Autonomic Drugs Flashcards
What acetylcholine receptor type innervates the ganglia of the ANS, including the adrenal medulla?
Nicotinic -> cuz we need fast conduction there
What effect do M3 receptors have on smooth muscle in general? What about the systemic circulation?
In general, M3 receptors contract via releasing intracellular calcium via the Gq pathway
However, M3 receptors also caused vasodilation / hypotension when they stimulate nitric oxide release (in the venous system). NO will increase cGMP which leads to decreased activity of MLCK.
How are sweat glands activated?
Via sympathetic postganglionics which actually release ACh on muscarinic receptors -> smooth muscle myoepithelial contraction
-> this is the reason why muscarinic blockade makes you hot as a hare
What is mechanism of action and primary indication of pilocarpine?
Muscarinic agonist
Treatment of acute and chronic glaucoma.
Chronic glaucoma - open angle - contraction of ciliary muscle (accommodation, zonular fibers of lens)
-> facilitates outflow of aqueous humor
Acute glaucoma - closed-angle - drug of choice - induces miosis by contracting sphincter pupillae muscle -> rapid relief of IOP
What are some other applications of pilocarpine than glaucoma?
Think of the pile of carp fish drooling - used to stimulate sweat, tear, and saliva production in patients with xerostomia (i.e. Sjogren syndrome).
What is the mechanism of action and use of carbachol?
Both a nicotinic and muscarinic agonist (think of the guy inhaling carbon fumes above the nicotinic smoker)
Used in the treatment of open-angle glaucoma by constricting pupil.
Is it physostigmine or pyridostigmine which is used for maintenance treatment of MG? Why? Which one is second line?
Pyridostigmine (pride). Physostigmine is the Phys Ed center and is a centrally acting tertiary AChE, which we don’t want!
Second line: Neon sign = Neostigmine
What three conditions do we worry about exacerbating with all cholinomimetic agents?
- COPD
- Asthma
- Peptic ulcer disease -> vagal stimulation of parietal cells and GRP-secreting cells
What is the most likely use of neostigmine and what is it given with?
Postoperative reversal of neuromuscular junction blockade (usually via curare’s i.e. pancuronium)
Quarternary amine like pyridostigmine. Given with atropine to prevent bradycardia (muscarinic blockade), but maintains activity at nicotinic junctions.
What does a negative tensilon test indicate?
Cholinergic crisis -> adding edrophonium did not relieve myasthenic symptoms, so the problem must be too much cholinergic stimulation at NMJ due to too much AChE-inhibitor
What indirect cholinomimetic is also used to treat post-op urinary retention like bethanecol?
Neostigmine - think of the neon-sign owning store owner with the hose.
What drug is used as the antidote for anticholinergic toxicity (i.e. atropine, Jimson weed)? Why can overdose of this antidote lead to weakness?
Physostigmine - since it’s centrally acting
Also causes FLACCID paralysis because increases ACh at the NMJ which can simulate depolarizing blockade of succinylcholine
Will obvious have other cholinergic side effects as well (DUMBELSS)
What is the mechanism of action of organophosphate poisoning and what is used for reversal?
They are acetylcholinesterase inhibitors -> increased ACh
Reversal: Atropine + Pralidoxime (give early before the bond becomes aged and pralidoxime will not be able to compete out the organophosphate -> regeneration of activity of AChE enzyme becomes impossible)
What is cycloplegia?
Inability to contract the ciliary muscle - cannot relax the lens to allow for accommodation
-> an antimuscarinic side effect
What Parkinsonian symptoms can be reduced by M1 receptor blockade? Give two therapeutic options for this purpose.
Tremor and rigidity (cogwheel rigidity in parking center sign) -> NOT useful for bradykinesia
- Benztropine
- Trihexyphenidyl
What sympathetic receptors are responsible for pupillary dilator muscle contraction? How about intestinal and bladder sphincter contraction?
Alpha1 - this is intuitive cuz it’s the only Gq receptor -> increases calcium and cause smooth muscle contraction
Urinary retention, constipation, as well as mydriasis will result
What do alpha2 receptors do to lipolysis?
They are inhibitory (Gi), so they inhibit lipolysis
What is one alpha2 agonist used in the treatment of glaucoma and what its mechanism of action?
Brimonidine -> decreases aqueous humor production
What effect do beta receptors have on aqueous humor production and why is this clinically relevant?
Increase aqueous humor production. Explains why beta blockers like timolol are used in the treatment of glaucoma
Why does the beta2 effect on insulin levels and gluconeogenesis make sense?
Beta2:
Gluconeogenesis - increased, mobilizing glucose for usage in fight or flight response
Increases insulin -> increases skeletal muscle sensitivity to insulin during fight or flight response, allowing glucose to get into skeletal muscles which need it
What is the mechanism of phenylephrine and why might ophthalmologists use it?
Pure alpha1 agonist -> used by ophthalmologists to constract pupillary dilator muscle
Also used to treat nasal congestion.
What type of shock is septic shock an example of and what is one pressor agent which would be good to treat it?
Distributive shock (hypotension)
Phenylephrine will help -> increases systemic vascular resistance -> raises systolic and diastolic BPs.
What receptors does dobutamine stimulate?
Beta1 > Beta2
Causes increased contractility but beta2 effects will decrease SVR -> decreased diastolic BP.
What drug is used for cardiac stress testing in those who can’t tolerate exercise?
Dobutamine -> increases myocardial oxygen consumption and can show areas of cardiac ischemia due to post-test decreases in function vs baseline.
Why is epinephrine super good for anaphylactic shock?
Strong beta2 effect -> good for bronchodilation (norepinephrine has no beta2 effects)
At high doses, alpha1 effects will predominate -> good for maintaining blood pressure.
What is the mechanism of action of metyrosine?
Me-Tyrosine - mimics tyrosine and competitive inhibitor of tyrosine hydroxylase
Was once used to treat blood pressure, but is no longer used in medicine.
What is the mechanism of action of cocaine? How does this relate to effects?
Inhibitor of NET and DAT
NET inhibition - sympathetic effects of tachycardia, mydriasis, hypertension
DAT inhibition - increases central dopamine -> arousal, addiction, seizures
What is the mechanism of action of atomoxetine and its clinical usage?
NET inhibitor -> remember it was developed for depression but fails since it wasn’t an SNRI
Used for treatment of ADHD
Think of the guy watching an Atom on TV
What does VMAT-2 transport and what blocks it?
Vesicular monoamine transporter
-> transporters dopamine into vesicles (which will be made into NE/E within the vesicles) or NE, E, and 5-HT which were recycled from the synapse -> remake vesicles storing neurotransmitters.
Blocked by RESERPINE - think of the snake on the VMAT inhibiting catecholamine catfish from being transferred to the boat (vesicle)
What is the mechanism of action of amphetamines?
Overall an indirect catecholamine agonist, acting as a reuptake inhibitor and releaser of stored catecholamines
They compete with VMAT to release stored catecholamines from vesicles, and also reverse NET/DAT to pour catecholamines out (reverse flux thru reuptake transporters).
What are the indications for amphetamines?
Think of the kid sitting in the boat watching TV - ADHD
Guy sleeping on the boat - Narcolepsy
What is the mechanism of action of methylphenidate and its indication?
This is ritalin - same as amphetamine. Indication is for ADHD
What is the other stimulate used for the treatment of narcolepsy which has fewer adverse effects?
Modafinil - think “sleep mode”
mechanism unknown, but it’s in the indirect sympathomimetic sketchy
How do you remember which G-protein is coupled to D1/D2 receptors? What does stimulation of D1 receptors in terms of blood flow?
think of the dopamine rope swing
SwIng:
D1 = S
D2 = I
Stimulation of D1 receptors improves renal perfusion (Gs effect -> increases cAMP -> relaxation of arteries. Similar to Beta2 mechanism).
What are the indications of clonidine?
- Tourette syndrome
- ADHD - looking in the mirror
- Hypertensive urgency - emergency without endo organ damage
What is the side effect to be aware of for alpha-methyldopa?
Drug-induced SLE syndrome -> think of the lady and the wolf next to the alpha-methyl-ropa.
What is the mechanism of action of tyramine similar to?
Similar to amphetamines - causes catecholamine release from nerve terminals
Found in aged cheeses / wines
What are some of the uses of phentolamine?
This is the reversible alpha1/alpha2 antagonist
- Cocaine overdose - prevents vasospasm and hypertensive crisis
- Tyramine hypertensive crisis - prevents alpha-1 mediated constriction similarly
- Extravasation of norepinephrine from injection site - prevents dermal necrosis
- INTRAoperative treatment of pheochromocytoma for BP stabilization - should use phenoxybenazamine (irreversible) before surgery
What is the side effect of most alpha1 blockers and what is their general indication, especially tamsulosin?
Orthostatic hypotension, especially first dose - from alpha1 blockade
Indication is for hypertension and urinary symptoms of BPH -> relaxes a1-mediated smooth muscle contraction which causes urinary retention
What is prazosin used for?
Known for its use in PTSD (think of the praying opera singer with PTSD dog tags)
-> good for treatment of nightmares and sleep disturabnce
How does mirtazapine work?
It is a treatment for depression which works as an alpha-2 ANTAGONIST
- > increases sympathetic outflow, including norepinephrine / serotonin release
- > basically the opposite of clonidine which centrally decreases sympathetic outflow
Why does treatment of aortic dissection differ from hypertensive emergency?
Hypertensive emergency - want to very slowly drop blood pressure since organs have become accustomed to high BP
Aortic dissection - want to rapidly drop BP to between 100-120 systolic since it’s so urgent to bring the BP down
Why are beta blockers used in hypertrophic cardiomyopathy?
Increase diastolic filling time and thus preload -> reducing LVOTO during pumping
What are the two beta blockers with partial agonist activity? Contraindication?
- Acebutolol - “bugle” - part of ABEAM - cardioselective alpha1 blockade
- Pindolol - boy with pin - nonselective beta blocker
Contraindicated in heart failure or MI due to cardiac stimulation -> think of boy putting pins into the balloon
What are the beta blockers specifically shown to decrease mortality in heart failure?
- Carvedilol (some alpha-1 blockade as well)
- Bisprolol
- Metoprolol
-> due to reduction in cardiac remodelling
What is the treatment for beta-blocker excessive heartblock?
Glucagon -> increases cAMP
Mechanism of Labetalol? Uses?
Nonselective alpha/beta blockade
-> can treat hypertensive emergency, and good in pregnancy
What are the symptoms of atropine overdose which help you differentiate it from cocaine overdose?
Blurred vision (Cycloplegia) and intense thirst (hot as a hare) -> remember that atropine overdose can still present with hallucinations / confusion due to anticholinergic effects in the brain #6483
