Some ANS pharm review

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Parasympathetic Nervous System

Cholinoreceptor:

G protein-linked (Muscarinic): CNS, PNS-targeted tissues, vascular endothelium (not innervated by CNS)

- seven transmembrane domains (third cytoplasmic loop is coupled to G proteins)

M1 & M3: Gq everything except heart → activates the IP3, DAG cascade = ↑ Ca2+

M2 & M4: Giα → heart, inhibits adenylyl cyclase activity (inhibit cAMP & Giβ = ↑K+ flux)

Ion channel (nicotinic): “Neuronal” - ANS postganglions, some CNS neurons; “NMJ” - somatic motor fibers innervating muscles

- 4 subunits form cation-selective ion channels→ electrical and ionic changes→ depolarization

*Prolonged agonist occupancy→ "depolarizing blockade" abolishes the effector response→ can produce muscle paralysis


Direct Muscarinic Agonists:

CV: Direct effect = vasoconstriction; masked by NO-mediated vasodilation (requires intact endothelium) → reflex tachycardia

Pulm: Bronchoconstriction, ↑mucus secretion, *exacerbates asthma

GIT: ↑secretions (salivary, gastric, pancreatic & intestinal) & ↑peristalsis (contract longitudinal muscle while relaxing sphincters)

GUT: Promotes voiding: Detrusor contraction, relax trigone & sphincters

Eye: Miosis (iris contraction), Accommodation (ciliary contraction - facilitates aqueous humor outflow)

Secretory: ↑ secretion by thermoregulatory sweat glands (anomalous Muscarinic receptors of SNS)

Choline Esters - poorly absorbed & poorly distributed into CNS

Acetylcholine [Endogenous transmitter] – rapidly hydrolyzed - Affects both Muscarinic & nicotinic receptors

Low Dose: mostly vascular Muscarinic receptors→ NO→ vasodilation→ reflex tachycardia; cardiac effects hidden by baroreceptor response

High Dose: vascular + direct bradycardia (potential atrial flutter) * Can evoke SNS response thru ganglia (see when using Muscarinic antag)

Methacholine - Slightly resistant to AChE - Specific to Muscarinic (methyl group reduces potency @ nicotinic)

Bethanechol - Resistant to degradation by AChE - Specific to Muscarinic (methyl group reduces potency @ nicotinic)

Carbachol - Resistant to degradation by AChE

- Affects both Muscarinic & nicotinic receptors (i.e. can cause endogenous ACh release through ganglionic nicotinic receptors)

Alkaloids

Muscarine - Fungal (4° amine) alkaloid ACh mimetic

- Activates Muscarinic receptors, CNS activity

- Resistant to AChE

- No therapeutic use

Pilocarpine (ophthalmic) – (natural 3° amine) alkaloid ACh mimetic

- Used to treat glaucoma by allowing for fluid drainage from eye & atropine poisoning

- Resistant to AChE


Muscarinic Receptor Antagonists: Block action of ACh/agonists at Muscarinic receptors;

CNS: Minimal effects – Toxic doses→ agitation, hallucinations & coma; often used w/ dopamine precursor in Parkinson’s, also relieves vagal syncope

CV: Tachycardia (blocks PNS tone @ SA node), few hemodynamic effects

Pulm: Bronchodilation & ↓mucus secretion (not as useful as B2 agonists in asthma)

GIT: ↓motility & secretions – useful for mild GI hypermotility, excessive salivation, or as pre-op adjuvant before abdominal surgery

GUT: can cause urinary retention, especially w/ BPH

Eye: Mydriasis (dilated pupils); Cycloplegia (paralyzed ciliary muscle) – good for ophthalmic exam; Acute glaucoma (narrow anterior chamber angle)

Secretory: “atropine fever” - ↓ thermoregulatory sweating (anomalous Muscarinic receptors of SNS); helpful in hyperhidrosis

Contraindications: Glaucoma (especially closed angle), Prostatic hyperplasia, may ↑ gastric ulcer symptoms

3° Amine – Used for effects in eye or CNS

Atropine [Prototype] – reversible (competitive) blockade with relatively long duration of action; non-selective between M1, 2 & 3

- classic antidote to organophosphate poisoning

- “Atropine Poisoning”: dry (as a bone) mouth, mydriasis (blind as a bat), tachycardia, flushed skin (red as a beet), delirium (mad as a hatter)

Treat with Physostigmine or symptom management

Scopolamine - has a relatively long duration of action, better CNS, motion sickness

Homatropine

Pirenzepine - M1-selective (nerves)

Tropicamide

Tolterodine - M3-selective (urinary urgency, frequency & incontinence)

4° Amine – Only peripheral effects, cannot penetrate CNS (due to charge) – NOT used to reverse cholinergic poisoning

Atropine Methyl Nitrate

Methscopolamine

Ipratropium - asthma

Propantheline

Glycopyrrolate

Indirect Cholinomimetics: ACh-esterase inhibitors (also inhibit ButyrylCh-esterase) → amplify effect of endogenous ACh (modifies PNS tone)

Prominent effects on CV, GIT, eye & skeletal muscle; but NO effect on peripheral vasculature

@ NMJ: low conc. → ↑force of contraction; high conc. →depolarizing neuromuscular blockade

Clinical Uses: Atropine or TCA (tricyclic antidepressant) intoxication/overdose

CNS: Mild to moderate Alzheimer’s disease

GIT & GUT: ↑smooth muscle activity – postop ileus, congenital megacolon, reflux esophagitis, neurogenic bladder, urinary retention

Eye: Glaucoma (closed angle) - ciliary contraction →↑ aqueous humor outflow→ ↓intraocular pressure

NMJ: Myasthenia Gravis

Toxicity: SLUDGE = Salivation, Lactation, Urinary incontinence, Diarrhea, Gastrointestinal cramps & Emesis – reversed by atropine (& 2-PAM)

Simple Alcohol Esters (simple alcohols bearing a 4° ammonium group)

Edrophonium – [very short half-life] - Diagnostic Test for myasthenia gravis

Carbamates (carbamic acid esters of alcohols bearing 3° or 4° ammonium group)

* Undergo 2-step hydrolysis (covalent bond formed w/ enzyme is resistant to hydration; inhibition is longer (30 minutes - 6 hours)

Ambenonium (Mestinon)

Carbaryl – high lipid solubility (rapid CNS effects)

Demecarium- Used to treat glaucoma

Neostigmine – (4° amine - permanent charge renders them relatively insoluble in lipids – poor absorption/CNS distribution)

* Used to treat myasthenia gravis, ileus (severe abdominal cramping due to obstruction)

* Has both indirect & direct effects in PNS (inhibits AChE & stimulated Muscarinic receptors)

Physostigmine – (3° amine - well absorbed, CNS distribution); duration of effect is determined by stability of inhibitor-enzyme complex

- Used to treat glaucoma, myasthenia gravis & atropine overdose

Pyridostigmine - Used to treat myasthenia gravis

Organophosphates - well absorbed topically w/ good CNS distribution (except Echo); * Before aging, pralidoxime (2-PAM) can restore enzyme fxn

bind→ hydrolyzed/phosphorylated AChe active site – extreme stability (strengthened by “Aging”) → lifetime inhibition

Diisoprophylfluorophosphate (DFP) - Can cause cumulative overdose due to extremely long duration of action

Donepezil

Echothiophate – poorly absorbed, very long half-life (~100 minutes) - Used to treat glaucoma

Isoflurophate (ophthalmic) - Used to treat glaucoma

Malathion – [irreversible] - converted to phosphate derivative, used as insecticide

Parathion – [irreversible] – converted to phosphate derivative (Active only after biotransformation), used as insecticide

Sarin

Soman - Immediately & completely binds AChE (no aging) - Potential biological weapon

Tacrine - anticholinesterase and cholinomimetic actions – used for mild/moderate Alzheimer’s disease


Cholinesterase Regenerator

Pralidoxime (2-PAM)

Direct Nicotinic Agonist: Mostly targets ganglia; ↑SNS & PSNS: predominant tone determines effect (SNS = vasculature, PSNS = everything else)

Toxicity: CNS stimulation→ convulsion, coma, resp arrest (NMJ depolarization block); HTN & arrhythmias – Tx w/ Muscarinic Antag. & mech. resp

Nicotine – (natural 3° amine)

Lobeline – (natural 3° amine) a plant derivative similar to nicotine


Ganglion-Blockers (Nicotinic Antagonists): Block action of ACh/agonists at nicotinic receptors in SNS & PSNS ganglia; All are synthetic amines

Blocks homeostatic reflexes (e.g. baro & sweating), but effector cell receptors are NOT blocked; End-Organ effects depend on predominant ANS tone

CV: ↓SNS tone→↓BP & orthostatic hypotension (no baro); ↓PSNS tone @ SA node→ mild tachycardia

GIT: ↓PSNS tone→↓secretions & motility→ constipation & xerostomia (dry mouth)

GUT: Hesitancy or urinary retention (esp. with Prostatic hyperplasia); Impaired sexual function (requires both SNS & PSNS)

Eye: ↓PSNS tone→ cycloplegia (paralyzed ciliary muscle) & moderate pupil dilation (Normal Input: PSNS>SNS)

Tetraethylammonium (TEA) [prototype] - short half-life; used to manage HTN

Hexamethonium

- No therapeutic use currently

Mecamylamine – readily enters CNS→ sedation, tremor, choreiform movements, mental aberrations

Trimethaphan (IV) – 4° Amine →lacks CNS effects

- Extremely short acting

- Can be used to treat acute dissecting aneurysm or autonomic hyperreflexia

Sympathetic Nervous System

Adrenergic Neuron Blockers:

Reserpine - non-selective blocker of uptake & storage of amines

Guanadrel - similar to reserpine


Adrenoreceptor Agonists:

A1- forms IP3, DAG & activates phospholipase C; A2 - presynaptic autoregulation of SNS outflow, inhibits cAMP formation

B1 & B2 - activates adenyl cyclase;


CV: A1→ vasoconstriction, ↓renin secretion; B1 – Ca++ influx into cells (↑ino & chronotropic), ↑renin secretion

Pulm: A1in vessels of URT mucosa→ contraction→decongestion

GIT: A2→↓PNS tone on enteric system; Beta on smooth muscle mediates relaxation

GUT: A1→contract bladder base & urethral sphincter; B2→relax bladder wall smooth muscles – both actions promote urinary retention

Eye: Alpha→ radial dilator contraction→ mydriasis (dilated pupil); Beta→↑aqueous humor production by ciliary epithelium→ ↑intraocular pressure

Exocrine: A1 on aprocrine (stress) sweat glands→ sweating on palms, brow & upper lip

Metabolic: A2→↓ insulin release; Beta→ ↑lipolysis, ↑glycogenolysis, ↑glucose release, ↑insulin secretion

Toxicity: Extended effects – hypertension, tachycardia, CNS – restless, tremor, insomnia, anxiety, paranoia


Catecholamines:

Epinephrine – A1, A2; B1, B2: skeletal muscle arteriodilation & ↑venous capacity (mixed TPR effects)

Norepinephrine - A1: ↑TPR, A2; B1: Heart effects overcome by vagal reflex; = ↑Sys, Dias; High doses = ↑HR

Isoproterenol - B1= ↑CO; B2: skeletal muscle arteriodilation & ↑venous capacity = ↓Dias & MAP

Dolbutamine (B1; A1 @ high doses) - Uses: Heart failure/cardiac decompensation (short-term) – limited by tolerance/desensitization

Dopamine - D1 stimulates adenyl cyclase in renal vasculature→ renal vasodilation→ ↑GFR; A1; B1 @ high doses


Alpha-1 Specific – mydriasis (fundoscopic exam) & decongestant, can ↑BP;

Uses: nasal congestion, hypotension, paroxysmal atrial tachycardia

Phenylephrine [prototype] – not a catechol derivative, thus not inactivated by MAO/COMT; longer duration of action

Methoxamine

Oxymetazoline & Xylometazoline – used as topical decongestants


Alpha-2 Specific – Use as anti-HTN

Clonidine

Methyldopa

Guanfacine

Guanabenz


Beta-1 Specific – ↑CO w/ less reflex tachycardia;

Dolbutamine

Prenalterol (partial)


Beta-2 Specific – bronchodilation; Uses: Asthma & bronchial constriction

Albuterol

Salmeterol

Terbutaline

Ritodrine - uterine relaxation in premature labor


Indirect Sympathomimetics:

Ephedrine – first orally active

Pseudoephedrine [also direct] – cause release of endogenous NE; widely available OTC decongestant

Cocaine - block uptake1 (potentiates effects of NE) - Used as local anesthetic

Tyramine – enter thru uptake1, displace stored catecholamines→ hypertensive crisis; potentiated by MAO inhibitors * fermented foods (cheese)

Amphetamine (NOT a catecholamine) – mech=same as tyramine; ↑mood & alertness; ↓appetite *Common Drug of Abuse – Used for narcolepsy

Methamphetamine – similar, but w/ ↑ratio of central to peripheral effects

Methylphenidate - used to treat ADHD

Adrenoreceptor Blockers:

Alpha Receptor Antagonists - * Nitrates are preferred in hypertensive crises

Non-selective Alpha Antagonists

Phentolamine [prototype] – reversible, competitive; ↓TPR & MAP→reflex tachycardia

Tolazoline – similar to phentolamine;

Phenoxybenzamine – irreversible, slightly alpha-1 selective; Uses: Pheochromocytoma, limited by postural hypotension & reflex tachycardia

*Excessive release of NE & Epi from adrenal medulla

Alpha-1 Selective Antagonists: Uses: HTN & BPH - ↓TPR & BP, May cause postural hypotension & reflex tachycardia

Prazosin

Terazosin

Trimazosin

Doxazosin – longer half-life

Tamsulosin & Alfuzosin – competitive; Uses: BPH (prostate subtype selectivity)

Labetalol - also non-specific beta blocker


Alpha-2 Selective Antagonists

Yohimbine - no established clinical role, has been used in ED


Beta Receptor Antagonists – well absorbed orally

CV: ↓SNS tone to heart → slower AV conduction & ↓BP, but NOT hypotension; ↓SNS tone to kidney→ ↓renin secretion

Pulm: B2 block→ ↑airway resistance

Eye: ↓aqueous humor production by ciliary epithelium→ ↓intraocular pressure

Metabolic/Endocrine: ↓SNS stimulation of lipolysis & glycogenolysis; Use with caution in IDDM patients; Chronic use→ ↑VLDL & ↓HDL

Clinical Uses: HTN (w/ diuretic or vasodilator);

Ischemic Heart Disease - ↓angina frequency, cardiac work/oxygen demand; improves exercise tolerance; prolongs post-MI survival

Cardiac Arrhythmias (atrial & ventricular) - ↑AV refractory period, ↓ventricular response in A-fib, ↓ventricular ectopic beats

Glaucoma – refer to Eye above, better tolerated than Epi or Pilocarpine in open-angle glaucoma

Hyperthyroidism – limits excessive catecholamine activity

Toxicity: Minor= F, rash, depression, sedation; Major= exacerbates asthma, cardiac decompensation, supersensitivity (taper), hypoglycemia in IDDM

Non-selective Beta Antagonists - used to treat: HTN, angina, arrhythmias, glaucoma, and migraine; do NOT use in asthmatics

Propranolol [prototype] – extensive hepatic (first-pass) metabolism, low bioavailability

Nadolol – very long duration of action

Timolol – very long duration of action

Partial Agonists – may prevent bradycardia, changes in lipid profile & precipitation of asthma

Dichloroisoproterenol – first beta-blocking drug

Pindolol

Cartelolol

Penbutolol

Labetalol – reversible alpha-1 antagonist; → hypotension w/ less tachycardia than alpha-blockers


Beta-1 Selective Antagonists - treat HTN; Can also ↑airway resistance when used in asthmatics

Metoprolol

Esmolol – rapid hydrolysis by esterases in RBCs: half-life = 10 min.

Atenolol

Acebutolol – intrinsic sympathomimetic effects

Betaxolol

Bisoprolol


Beta-2 Selective Antagonists

Butoxamine - no clinical use