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105 terms

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)