8. SNS agonists/antagonists Flashcards
Where are sympathetic adrenoceptors found and how can they be activated (2 ways)?
- Ends of sympathetic nerves
* Nervous (NA) and hormonal (adrenaline)
What do SNS agonists mimic the action of?
NA and adrenaline
What is the the predominant effect of sympathetic adrenoceptor stimulation in blood vessels?
Vasoconstriction due to α1 receptors
Which receptors are NA and adrenaline more selective for?
- NA is slightly more alpha selective
* Adrenaline is slightly more beta selective
Where is NA derived from?
- Tyrosine in the diet
* Tyrosine => DOPA => Dopamine => NA
Describe the α2 receptor
- Pre-junctional receptor
- Found on the neurone itself
- NA released acts back on α2, diminishing sympathetic effects - negative feedback
Give examples of directly acting SNS agonists
- Adrenaline (non-selective)
- Phenylephrine (α1)
- Clonidine (α2)
- Dobutamine (β1)
- Salbutamol (β2)
What happens in anaphylaxis?
• Sensitivity to innocuous (harmless) antigen
- recognition by mast cells with IgG antibodies
- mast cell degranulation
- histamine release
- bronchoconstriction + vasodilation
Why do we give adrenaline to treat anaphylaxis?
- β2 - bronchodilation
- β1 - tachycardia
- α1 - vasoconstriction
Why can adrenaline be known as a physiological antagonist?
• Doesn’t actually bind to a receptor to produce a opposing effect (histamine receptor in this case)
• Ultimately produces a response to reverse effects of histamine
- reverses bronchoconstriction and increases HR and CO
- suppression of mediator release - adrenaline stops degranulation
What are the clinical uses of adrenaline (apart from anaphylaxis)?
- β2 - asthma (emergencies - IM or subcutaneous), acute bronchospasm associated with COPD
- β1 - cardiogenic shock - sudden inability of heart to pump sufficient blood
- α1 - spinal anaethesia (maintain BP before surgery), local anaesthesia (vasoconstriction prolongs action of anaesthetic)
What are the unwanted effects of adrenaline?
- Reduced and thickened mucous
- Tachycardia, palpitations, arrhythmias
- Cold extremities, hypertension
- Overdose - cerebral haemorrhage, pulmonary oedema
- Minimal GIT effects due to parasympathetic control
- Tremor
What is phenylephrine?
- Selective α1-adrenergic receptor agonist related to adrenaline
- Very alpha selective (α1 > α2»_space; β1/2)
- More resistant to breakdown by COMT, but not MAO (compared to NA/A)
- Very good nasal decongestant - α1-mediated vasoconstriction
- Mydriatic - induces dilation of pupil for examination of the back of the eye
What is clonidine?
• Selective α2-adrenergic receptor agonist
• α2 > α1»_space; β1/2
- negative feedback effect
- decreases sympathetic function
• Is a receptor agonist, even though it has an opposing effect
Why is clonidine used to treat glaucoma?
• Glaucoma - increased intraocular pressure
• Poor drainage of aqueous humour by the venous system
• Optic nerve can be permanently damaged - blindness
• Clonidine stimulates the α2-adrenoceptors on the ciliary body, reducing aqueous humour production
(• Stimulating α1-adrenoceptors can also help - vasoconstriction reduces blood supply to ciliary body, reducing AH production)
What can clonidine be used to treat (apart from glaucoma)?
- Hypertension and migraine
* Reduces activation of heart, reduces renin production, reduces overall renin production
What is isoprenaline?
- Beta selective (β1 = β2»_space; α1 = α2)
- Related to adrenaline
- More resistant to MAO and uptake 1 - prolonged action
- Used for cardiogenic shock, acute heart failure and MI
Why might β2-adrenoceptor stimulation be a problem?
- Dilation of blood vessels in the muscles
- Pooling of blood
- Decreased venous return
- Fall in venous bP
- Stimulated baroreceptors
- Reflex tachycardia triggered
- Arrhythmias can be exacerbated - negatively impacts effective functioning of the heart
Why is dobutamine better than isoprenaline?
- More β1 selective than isoprenaline
- Less worry about reflex tachycardia arising
(however it has a half-life of 2 minutes as it’s rapidly metabolised by COMT)
What is salbutamol?
- Synthetic catecholamine derivative with relative resistance to MAO and COMT
- Much more β2 selective than other drugs - relaxation of bronchial smooth muscle
- Decreased PI (type of lipids) hydrolysis
- Increased Na/Ca exchange
- Opens K+ channels
What are the clinical uses of salbutamol?
• Treatment of asthma (localised effect)
- relaxed bronchial smooth muscle
- inhibition of release of bronchoconstrictor substances from mast cells
• Treatment of threatened premature labour
- relaxation of uterine smooth muscle
- prevents abortion of a foetus
What are the side-effects of salbutamol?
- Reflex tachycardia
- Tremor
- Blood sugar dysregulation
What does stimulation of β1-adrenoceptors result in, in the kidneys?
Renin release
Describe the selectivity for carvedilol
- Non-selective adrenoceptor antagonist (α1, β1, β2)
* α1 blockade gives additional vasodilator properties
Describe the selectivity for phentolamine and propanolol
- Phentolamine - α1 + α2 antagonist (non-selective for α)
* Propanolol - β1 + β2 antagonist (non-selective for β)
Describe the selectivity for prazosin and atenolol
- Prazosin - α1
* Atenolol - β1 (more so than β2)
Describe the selectivity for nebivolol
- Selective for β1
* Also potentiates NO
Describe the selectivity for sotalol
- β1 + β2
* Also inhibits K+ channels
What are the main clinical uses of SNS antagonists
Same as SNS agonists (hypertension, arrhythmias, glaucoma etc.)
Why are beta-blockers useful in treating hypertension, with reference to the adrenoceptors?
- Heart (β1) to reduce HR and CO (effect disappears in chronic treatment)
- Kidney (β1) to reduce renin production
- β2 antagonism may be important - but what extent is not clear
- β1 + β2 antagonism in CNS as this determines the BP set point - reduces sympathetic tone
What is the significance of bronchoconstriction as a side effect of beta-blockers?
- Little importance in the absence of airways disease
- Can be dramatic and life-threatening in asthmatics
- Also clinical importance in patients with COPD
What is the effect of beta-blockers on hypoglycaemia?
• Masks the symptoms of hypoglycaemia (sweating, palpitations, tremor)
• Also block the β2-adrenoceptor-driven breakdown of glycogen => less glucose
- β1-selective agent have advantages
Why can beta-blockers cause fatigue and cold extremities?
- Fatigue - reduced CO and skeletal muscle perfusion due to β2-blockade on vasculature
- Cold extremities - loss of β-adrenoceptor mediated vasodilation in cutaneous vessels
What is the advantage of atenolol over propanolol?
- Atenolol is β1-selective, rather than non-selective for β
- Still antagonises the effects of NA on the heart
- Less of an effect on airways (still not safe with asthmatics)
- Less side effects
(selectivity is concentration dependent)
What is the advantage of carvedilol over atenolol and propanolol?
- Acts on α1 as well as β
- α1 blockade - additional vasodilator properties
- Still works more on β1 than α1
- Lowers bP via reduction in TPR
- Induces change in HR/CO like other drugs, but effect wanes with chronic use
- Therefore, it’s a better anti-hypertensive drug, but has more side effects
What type of receptors are α1 and α2?
- α1 - Gq-linked (PLC => increased [intracellular Ca])
* α2 - Gi-linked (decreased cAMP => decreased NA release)
What is phentolamine?
- Non-selective α-blocker
- Vasodilation (α1) - fall in BP
- Increase in NA (α2 - reduced reuptake)
- Used to treat pheochromocytoma-induced hypertension
- Increased GIT motility - diarrhoea
What are the negative CV effects of α-blockers?
- Fall in TPR + BP => postural hypotension
* Reflex response - CO/HR increases - baroreceptor mediated tachycardia
Why do α2 receptors and baroreceptors reduce the effectiveness of phentolamine?
- Blockade of α2 => loss of negative feedback + increased NA
- NA competes with phentolamine for α1
- Baroreceptor reflex reduces effectiveness too
Describe the effect of prazosin
- α1-adrenoceptor antagonist
- Vasodilation and fall in arterial pressure
- CO decreases due to fall in venous pressure
- Dramatic hypotensive effect (better than phentolamine as α2 feedback is still intact)
- Doesn’t affect cardiac function appreciably
- Also causes decreased LDL and increased HDL
What is methyldopa and how does it work?
- Anti-hypertensive drug
- Taken up by noradrenergic neurones - decarboxylated and hydroxylated to form false transmitter - α-methyl noradrenaline
- Not deaminated by MAO - accumulates >NA
- Displaces NA from synaptic vesicles - released same way as NA
- Less active than NA on α1 - less effective at vasoconstriction
- More active on α2 - auto-inhibitory feedback stronger - reduces NA
- CNS effects - stimulates vasopressor centre in brainstem to inhibit sympathetic flow
Apart from it’s main use, what are the other effects of methyldopa, and what are the adverse effects?
- Used in renal insufficiency or cerebrovascular disease
- Recommended anti-hypertensive in pregnant women - no adverse on foetus despite crossing the blood-placenta barrier
• Dry mouth, sedation, orthostatic hypotension, male sexual dysfunction
How do Class II Antiarrhythmics work?
- Increase in sympathetic drive to the heart via β1 can precipitate or aggravate arrhythmias
- Increase in sympathetic tone, particularly after MI
- Beta-blockers increase the refractory period of the AV nodes
- Interferes with AV conduction in atrial tachycardias and slows down ventricular rate
- An unusual re-entry type electrical activity in damaged tissue won’t stimulate another heart beat
What is angina?
- Pain that occurs when oxygen supply to the myocardium is insufficient for its needs
- Distributed across chest, arm and aneck
What is stable angina?
- Pain on exertion
- Due to a fixed narrowing of the coronary vessels e.g. atheroma
- Increased demand on the heart
What is unstable angina?
- Pain with less and less exertion, culminating with pain at rest
- e.g. atheromatous plaque starting to rupture
- Platelet-fibrin thrombus associated with the ruptured atheromatous plaque - but without complete occlusion
- High risk of infarction
What is variable angina?
- Occurs at rest
- Coronary artery spasm
- Associated with atheromatous disease
How do beta-blockers help with angina?
- Decrease HR, SBP and cardiac contractile activity
- β1-selective antagonists (metoprolol) can do this without affecting bronchial smooth muscle at low doses
- Beta-blockers reduce oxygen demand (of heart) whilst maintaining same degree of effort
What are the adverse effects of meoprolol (for angina)?
- Fatigue
- Insomnia
- Dizziness
- Sexual dysfunction
- Bradycardia
- Hypotension
- Bronchospasm
How do drugs that act on β-adrenoceptors treat glaucoma?
- Aqueous humour is produced via carbonic anhydrase
- Beta-blockers e.g. carteolol hydrochloride affects the action of carbonic anhydrase
- Reduces the rate of AH production
What can beta-blockers be used to treat other than hypertension, cardiac problems and glaucoma?
- Anxiety - controls somatic symptoms associated with sympathetic over-reactivity e.g. palpitations and tremor
- Migraine prophylaxis - maintains good blood supply within CNS
- Benign essential tremor
