Alpha Blockers And Other Sympatholytics

Question 1

What are sympatholytics

Answer 1

All drugs that reduce ability of sympathetic nervous system to raise blood pressure

Question 2

Examples of sympatholytics

Answer 2

Alpha 1 adrenoreceptor antagonists
Alpha 2 adrenoreceptor agonists (acting in CNS?)
Beta adrenoreceptor antagonists (beta blockers)

Question 3

what is the definition of adrenoreceptor antagonists

Answer 3

Drugs which occupy adrenoreceptors and prevent the cation of endogenous catecholamines - adrenaline and noradrenaline

Question 4

Describe alpha adrenoreceptor antagonists

Answer 4

Non-selective (alpha 1 and alpha 2) - phentolaamine (competitive reversible); phenoxybenzamine (competitive irreversible)
Alpha 1 adrenoreceptor selective - prazosin, doxazosin; tamsulosin (alpha 1A selective)

Question 5

Alpha 1 adrenoreceptors prevent….

Answer 5

Vasoconstriction by noradrenaline

Question 6

Effects of noradrenaline are…..

Answer 6

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

Question 7

Describe the cardiovascular effects of alpha adrenoreceptor antagonists

Answer 7

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

Question 8

Describe the role of alpha1-adrenoreceptor antagonists in treatment of hypertension

Answer 8

> / 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

Question 9

Describe the clinical uses of alpha 1 adrenoreceptor antagonists

Answer 9

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

Question 10

Adverse effects of alpha1 adrenoreceptor antagonists

Answer 10

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)

Question 11

Describe why postural hypotension occurs after use of a1 adrenoreceptor antagonists

Answer 11

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

Question 12

Describe non-selective alpha-adrenoreceptor antagonists and examples

Answer 12

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

Question 13

Non-selective antagonists more likely to cause ….

Answer 13

Reflex tachycardia

Question 14

Describe a2 adrenoreceptor agonists and examples

Answer 14

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)

Question 15

Describe the action of a2 adrenoreceptor agonists

Answer 15

Decrease activity of CNS vasomotor centre (a2 adrenoreceptor or imidazoline receptor?)
Decreases sympathetic nerve activity
Decrease peripheral vascular resistance, lower HR, decreasing CO

Question 16

Pre-synaptic a2 adrenoreceptor agonist do what??

Answer 16

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)

Question 17

When to give clonidine?

Answer 17

Reserve treatment for hypertension if other drug combinations not tolerated or ineffective

Question 18

Adverse effects of clonidine

Answer 18

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)

Question 19

Describe alpha methyldopa and when it is useful

Answer 19

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)

Question 20

Describe the adverse effects of a-methyldopa

Answer 20

• sedation
• bradycardia
• postural hypotension (in elderly)
• dry mouth
• gastrointestinal disturbance
• myalgia
• depression
• liver damage (monitor)
• blood disorders (monitor)
• fever?

Question 21

Describe an overview of Imidazoline I1receptor agonists and examples

Answer 21

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

Question 22

Imidazoline favourable side effect profile?

Answer 22

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

Question 23

Imidazoline additional benefits ?

Answer 23

• ↓ 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

Question 24

Noradrenaline store-depleters and example

Answer 24

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

Question 25

Adrenergic neurone blockers and example

Answer 25

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

Question 26

Adverse effects of guanethidine and reserpine

Answer 26

• 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

Question 27

Ganglion blockers and example

Answer 27

Trimetaphan
Antagonise nicotinic cholinoceptors found in autonomic ganglia
Prevent transmission between pre and post ganglionic nerves [(para)sympathetic]
Decr CO, decr peripheral vascular resistance

Question 28

Adverse effects of ganglion blockers

Answer 28

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