Autonomic Pharmacology Flashcards
Muscarinic receptor agonists
- bethanechol
- carbachol
- pilocarpine
Muscarinic receptor antagonists
atropine, glycopyrrolate, ipratropium, scopolamine, solifenacin, tolterodine, tropicamide
Sympathetic nervous system (SNS)
- increased heart rate, pupillary dilation, reduced GI perstalsis
- neurotransmitter: NE, receptor: adrenergic
- exception: some sweat glands use muscarinic acetylcholine receptor
Parasympathetic nervous system (PNS)
- increased salivation, increased peristalsis, decreased heart rate
- neurotransmitter: acetylcholine (ACh), receptor: muscarinic
Catecholamine (dopamine, NE, epinephrine) synthesis
- rate limiting step: tyrosine>L-DOPA (tyrosine hydroxylase)
- epinephrine synthesized in adrenal medulla (PHENETHANOLAMINE-N-METHYLTRANSFERASE) from norepinephrine
- dopamine effects are in renal smooth muscle
Acetylcholine (Cholinergic) receptors
- muscarinic (certain mushrooms) & nicotinic (tobacco plant)
Muscarinic receptors
M1: neural M2: cardiac M3: glandular/smooth muscle M4: CNS M5: unclear role in vivo
Odd-numbered (M1,M3,M5) muscarinic receptors
- act via inositol triphosphase (IP3) involved in smooth muscle contract
- vasodilation, bronchoconstriction, increased GI motility, increased salivation, increased sweating, voiding, defacation
Even numbered (M2,M4) muscarinic receptors
- inhibit adenylyl cyclase & reduce cyclic AMP (cAMP)
- M2: opening of K+ channels & inhibition of Ca2+ channels slowing heart rate and decreasing contractility
Nicotinic acetylcholine receptors
- muscle & neuronal types
- muscle: skeletal muscle, mediates contraction
- neuronal: both PNS & SNS
Nicotinic acetylcholine receptor agonists
- prominent actions on neuronal receptors both in brain and autonomic ganglia
- minimal actions on muscle type receptors
Nicotine pharmacology
- CNS activation of receptors in regions involved w/ cognitive functions and reward
- autonomic effects: tachycardia, increased atrial pressure, sweating
- metabolite is cotinine: lab testing can tell smokers from non smokers from nicotine replacement
Varenicline
- partial agonist at the alpha4beta2 subtype of neuronal nicotinic receptor
- mediates reward effect of nicotine
- shown to help treat nicotine dependence
Nicotinic acetylcholine receptor antagonists
- antagonists of muscle type receptors used as neuromuscular blocker
- mivacurium, pancuronium, vecuronium
Acetylcholinesterase inhibitors
- increase amount of ACh in synaptic cleft at both nicotinic and muscarinic synapses
Clinical uses of AChe inhibitors
- neuromuscular reversal agents
- myasthenia gravis
- alzheimer’s disease
- insecticides
- nerve gases
Myasthenia gravis
- caused by antibodies targeted against muscle type nicotinic acetylcholine receptor resulting in fatigue/muscle weakness
- treatment: long acting AChE inhibitor pyridostihmine
Alzheimer’s disease
- AChE inhibitors that penetrate CNS
- donepezil, rivastigmine, galantamine
- limited effect often with only improvement for less than a year
Toxicologic importance of AChE inhibitors
- insecticides: chlorpyrifos, parathion, malathion
- nerve gases: VX, sarin, tabun
- organophasphate insecticide AChE inhibitors can cause irreversible inhibition of AChE after several hours of exposure
AChE inhibitor poisoning
- Diarrhea, Urination, Miosis, Bronchoconstriction (PNS), Excitation (muscle & CNS), Lacrimation, Salivation, Sweating
- DUMBELSS
- treatment: respiratory support most important-ATROPINE, if organophasphate AChE poisoning-PRALIDOXIME
Muscarinic acetylcholine receptor agonists
- used to treat glaucoma, urinary retention, dry mouth (xerostomia)
- bethanechol, carbachol, pilocarpine used topically for glaucoma
- bethanechol used to manage urinary retention
Muscarinic acetylcholine receptor antagonists
- ATROPINE, tricyclic antidepressants (amitriptyline & diphenhydramine)
Effects of anti-muscarinic drugs
- decreased secretions (dry mouth), mydriasis (dilated pupils), cycloplegia (decreased accommodation), hyperthermia, tachycardia, bronchodilation, urinary retention & constipation
- sedation, behavioral excitation & hallucinations seen with drugs that cross blood brain barrier
Clinical applications of antimuscarinics
- sever bradycardia: atropine
- acetylcholinesterase poisoning: atropine
- pupil dilation for ophthalmology: tropicamide
- motion sickness: scopolamine
- dry secretions: glycopyroolate
- parkinsonism: benztropine & diphenhydramine
- asthma & COPD: ipratropium, tiotropium
- bladder spasm, urinary incontinence: tolterodine, solifenacin
Toxicity of antimuscarinic agents
- hyperthermia, tachycardia, cardiac arrhythmias, sedation, behavioral excitation, hallucinations
- AChE inhibitors used in management
Adrenergic receptors
- alpha1, alpha2, beta1, beta2, beta3
Alpha 1 adrenergic receptor
- increase inositol triphosphate (IP3), diacylglycerol, intracellular Ca2+
- contract smooth muscle leading to vasoconstriction
- urinary retention, dilates pupils
Alpha 2 adrenergic receptors
- inhibit adenylyl cyclase
- constrict vascular smooth muscle
- presynaptic receptors in CNS that inhibit NE release
Beta adrenergic receptors common effect
- activate adenylyl cyclase & increase intracellular cAMP
Beta 1 adrenergic receptor
- predominately in the heart
- increased heart rate & contractility
Beta 2 adrenergic receptor
- dilate or relax smooth muscle, causing vasodilation, bronchodilation, and uterine relaxation
Beta 3 adrenergic receptor
- lipolysis of adipose tissue & relaxation of urinary bladder
Alpha 1 adrenergic agonists
- mydriasis (dilated pupils), vasoconstriction, urinary retention, contraction of smooth muscle of prostate gland
- specific alpha 1 agonist is PHENYLEPHRINE: used to treat nasal congestion by limiting blood flow to nasal mucosa, & when given through IV in hospital to raise blood pressure
Alpha 2 adrenergic agonists
- CLONIDINE is specific alpha 2 agonist that activates presynaptic receptor that has an inhibitory effect on SNS
- clonidine prone to cause REBOUND HYPERTENSION if drug is stopped abruptly
Alpha 1 specific antagonists
- prazosin, doxazosin, terazosin, tamsulosin
- prazosin & doxazosin used to treat HTN
- terazosin & tamsulosin used to treat BPH
- all can cause orthostatic hypotension especailly prazosin
Alpha 2 specific antagonists
- yohimbine
- not used clinically but is purported to have aphrodisiac effects
Non-specific antagonists of alpha adrenergic receptors
- phenoxybenzamine (IRREVERSIBLE) & phentolamine
- management of PHENOCHROMOCYTOMA to block catecholamines released by these tumors
Acetylcholinesterase inhibitors
- donepezil
- insecticides
- neostigmine
- pyridostigmine
- rivastigminea
Beta 1 adrenergic agonists
- dobutamine: used to treat cardiogenic shock and heart failure
Beta 2 adrenergic agonists
- used to treat asthma and rarely to stop premature labor
Albuterol
- short acting B2 agonist used for asthma attacks
- also activates B1 receptors and can cause tachycardia
Salmeterol, formoterol, bambuterol
- LONG ACTING selective B2 agonists used for chronic asthma therapy
- association of these drugs w/ increased risk of asthma death
Terbutaline
- B2 agonist that can be used to halt premature labor
- B2 agonists cause relaxation of uterine smooth muscle
- safety concerns so terbutaline is now discouraged
Isoproterenol
- NON SELECTIVE Beta adrenergic agonist that lowers PVR (B2) and increases heart rate & contractility (B1)
- used primarily for symptomatic bradycardia
- effects blocked by non selective B-blocker like propranolol/nadolol
Beta 3 adrenergic agonists
- MIRABEGRON: used to treat overactive bladder
Agonists of both alpha and beta receptors
- norepinephrine
- epinephrine
Norepinephrine
- potent a1,a2, & B1 but little action at B2
- used in septic shock to increase BP through increased PVR & HR
- systolic and diastolic pressure increase, which triggers compensatory vagal action to slow heart rate, PVR increases while cardiac output is unchanged or decreased
Epinephrine
- potent agonist at both alpha and beta receptors
- dilate bronchial smooth muscle & raise blood pressure
- management of anaphylactic shock
Epinephrine blood pressure effects
- modest rise in arterial pressure
- increase in systolic pressure and a decrease in diastolic pressure
- pulse rate increases
Epinephrine combined with alpha adrenergic antagonist
- B agonist effect are now unopposed
- increased heart rate (B1) & vasodilation (B2) & drop in MAP
- this is called EPINEPHRINE REVERSAL
Beta antagonist (B blockers) clinical uses
hypertension, cardiac arrhythmias, heart failure, angina, anxiety, muscle tremors, hyperthyroidism, glaucoma
Non selective beta blocker
- propranolol: used to treat anxiety, muscle tremors, hyperthyroidism because B2 receptors are involved in these disorders
Glaucoma treatment
- timolol: topically used to reduce aqueous humor secretion
Adverse effects of B-blockers
- bradycardia, AV conduction block, hypotension, sexual dysfunction
- *non-selective B-blockers should be avoided in asthma patients due to bronchoconstriction caused by B2 receptors. non selective agents can also cause problems in diabetic patients blocking glycogenolysis (B2 effect)
Selectivity of B-blockers
- selective B1: atenolol, metoprolol, esmolol
Carvedilol & labetalol
- block a1, B1, & B2
- carvedilol: manage heart failure
- labetalol: hypertension in pregnancy
Esmolol
- selective B1 blocker
- IV administration w/ short duration of action (minutes)
- acute management of cardiac arrhythmias
Nadolol duration of action
- long acting
- half life of ~24 hours
Acebutolol & pindolol
- B blockers w/ partial agonist effect
- INTRINSIC SYMPATHOMIMETIC ACTIVITY
- act as antagonist when there is high adrenergic activity
- theoretic advantage is that they should cause less bradycardia
Amphetamine effects
- increase norepinephrine release from nerve terminals
- increase release of dopamine (schizophrenic like symptoms)
- NO ANTIDOTE
Amphetamine & amphetamine like drugs (related to ephedrine and pseudoephedrine)
- amphetamine (adderall)
- methamphetamine
- MDMA/ecstasy
- MDA
- bath salts
Amphetamine clinical uses
- ADHD
- amphetamine mixed salts (adderall)
- lisdexamfetamine (vyvanse): prodrug, lysine linked to dextroamphetamine
- short term weight loss & narcolepsy
Methamphetamine
- abused drug is d-methamphetamine
- levo (l-) isomer marked as Vicks vapor inhaler
- only one prescription form on market (desoxyn): limited use for obesity and ADHD
- smoking or injecting meth associated w/ binge use
Bath salts
- misleading name for illicit amphetamine like drugs
- related to cathinone and amphetamines: mephedrone, MDPV, methylone
- causes hallucinations and panic attacks
Cocaine
- blocks norepinephrine & dopamine reuptake
- schedule II drug w/ limited use as local anesthetic in ENT surgeris
- NO ANTIDOTE
Cocaine metabolism
- half life varies from 30 min (chronic users) to 11 hrs (newborn)
- diagnostic metabolite is BENZOYLECGONINE (drug test target)
- traces remain in body for weeks
Health complications of cocaine
- myocardial infarct, strokes, brain hemorrhage, seizures, birth defects, placental abruption (constricts placental vessels)
- increased risk of birth defects, stimulates uterine contractions
- crack cocaine: crack mixed with bicarbonate
Cocaine facts
- fatal cocaine use: death not related to blood levels, large hearts found with chronic users
- perforated septum is common, burns on hands, lips, injection sites
- dopamine effects: euphoria & paranoia
