Cholinergic & Adrenergic Agonists & Antagonists, Pharm 2011

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Direct effects of Ach

Cholinergic agonist, direct acting
vasodilation (M3), dec HR (M2), dec conduction rate in SA and AV nodes (M2), dec force of contraction (M2)

Acetylcholine effects on organ systems

Cholinergic agonist, direct acting
vasodilation (NO release); eye contraction and miosis; contraction and accommodation to near vision; inc secretions; bronchoconstriction (inc secretions); bradycardia, dec conduction velocity, inc GI tone, relaxation of sphincters; contraction of detrusor, relaxation of sphincter; erection.

Ach MOA

Cholinergic agonist, direct acting
Acts on nicotinic and muscarinic receptors.
Rapidly hydrolyzed

Bethanechol

Cholinergic agonist, direct acting
Strong muscarinic activity; NO nicotinic actions
Not hydrolyzed by AchE (inactivated by other esterase)

Bethanechol uses

Cholinergic agonist, direct acting
Tmt of acute postoperative and postpartum urinary retention
Neurogenic atony of urinary bladder with retention
"Bethanechol for Bowel and bladder"

Bethanechol adverse effects

Cholinergic agonist, direct acting
Generalized cholinergic stimulation: sweating, salivation, flushing, low BP, nausea, abdonimal pain, diarrhea, bronchospasm

Carbachol

Direct cholinergic agonist
Non-selective - both muscarinic and nicotonic agonist
Not hydrolyzed by AchE

Carbachol uses

Direct cholinergic agonist
Miosis during sx, reduces IOP after cataract sx
"CARBon copy of Ach"

Methacholine

Direct cholinergic agonist
More resistant to hydrolysis by AchE than Ach

Methacholine uses

Direct cholinergic agonist
Diagnosis of bronchial airway hyperreactivity
(Methacholine challenge test for dx of asthma)

Muscarine

Direct muscarinic agonist

Arecoline

Muscarinic and nicotinic agonist - direct acting cholinergic agonist

Pilocarpine

Direct cholinergic agonist
Not hydrolyzed by AcheE
Partial muscarinic agonist

Pilocarpine uses

Direct cholinergic agonist
Second line for open angle glaucoma
Management of acute angle-closure glaucoma
"PILe on the sweat and tears"

Nicotine MOA

Direct cholinergic agonist
Affects NMJ and ganglia

Nicotine actions at low doses

Direct cholinergic agonist
Ganglionic stimulation by depolarization
-Response resembles simultaneous discharge of both parasympathetic and sympathetic

Nicotine actions

Direct cholinergic agonist
CVS: sympathomimetic (d/t catecholamine release from adrenergic nerve terminals and adrenal medulla) - inc HR, inc BP
GI/UT: parasympathomimetic - nausea, vomiting, diarrhea, voiding of urine
Secretions: stimulation of salivary and bronchial secretions

Nicotine actions at high doses

Direct cholinergic agonist
Ganglionic blockade and neuromuscular blockade

Nicotine acute poisoning - sx?

Direct cholinergic agonist
Nausea, salivation, abdominal pain, vomiting, diarrhea, cold sweat, mental confusion, weakness
BP falls, weak pulse
Death may occur from paralysis of resp muscles and/or central resp failure

Nicotine uses

Direct cholinergic agonist
Smoking cessation therapy

Edrophonium MOA

AchE inhibitor (cholinergic agonist)
Binds reversibly to active sit of AchE

Edrophonium uses

AchE inhibitor (cholinergic agonist)
Dx of MG - edrophonium IV leads to rapid increase in muscle strength
Reverses neuromuscular block produced by non-depolarizing muscular blockers.

Physostigmine uses, cautions

AchE inhibitor (cholinergic agonist)
Can enter and stimulate CNS
Uses: Tmt of OD's of anticholinergic drugs (eg. atropine); glaucoma
Should not be given for suspected TCA overdose - can aggravate depression of cardiac conduction
"PHYS is for eyes"

Neostigmine

AchE inhibitor (cholinergic agonist)
Doesn't enter CNS
Uses: stimulate bladder and GIT; antidote for competitive blockers of NMJ; symptomatic tmt for MG

Pyridostigmine

AchE inhibitor (cholinergic agonist)
Tmt of MG
"pyRIDostigmine Gets RID of myasthenia gravis"

Echothiophate

AchE inhibitor (cholinergic agonist)
Used for glaucoma

Malathion & Parathion

AchE inhibitor (cholinergic agonist)
Thiophosphate insecticides
Must be activated in the body by conversion to oxygen analogs

Tabun, Sarin, Soman

AchE inhibitor (cholinergic agonist)
Nerve agents

Tacrine, Donepezil, Rivastigmine, Galantamine

AchE inhibitor (cholinergic agonist)
Oral AChE inhibitors
Tmt of Alzheimer's disease

Pralidoxime

Reactivator of AChE
Cholinesterase regenerator for organophosphate insecticide poisoning
If given before ageing has occurred, splits phosphorous-enzyme bond

Atropine MOA

Cholinergic muscarinic antagonist
Binds competitively to muscarinic receptors

Atropine actions

Cholinergic muscarinic antagonist
Mydriasis, cycloplegia; reduced gastric motility; dec hypermotility of bladder; bradycardia at low doses (d/t blockade of presynaptic M2 that normally inhibit ACh release), tachycardia at mod to high dose (d/t blockade of atrial M2 receptors); secretions blocked (salivary, sweat, lacrimal) - high body temp.

Explain atropine flush

High doses of antimuscarinic agents may cause cutaneous vasodilation - mechanism is unknown.

Atropine uses

Cholinergic muscarinic antagonist
Mydriasis, cycloplegia; antispasmodic (GIT, bladder); antidote for cholinergic agonists; antidote for mushroom (muscarine) poisoning (Amanita muscaria, fungi); block RT before sx.

Atropine adverse effects

Cholinergic muscarinic antagonist
Dry mouth, blurred vision, sandy eyes, tachycardia, constipation; restlessness, confusion, hallucinations, delirium, depression, collapse of circulatory and resp systems and death.

Scopolamine

Cholinergic muscarinic antagonist
Uses: Prevention of motion sickness, block short-term memory - sometimes used in anesthetic procedures.

Ipratropium ("I PRAy tropium")

Cholinergic muscarinic antagonist
Quaternary ammonium
Used in asthma and COPD
"I PRAy I can breathe soon"

Tiotropium

Cholinergic muscarinic antagonist
Quaternary ammonium
Used for COPD

Homatropine, Cyclopentolate, Tropicamide

Cholinergic muscarinic antagonist
Tertiary amine
Uses: Ophthalmology - preferred to atropine d/t shorter duration of action --> Mydriasis with cycloplegia

Benztropine, Trihexyphenidyl

Cholinergic muscarinic antagonist
Tertiary amine
Uses: treat PARKinsonism and extrapyramidal effects of antipsychotic drugs
"PARK my BENZ"

Glycopyrrolate

Cholinergic muscarinic antagonist
Used orally: inhibit GI motility
Used parentally: prevent bradycardia during sx

Tolterodine

Cholinergic muscarinic antagonist
Uses: overactive bladder
"TOLd you to go before we left"

Contraindications of antimuscarinic agents

Angle-closure glaucoma pts
Use with caution in prostatic hypertrophy (since urine retention aggravates BPH) and elderly

Ganglionic blockade by prolonged depolarization: drug example

Nicotine

Ganglionic blockade by antagonism of nicotinic receptors: drug examples

Hexamethonium, mecamylamine, trimethaphan

Mecamylamine, Trimethaphan, Hexamethonium MOA

Ganglion blockers
Ganglion blockade by antagonism of nicotinic receptors

Mecamylamine, Trimethaphan, Hexamethonium uses

Ganglion blockers
HTN in the past - replaced now

Dominant tone of organs:

arterioles: sympathetic
veins: sympathetic
heart: parasympathetic
iris: parasympathetic
ciliary muscle: parasympathetic
GI tract: parasympathetic
urinary bladder: parasympathetic
salivary glands: parasympathetic
sweat glands: sympathetic

Tubocurarine

Nondepolarizing neuromusc. blocker - cholinergic antagonist
Competitive antagonist at nicotinic receptors
Uses: adjuvant in anesthesia during sx to relax skeletal muscle

Succinylcholine actions, uses

Depolarizing neuromusc. blocker - cholinergic antagonist
Nicotinic receptor desensitizes --> flaccid paralysis
Uses: rapid endotracheal intubation; during ECT

Depolarizing agents, adverse effects

Malignant hyperthermia - d/t excessive calcium release from SR
Combination of succinylcholine and halogenated anesthetic in most incidents
TMT: dantrolene blocks release of calcium from SR

3 cholinergic drugs that act pre-synaptically

Hemicholinium, Vesamicol, Botulinum Toxin

Hemicholinium-3

Presynaptic cholinergic antagonist
Inhibitor of ACh synthesis
Blocks the CHT; prevents uptake of choline

Vesamicol

Presynaptic cholinergic antagonist
Inhibitor of ACh storage
Blocks ACh-H antiporter

Botulinum toxin

Presynaptic cholinergic antagonist
Inhibitor of ACh release
Uses: tmt of several diseases involving muscle spasms (at NMJ); cosmetic tmt of wrinkles

Epinephrine

Direct adrenergic agonist
Released by adrenal medulla
Interacts with both alpha and beta receptors: low doses=beta (vasodilation); high doses=alpha (vasoconstriction)

Epinephrine: large dose CV effects

Direct adrenergic agonist
Inc BP:
-inc ventricular contraction (beta 1)
-inc HR (beta 1) --> may be opposed by baroreceptor reflex
-vasoconstriction (alpha 1)

Epinephrine: low dose CV effects

Direct adrenergic agonist
-inc HR d/t beta 1 effects
-beta 2 more sensitive to epi than alpha 1 --> dec peripheral resistance d/t beta 2, dec diastolic P --> mean BP may fall
-no baroreceptor reflex since no inc in mean BP

Epinephrine effects

Direct adrenergic agonist
-bronchodilation (beta2)
-hyperglycemia --> inc glycogenolysis in liver (beta 1), inc lipolysis (beta3)

Epinephrine uses

Direct adrenergic agonist
-Anaphylactic shock
-acute asthmatic attacks
-in local anesthetics --> inc duration of anesthetic with vasoconstriction (prevents dissipation of anesth)
-glaucoma (not common)

Norepinephrine

Direct adrenergic agonist
Acts on alpha and beta1 receptors, not on beta2

Norepinephrine CVS effects

Direct adrenergic agonist
-vasoconstriction (alpha1 effect)
-inc BP (beta1 effect)
-CO is unchanged or dec
-baroreceptor reflex bradycardia
-->BP high, peripheral resistance high (alpha1), pulse rate low (baroreceptor reflex)

Norepinephrine uses

Direct adrenergic agonist
Treat shock --> inc vascular resistance (inc BP)
-dec blood flow to kidney (this is bad - dopamine is better)

Effect of atropine pre-treatment with norepinephrine

Tachycardia (d/t anti-muscarinic effect of atropine with additional NE-induced activation of alpha and beta1)

Dopamine

Direct adrenergic agonist
-Activates D rec and alpha and beta rec
-Substrate for MAO and COMT
-ineffective when taken orally

Dopamine actions/uses

Direct adrenergic agonist
-drug of choice for shock (inc BP with beta1; inc kidney perfusion with D1)

Isoproterenol MAO/actions

Direct beta agonist (beta 1 and 2)
-inc HR and force of contraction (beta1)
-dilates skeletal muscle arterioles (beta2); dec peripheral resistance (beta2)
-bronchodilation (beta2)

Isoproterenol CV effect

Direct beta agonist (beta 1 and 2)
Inc HR from beta1; dec peripheral resistance from beta2 --> BP does not increase!

Isoproterenol uses

Direct beta agonist (beta 1 and 2)
Stimulate heart in emergency

Dobutamine uses

Direct beta1 agonist
-inc CO in CHF
-inc CO with little change in HR
-does not significantly inc oxygen demands of myocardium (big advantage)

Albuterol, Terbutaline uses

Direct beta2 agonist
-asthma --> acute episodes

Salmeterol, Formoterol

Direct beta2 agonist
-asthma --> long-acting agonist (NOT for breakthrough attacks); slow onset, lasts long (12 hrs)

Phenylephrine

Direct alpha1 agonist
-vasoconstrictor --> used as nasal decongestant and mydriatic
-used to inc BP and terminate episodes of supraventricular tachycardia
-induces reflex bradycardia (IV)

Clonidine

Direct alpha2 agonist
-antihypertensive --> acts centrally to inhibit sympathetic vasomotor centres

Methyldopa

Direct alpha2 agonist
-converted to alpha-methylnorepinephrine which activates central alpha2 adrenoceptors
-dec BP
-hypertension in pregnancy

Amphetamine

Indirect adrenergic agonist
-central stimulatory action
-inc BP (alpha effect on vasculature); stimulate heart (beta effect)

Methylphenidate

Indirect adrenergic agonist
-structural analogue of amphetamine
-tmt of ADHD in kids

Tyramine

Indirect adrenergic agonist
-found in fermented food like cheese and wine
-oxidized by MAO --> if taking MAO inhibitors, can ppt vasopressor episodes (hypertensive crisis)

Ephedrine

Mixed action adrenergic agonist
-stimulates alpha and beta, release NE from nerve endings
-long duration since not substrate for MAO or COMT
-excellent oral absorption and penetrates CNS

Ephedrine actions

Mixed action adrenergic agonist
-inc BP
-bronchodilation --> chronic prophylactic asthma tmt
-mild CNS stimulation: inc alertness, prevents sleep
-improves athletic performance

Ephedrine uses

Mixed action adrenergic agonist
-asthma prophylaxis (chronic), nasal decongestant, raise BP

Pseudoephedrine

Mixed action adrenergic agonist
-OTC component of decongestant mixtures

Phenoxybenzamine

non-selective alpha antagonist
-irreversible antagonist
-used in pheochromocytoma --> before sx removal of tumour, chronic management of inoperable tumours

Phentolamine

non-selective alpha antagonist
-reversible antagonist
-Dx of pheochromocytoma by phentolamine blocking test
-hypertensive crisis assoc with stimulant drug overdose
-hypertensive crisis d/t sudden withdrawal of sympatholytic antihypertensives (eg. clonidine)

BP response to epinephrine given in presence of phenoxybenzamine

alpha1 blocked by phenoxybenzamine so epi acts on beta2 to vasodilate (ie. unopposed beta2 activation) ---> BP decreases

Prazosin

selective alpha1 antagonist
Uses:
-hypertensives (relaxes arterial and venous sm)
-first dose--> hypotensive response and syncope
-BPH (drug of choice) --> improve urinary flow

Terazosin, Doxazosin

selective alpha1 antagonist
Uses: (same as Prazosin)
- HTN and BPH

Tamsulosin

selective alpha1 antagonist
Uses:
-BPH
-not much effect on BP

Yohimbine

selective alpha2 antagonist
-blockade of alpha2 autoreceptors -> inc NE release -> stimulation of beta1 and alpha1
Uses:
-tmt of ED (but PDE5 have replaced now)

Uses and actions of non-selective beta blockers

Propranolol is prototype
-dec HR and dec myocardial contractility
-dec glycogenolysis; dec glucagon secretion
-lower BP by dec CO
-dec IOP
-prophylaxis of migraines (block vasodilation)
-blunt hyperthyroidism-induced symp stimulation
-dec oxygen requirement of heart - treat angina pectoris
-treat atrial fibrillation
-treat MI
-treat performance anxiety
-CNS effect --> sleep disturb, depression, sedation

Adverse effects of non-selective beta blockers

-bronchoconstriction (potentially lethal in asthmatics)
-up-regulation of receptors --> stop therapy, inc receptors worsen angina or HTN

Propranolol uses and actions

non-selective beta blocker
-dec HR and dec myocardial contractility
-dec glycogenolysis; dec glucagon secretion
-lower BP by dec CO
-dec IOP
-prophylaxis of migraines (block vasodilation)
-blunt hyperthyroidism-induced symp stimulation
-dec oxygen requirement of heart - treat angina pectoris
-treat atrial fibrillation
-treat MI
-treat performance anxiety
-CNS effect --> sleep disturb, depression, sedation

Propranolol adverse effects

non-selective beta blocker
-bronchoconstriction (potentially lethal in asthmatics)
-up-regulation of receptors --> stop therapy, inc receptors worsen angina or HTN

Nadolol

non-selective beta blocker
-long duration of action
-management of angina pectoris
-management of HTN

Timolol

non-selective beta blocker
-tmt of intraocular HTN/open-angle glaucoma
-tmt of HTN
-prophylaxis of migraines

Atenolol, Metoprolol, Esmolol

beta1 antagonist
-for hypertensive pts with impaired pulm fxn
-for diabetic hypertensive pts receiving insulin/oral hypoglycemic agents
--> Esmolol = ultra-short acting

Labetalol

alpha1 and beta antagonist
-management of HTN
-useful to treat HTN of pheochromocytoma and HTN emergencies

Carvedilol

alpha1 and beta antagonist
-used in HTN and CHF

Pindolol

partial beta agonist
--> have intrinsic sympathomimetic activity
--> smaller reductions in resting HR and BP
-use: antihypertensive in pts with less cardiac reserve or propensity to bradycardia

4 adrenergic drugs that act pre-synaptically

alpha-methyltyrosine, reserpine, guanethidine, cocaine

Alpha-methyltyrosine (metyrosine)

inhibitor of NE synthesis
--> competitive inhibitor of tyrosine hydroxylase
Uses:
-management of malignant pheochromocytoma
-preop preparation of pts for pheochromocytoma resection

Reserpine

inhibitor of NE storage or release
--> irreversibly damages VMAT -> MAO degrades NE causing depletion
Uses: HTN in the past

Guanethidine

inhibitor of NE storage or release
--> displaces NE from vesicles; inhibits release of NE
-antihypertensive action

MAOIs

inhibitor of NE metabolism
--> prevent deamination of catecholamines
Uses:
-tmt of depression and Parkinson's

Cocaine

inhibitor of NE uptake
--> blocks monoamine reuptake
-potentiation/prolongation of monoamine central and peripheral actions (inc sympathetic effects)

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