Pharmacological Modulation of the ANS Flashcards
What are some clinical uses of cholinergic agonists? (Muscarinic and nicotinic)
Muscarinic agonists include:
Pilocarpine (mAchR) is used to treat glaucoma and dry mouth and also used in sweat test
Bethanechol (mAchR agonist) occasionally used to aid bladder/gastric emptying
Nicotinic agonists include:
Succinylcholine- a high affinity nAChR agonist used in surgery- depolarising paralysis
The reason why there’s not much use for nicotinic agonists is because they are located on all autonomic ganglia, the head and skeletal muscle (so too many places needs a highly selective drug)
What are some clinical uses of cholinesterase inhibitors?
Raising the level of endogenous acetylcholine
Agents such as tacrine, donepezil or rivastigmine used in:
Dementia (early stage usually Alzheimer’s)
Neuromuscular diseases such as myasthenia gravis or Eaton-lambert syndrome
What are some clinical uses of muscarinic blockers?
Premedication before anaesthesia to reduce secretions, sedation (hyoscine), prevent vagal effects
In heart block to increase AV conduction
Ophthalmology to produce mydriasis(unrepenting dilatation) for examination
Bronchodilatation in severe airways disease (ipratropium due to poor lipid solubility) but it will inhibit the cholinergic constriction of smooth muscle
Anti-spasmodic in GI colic
Antacid- pirenzepine- M1 selective
Treatment of antiChE poisoning
Motion sickness
What are some clinical uses of nicotinic blockers?
Muscle relaxants Direct nAChR blockers: Tubocurarine Pancuronium, vecuronium, atacurium Depolarising blockers therefore you get prolonged depolarisation of the membrane potential Direct nAChR agonists Suxamethonium
What are some uses of adrenergic agonists?
Along with an anaesthetic you might get given adrenaline in the place of administration
This is to constrict the blood vessels around that area so that the anaesthetic doesn’t travel anywhere else around the body for example the heart which would lead to an arrhythmia
What is the beneficial effect of beta1 blockers in cardiovascular disease?
Slow heart rate results in
Reduced demand for oxygen and nutrients
Reduced arrhythmia
You also get increased coronary perfusion because, as the heart fills with blood, the blood vessels trapped within the muscle mass get pinched together by the movement of the ventricle wall outwards, but the cardiac heart itself doesn’t expand
And so by slowing the heart rate down, the heart fills up less often and you get less narrowing of the blood vessels
What is beta1’s effect on the adrenoceptors (particularly around the kidneys and heart)?
Juxta glomerular apparatus (JGA)
Located between afferent and efferent renal arteries
Increase renin release
Transforms inactive angiotensinogen to angiotensin I which is active which is then converted into angiotensin II, a potent vasoconstrictor, by an enzyme.
Angiotensin II also increases water reabsorption so it increases circulating volume
What that does is it will increase the load against which the heart has to work so theres more blood swilling around which isn’t great if the heart is failing
So these Beta adrenoceptor blocker will offset these effects to some extent (though there are other triggers for renin release)
What is Timolol?
Another use of beta adrenoceptor blockers is eye drops such as timolol which will reduce the secretion of ocular fluid from the epithelial cells at the back of the eye
What are the main uses of alpha adrenoceptor blockers?
Phenoxybenzamine is a non-selective alpha blocker has been used to treat people with adrenal gland tumour who are pumping out lots of adrenaline
Alpha1a-selective was initially used to treat high blood pressure but now is more commonly used to treat men for urinary problems
What is benign prostatic hyperplasia and how is it treated?
This is where the prostate grows and becomes large and fibrotic and the prostate does have some smooth muscle in it and so it narrows the urethra causing:
Weak, slow urinary stream
A hesitancy and straining to urinate
Prolonged voiding
Dribbling at the end of urination
An inability to empty the bladder completely
An urgent sometimes uncontrollable need to void
Night time urination (nocturia)
Blocking alpha1-adrenergic receptors causes relaxation of smooth muscle in the bladder neck, urethra and prostate gland
How has the medication for benign prostatic hyperplasia changed over time?
1st generation- selective alpha blockers like prazosin offered the advantage over phenoxybenzamine
2nd- long-acting selective alpha 1 blockers like terazosin (HYTRIN) and doxazosin (CARDURA) offered the convenience of once a day dosing with better tolerability however both of these lead to a drop in systolic blood pressure and dizziness
3rd- Tamsulosin (FLOWMAX) achieved a therapeutic effect without the need for dose titration and with minimal effects on blood pressure.
Some preference for urinary alpha1 receptors (alpha1A selective? We don’t know yet)
Can cause ejaculatory dysfunction
4th- Alfuzosin (UROXATRAL) has comparable clinical efficacy with tamsulosin and the other approved alpha blockers but does not cause ejaculatory dysfunction
What substances can alter endogenous noradrenaline and how does it do this?
Indirectly acting chemicals which enhance endogenous noradrenaline therefor enhance sympathetic activity.
These are substances such as:
Cocaine
Amphetamine
And some monoamine oxidase inhibitors
There is this uptake mechanism that keeps the level of noradrenaline relatively brief
Cocaine (along with desipramine and imipramine which are early gen anti-depressant agents) inhibit the uptake mechanism directly
Amphetamine (along with Tyramine and Ephedrine) have a similar effect but they don’t inhibit the pump, they get taken up by it
This effectively competes with the noradrenaline to stop it being taken up
They can also displace the noradrenaline from the vesicles so that there’s more noradrenaline around
MOA Inhibitors, such as the anti-depressant Tranylcypromine, inhibit the enzymes that break down the noradrenaline
