ACEM Primary
Pharmacology of medications affecting the autonomic nervous system
Sympathetic nervous system
| Receptor | Main sites | Agonist | Antagonist |
| a1 Gq protein coupled = increased IP3/DAG Stimulated by DA at high doses. | Vascular smooth muscle (arterial and venous vasoconstriction) Reduce blood flow to kidneys, GIT Prostate, bladder base and urethral sphincter – contraction, continence Dilator pupillae – mydriasis and outflow aqueous humour Gonads – male prostate contraction/ ejaculation and female uterine contractions Skin – piloerection Heart – increased contractility | Direct Phenylephrine (a1>a2 >>>b) not inactivated by COMT longer duration of action than catecholamines Mydriatic, decongestant, raise BP. Decreases HR due to vagal reflex Norepinephrine (a1=a2, b1>>b2) Midodrine treatment of orthostatic hypotension Ephedrine mixed acting Indirect Meth/amphetamine (similar ephedrine) Phenmetrazine Methylphenidate (ADHD tx) Modafinil (narcolepsy tx) increases synaptic concentration of NE/ DA/ 5HT3/ glutamate Tyramine (similar to NE) intensified in patients on MAO-I = avoid high tyramine containing foods Atomoxetine (Reduced reuptake of NE) Duloxetine (Reduced reuptake NE/ 5HT) Cocaine | Prazosin, doxazosin (a1 >>>a2) lower BPHTN, BPH tx Phenoxybenzamine (a1>a2) Irreversible blockade = long duration >1 day Lowers BP and increases HR due to baroreflex activation Phaeochromocytoma tx AE: orthostatic hypotension, nasal stuffiness, inhibition of ejaculation Phentolamine (a1= a2) reversible blockade, t ½ 45 mins Cardiac stimulation due to a2 antagonism-> enhanced NE release-> severe tachycardia, arrythmias, MI Tamsulosin high affinity for a1A and D = contracts vascular smooth muscle in prostrate AE orthostatic hypotension |
| a2 Gi protein = decreased cAMP and PKA activity, K+ efflux | Pancreas – stimulate glucagon release Platelets – aggregation Axon terminals – reuptake NE Adipose – inhibits lipolysis Renal – inhibits renin | Direct Clonidine systemic, inhibition of sympathetic tone and reduced BP a2>a1 >>>b AE sedation Methyldopa Dexmedetomidine Sedation in ICU/ anaesthetics Oxymetazoline Local vasoconstriction for decongestant | Yohimbine (a2 >> a1) increased SNS activity and NE release Raises BP, HR Tx male erectile dysfunction |
| b1 Gs protein = Increased cAMP and PKA activity Stimulated by DA at low doses. | Heart – increase HR (inotropy) + contractility (chronotropy) + conduction velocity through nodes (dromotropy) Kidney – JGA, renin release for RAAS | Direct Epinephrine (a1=a2, b1=b2) Initial rise in SBP due to b1 then fall due to b2 Isoprenaline (b1=b2 >>>a) Dobutamine (b1>b2>>>a) positive ino/chronotrope activation a1 thus TPR does not fall significantly used in cardiac stress test | Labetalol, carvedilol (mixed, b1= b2, > a1) Propranolol, timolol (non-selective, b1=b2) Metoprolol, atenolol, esmolol, nebivolol (selective, b1 >> b2) Tx IHD to decrease cardiac oxygen demand, arrhythmias, CCF, hyperthyroidism |
| b2 Same as b1 | Lungs – bronchodilation, inhibition mast cells Relaxes smooth muscle (vasodilation, decreased motility in G/ GU, ciliary muscle for far vision) Liver – gluconeogenesis, glycogenolysis Salivary glands – mucinous secretions Skeletal muscle – promotes K uptake | Direct Isoprenaline(b1=b2 >>>a) Positive ino/chronotropy Potent vasodilator Net effect = increase systolic, decrease diastolic thus decrease MAP Salbutamol (b2>b1>>>a) | Timolol (glaucoma) Decrease production of aqueous humour and reduce IOP Butoxamine (b2 >> b1) |
| b3 Same as b1 | Adipose – lipolysis Detrusor muscle – relax | Mirabegron – Urinary urgency tx | |
| D1 Stimulates AC = cAMP | Smooth muscle – vasodilation renal, splanchnic, coronary, cerebral vessels | Levodopa (PD, hyperprolactinaemia) Fenoldopam (severe HTN) | |
| D2 Inhibits AC = Reduced cAMP and K+ efflux | Axon terminals – suppresses NE release | Bromocriptine (PD, hyperprolactinaemia) |
Sweat glands
Apocrine sweat glands (axillary/ perineal regions) – adrenergic sympathetic innervation-> NE
Eccrine sweat glands (throughout body) – thermoregulatory function: short preganglionic cholinergic fibre (thoracolumbar region) release Ach on nicotinic R of long post ganglionic neuron-> postganglionic neuron release Ach on muscarinic R of effector organ
Eye
- Dilator pupillae contraction via a1 = open pupil (mydriasis) + outflow of aqueous humour
- a2 = Reduced aqueous humour secretion (brimonidine)
- Ciliaris muscle
- relaxation via b2 to flatten lens (far vision) + secretion aqueous humour from ciliary epithelium (blocked via topical timolol)
- contraction via M3 to make globular lens (near vision) + outflow (stimulated by pilocarpine)
- Sphincter pupillae contraction via Ach on M3 R
- Aqueous humour/ IOP reduced via b antagonist/ a agonist
- Topical prostaglandins = outflow (latanoprost)
Horner’s syndrome
- Interruption of sympathetic nerves to face = vasodilation, ptosis, miosis, anhidrosis
- Location of lesion:
- Preganglionic
- Localised nerve damage but postganglionic nerve intact thus responsive to indirect sympathomimetics
- Postganglionic
- Loss of stored catecholamines, no response to indirect sympathomimetics
- Preganglionic
- Differentiation: Administration of indirect sympathomimetic to iris:
- Preganglionic lesion-> normal response, mydriasis
- Postganglionic lesion-> abnormal response, remain constriction. Will dilate to direct sympathomimetics as R are intact
Receptor: Direct vs. Indirect
- Direct = NE/E directly onto adrenoR
- Indirect =
- Displace stored catecholamine from adrenergic nerve ending (tyramine)
- Reduce clearance of released catecholamine by:
- Reduced reuptake (cocaine, TCA)
- Increased enzymatic metabolism (MAO I)
Receptor regulation
- Not all fixed and static, regulated by catecholamines, hormones, drugs, age and disease states
- Desensitization (tolerance, tachyphylaxis, refractoriness) = decreased response to agonist stimulation after prolonged exposure. Two types:
- Homologous – loss of responsiveness of receptors exposed to repeated or sustained activation by agonist
- Adrenoceptor + agonist = substrates for kinases-> phosphorylation, increased affinity for arrestin, binds to adrenoceptor-> decreased capacity to activate adrenoceptor. Binds clarithrin-> endocytosis of receptor
- Heterologous – desensitisation of one receptor by its agonist also results in desensitisation of another receptor that has not directly been activated by agonist in question
- Homologous – loss of responsiveness of receptors exposed to repeated or sustained activation by agonist
Parasympathetic nervous system
Cholinergic R:
- Nicotinic R (ligand gated ion channels)
- Nn = neurons of CNS, autonomic ganglia
- presynaptic neuron releases Ach onto Nn R = Na+ IN-> voltage gated ion channels open-> excitatory postsynaptic potential (EPSE)
- Nm = NMJ of skeletal muscles
- Ventral dorsal horn motor neuron releases Ach onto Nm R = Na+ IN, K+ OUT -> motor end plate potential-> opens voltage gated Na+ channel-> AP
- Nn = neurons of CNS, autonomic ganglia
- Muscarinic (G protein coupled “serpentine” R)
- M1,3, 5 = stimulate via Gq-> activates PLC-> IP3/ DAG-> activation of PKC + calcium kinases
- M2,4 = inhibit via Gi-> decrease activity of AC, ¯ PKA and promote K+ efflux
Cholinesterase inhibitors:
- Actions depend on lipid solubility-> CNS effects
- CNS = low doses cause alerting response, then seizures/ coma at higher doses
- NMJ = low doses causing prolong and intensify Ach action, then fibrillation of muscle fibers/ fasciculations
| Receptor | Main sites | Agonist | Antagonist |
| Nn | CNS, autonomic ganglia play role in memory, arousal, analgesia and cognitive function | Nicotine direct acting activates post ganglionic neurons and skeletal muscle end platesused for smoking cessation Varenicline = partial agonist | |
| Nm | Skeletal muscle NMJ | ||
| M1 (Gq) | CNS Parietal cells of stomach-> HCl release | Bethanechol direct acting choline estermuscarinic agonist at M1/2/3 (does not enter CNS) Negligible effect at nicotinic R Increased secretion, smooth muscle contraction and changes in HR Used for post op neurogenic ileus and bladder retention Pilocarpine direct acting muscarinic synthetic partial agonistUsed for glaucoma, Sjogren’s syndrome Cholinesterase inhibitors: Indirect acting Short acting (alcohol) = Edrophonium binds to acetylcholinesterase site, prevents binding of Ach amplifies all Ach activity Used in myasthenia gravis Does not enter CNS Immediate acting (carbamates) = Neostigmine (0.5-4 hours) Binds with AChE, but hydrolysed and released Used for MG, urinary retention and post op ileus Reversal of NM blockers. Does not enter CNS Pyridostigmine longer acting 4-6 hours Tx MG Physostigmine action duration 0.5-2 hours Enters CNS Tx anti- cholinergic toxicity or anti-muscarinic drug intoxication via atropine or TCA Long acting (organophosphates) = Echothiophate (100 hours) Enters CNS Not used clinically Malathion/ parathion (insecticides) Sarin “nerve gas” (warfare) | Scopolamine: motion sickness Dicyclomine, hyoscine, glycopyrrolate: M3 antagonism decrease smooth muscle and secretions from gut Tx IBS, diarrhoea, palliative care Atropine (topical) – blocks all M R Mydriasis and weakened contraction of ciliaris = cycloplegia (long 5-6 days) Reduced lacrimal secretion Ocular for retinal examination Alternatives: Homatropine (shorter 12-24 hours) Cyclopentolate (3-6 hours) Tropicamide (15-60 min) Atropine (IV) = tertiary amine, t ½ 2 hours (rapid phase) – 13 hours (slow phase) enters CNS Effect on PSNS function rapidly declines in all organs EXCEPT eye, where it lasts for >72 hrsBlockade causes reduced vagal tone to heart, increase HR at high dose Low dose results in bradycardia Suppresses thermoregulatory sweating via eccrine glands-> fever Blockade can be overcome by larger conc Ach or muscarinic agonist 60% unchanged drug excreted in urine Ipratropium, tiotropium: antagonism all M R bronchodilation, prevents spasm. Tx asthma, COPD Oxybutynin: M3 antagonist Reduces detrusor muscle tone for urinary incontinence Cholinergic poisoning: mushrooms Atropine (parenteral) blocks all M R in CNS and peripheries. Blocks muscarinic excess at exocrine glands, heart, smooth muscle Pralidoxime (IV) Does not enter CNS Regenerates active AChE-> relieve skeletal muscle and plate block |
| M2 (Gi) | Heart negative ino/ chrono/ dromotropy increase refractory period of AV node Presynaptic membrane | ||
| M3 (Gq) | Gastric glands Exocrine glands lacrimal, salivary, sweat, bronchial pancreas Smooth muscle bronchoconstriction peristalsis GI Bladder detrusor contraction sphincter relaxation Internal anal sphincter defecation Eye ciliaris contracts-> globular lens for near vision + outflow AH Sphincter pupillae contracts-> miosis | ||
| M5 (Gq) | CNS | ||
| M4 (Gi) | CNS |
Myaesthenia gravis
Autoimmune disease affecting NMJ of skeletal muscles
- Ab against a1 sub-unit of Nm R, detected in 85% patients
- Ptosis, diplopia, dysarthria, dysphagia, extremity weakness, respiratory muscles
- Resembles NMJ blockade by non depolarizing neuromuscular blocking drugs
- Edrophonium as diagnostic test: 2mg IV dose, improved muscle strength observed for 5 minutes
Long term therapy: pyridostigmine or neostigmine
Last Updated on August 12, 2021 by Andrew Crofton
Andrew Crofton
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