr cardiac output, decr peripheral vascular resistance
Adverse effects of guanethidine and reserpine
• generalised blockade of sympathetic neurotransmission
• postural hypotension
– loss of reflex sympathetic vasoconstriction of arteries and veins
• reserpine- severe psychological depression?
• superseded by safer drugs
• rarely used
– severe hypertension unresponsive to other treatments
– hypertensive crisis
Ganglion blockers and example
Trimetaphan
Antagonise nicotinic cholinoceptors found in autonomic ganglia
Prevent transmission between pre and post ganglionic nerves [(para)sympathetic]
Decr CO, decr peripheral vascular resistance
Adverse effects of ganglion blockers
Very severe
General antagonism of ANS - consitpation, dry mouth etc
Rarely used except in surgical emergencies - repair of aortic aneurysm
Unsuitable for long-term use
