Autonomic pharmacology (drugs) Flashcards
What are the direct-acting adrenergic agonists?
Nonselective (1) Selective (10): α, β agonists (3) α agonists (3) β agonists (4)
(11 total)
Nonselective:
(1) Epinephrine
Selective: α, β agonists (2) Norepinephrine (3) Dopamine (4) Dobutamine
α agonists
(5) Phenylephrine
(6) Clonidine
(7) Brimonidine
β agonists
(8) Isopoterenol
(9) Albuterol
(10) Ritodrine
(11) Terbutaline
What receptors does epinephrine act on? For which does it have the greatest affinity?
(2)
(1) α1, α2, β1, β2, agonist
(2) Greatest affinity for β2
What are the effects of epinephrine?
3
(1) Cardiovascular - increase systolic and diastolic BP
(2) Pulmonary - bronchodilation on bronchial smooth muscle
(3) Metabolic - activates β2 receptors on hepatocytes, leading to breakdown of glycogen
Why can epinephrine not be given orally?
It is a catecholamine and catecholamines are degraded quickly by MAOs
When is epinephrine used?
4
(1) Stimulation of the heart in cardiac emergencies
(2) Treatment of serious hypersensitivity reactions
(3) Asthma
(4) Co-administration with local anesthesia
What are the side effects of epinephrine? Which is a common side effect of all catecholamines?
(3)
(1) Heart attack
(2) Hyperelevated BP leading to hemorrhagic stroke
(3) Ventricular arrhythmias, common to all catecholamines
How does epinephrine treat anaphylaxis?
(1) Histamine release causes severe bronchoconstriction and vasodilation
(2) Epinephrine acts on β2 receptors of bronchial smooth muscle to bronchodilate
(3) Epinephrine acts on α1 and β2 receptors on vascular smooth muscle to vasoconstrict
What receptors does norepinephrine act on?
α1, α2, and β1, agonist
What receptors does dopamine act on?
α1 and β1, agonist
What receptors does dobutamine act on?
α1, β1, and β2
What is an advantage of dopamine over epinephrine?
While epinephrine causes systemic vasoconstriction that raises BP, dopamine spares the kidneys due to dopamine receptors in the renal arteries that cause vasodilation, allowing for healthy bloodflow
How does dobutamine work?
3
(1) Dobutamine has a (-) and (+) isomer with α1 agonist and antagonist properties which cancel out
(2) It is a weak β2 agonist
(3) It is a good β1 agonist, so it is used for the heart
What can high does of norepinephrine cause?
Slowing of the heart
What receptor does phenylephrine act on? What does it cause? What are its uses? What is a side effect? (4)
(1) α1, agonist
(2) Causes vasoconstriction
(3) Used as nasal decongestant and to get rid of bloodshot eyes
(4) Side effect is dilated pupils
What receptor does clonidine act on?
What does it cause?
What is its use?
(3)
(1) α2, agonist
(2) Causes decreased sympathetic output from the brain (leading to vasodilation and decreased heart rate/force of contraction)
(3) Used to treat chronic hypertension
What receptor does brimonidine act on?
What does it cause?
What is its use?
(3)
(1) α2, agonist
(2) α2 agonists decrease formation of aqueous humor
(3) Used to treat glaucoma because it doesn’t irritate the eye like other α2 agonists
What receptors does isoproterenol act on?
What is its use?
(1) β1 and β2, agonist
2) Used to treat asthma but β1 activation can affect the heart (albuterol preferred for this reason
What receptor does albuterol act on?
β2, agonist
What receptor does ritodrine act on?
β2, agonist
What receptor does terbutaline act on?
What is its use?
(1) β2, agonist
(2) Used to suppress uterine contractions during premature labor
What are the indirect-acting adrenergic agonists?
Releasers (3
Uptake inhibitors (2)
Inhibitors of metabolism (1)
6 total)
Releasers:
(1) Amphetamine
(2) Methylphenidate
(3) Tyramine
Uptake inhibitors:
(4) Cocaine
(5) Tricyclic antidepressants
Inhibitors of metabolism:
(6) MAO inhibitors
How does amphetamine act?
What does it cause?
What is a side effect?
(3)
(1) Amphetamine acts on uptake pump of neuronal varicosity, which pumps epinephrine into the synapse
(2) Causes increased heart rate and force of contraction, vasoconstriction by α1 activation of vascular smooth muscle
(3) Side effect is ventricular arrhythmia in the heart at high levels
What does amphetamine treat?
3
(1) ADHD
(2) Narcolepsy
(3) Chronic fatigue syndrome
What is methylphenidate used to treat?
ADHD
What is tyramine and what does it cause?
Tyramine is a natural breakdown product of tyrosine that increases norepinephrine levels to dangerous levels in people taking MAOIs
How does cocaine act?
What is its use?
What is a side effect?
(1) Cocaine blocks uptake pump on neuronal varicosity so norepinephrine accumulates in the synapse
(2) Used as a local anesthetic, has CNS effects
(3) Side effect is ventricular arrhythmia
What is ephedrine?
A mixed adrenergic agonist that works as direct- (nonselective) and indirect-acting agonist (increases norepinephrine release)
What are the α adrenergic antagonists?
Nonelective (1
Selective (3)
4 total)
Nonselective:
(1) Phentolamine
Selective:
(2) Prazosin
(3) Tamsulosin
(4) Yohimbine
What receptors does phentolamine act on?
What does it cause?
(2)
(1) α1 and α2, antagonist
(2) Causes vasodilation and decrease in systolic and diastolic BP
Why is phentolamine not used chronically?
Phentolamine can cause (1) severe orthostatic hypotension due to blockage of α1 receptors and (2) increased heart rate due to blockage of α2 receptors (extra norepinephrine in synapse)
What are the β adrenergic antagonists?
Nonselective (2
Selective (1)
Additional actions (1)
4 total)
Nonselective:
(1) Propranolol
(2) Timolol
Selective:
(3) Metoprolol
Additional actions:
(4) Labetalol
What are β blockers used for?
6
(1) Hypertension
(2) Angina
(3) Arrhythmias
(4) Myocardial infarction
(5) Glaucoma
(6) Migraines
What receptors do propranolol and timolol act on?
What is one of their major uses?
(2)
(1) β1 and β2, antagonist
(2) Reduce rate and force of contraction to reduce BP. Even though you would expect β2 blockage to lead to vasoconstriction, it actually causes vasodilation
How do β blockers improve prognosis in MI?
Reduction of oxygen consumption by the heart
How do β blockers treat glaucoma?
Blockage of β2 receptors on ciliary bodies reduces aqueous humor production
What are three potential problems with the use of nonselective β blockers and why?
(3)
(1) Asthmatics - asthmatics should never be given nonselective β blockers because blockage of β2 receptor on bronchial smooth muscle will precipitate an asthma attack
(2) Nonselective β blockers in insulin-dependent diabetics will prevent regulation of glucose levels because they rely on epinephrine acting on β2 receptors of hepatocytes to stimulate glycogen breakdown because they don’t produce glucagon from β cells
(3) Chronic β blocker use will lead to withdrawal after cessation of use because cells will upregulate β receptors and without β blockers, epinephrine and norepinephrine will generate massive responses in the body
What receptor does metoprolol act on?
What is its use?
(2)
(1) β1, antagonist
(2) Can be used cautiously in diabetics and asthmatics, but only if they’re well-controlled
What receptors does labetalol act on?
(1) α1 and β, antagonist
What drug is an indirect antagonist (depletor)?
Reserpine
What is the mechanism of action of reserpine?
Prevents uptake of norepinephrine into storage vesicles within the sympathetic neuronal varicosity, so it gets broken down by MAO
What is a side effect of reserpine and how is it caused?
Parkinsonian symptoms because it eliminates dopamine in the substantia nigra the same way it eliminates norepinephrine
How is acetylcholine synthesized?
Acetyl CoA + choline → Ach, facilitated by choline acetyltransferase (CAT)
What are three categories of cholinergic drugs?
(1) Toxins/poisons - botulinum toxin, black widow spider venom
(2) Ach agonists/antagonists
(3) Anticholinesterases
What is the mechanism of action of botulinum toxin?
Prevention of release of Ach from storage vesicle by cleavage of SNARE proteins
What does black widow spider venom cause?
Explosive release of Ach
How is Ach broken down?
Ach is broken down by acetylcholinesterase to acetate and choline, mainly postjunctionally unlike norepinephrine
What are the characteristics of nicotinic cholinergic receptors?
(4)
(1) On SNS and PNS postganglionic cells
(2) Activated by nicotine
(3) Sodium channel
(4) Two types: Nm (muscle type) and Nn (neuronal type)
What are the characteristics of muscarinic cholinergic receptors?
(4)
(1) On PNS effector cells
(2) Activated by muscarine
(3) Coupled through G proteins
(4) M1-M5
What is the effect of cholinergic stimulation on exocrine glands?
Increased secretion (mucus secretion in lungs is clinically relevant)
What is cycloplegia and what is a pharmacological cause?
Cycloplegia is the inability to see things up close, can be caused by cholinergic blockade leading to paralysis of the ciliary muscle
What is the effect of cholinergic blockade on blood vessels?
No effect because there is no parasympathetic innervation to the blood vessels
What are the direct-acting cholinergic agonists?
Choline esters (3) Alkaloids (3)
Choline esters:
(1) Acetylcholine
(2) Carbachol
(3) Bethanechol
Alkaloids:
(1) Muscarine
(2) Nicotine
(3) Pilocarpine
What receptors does acetylcholine act on? Is it hydrolyzed?
2
(1) Muscarinic and nicotinic, agonist
(2) Very rapidly hydrolyzed by cholinesterase so limited clinical use
What receptors does carbachol act on?
Is it hydrolyzed?
What is its use?
(3)
(1) Muscarinic and nicotinic, agonist
(2) Not hydrolyzed
(3) Only used to treat glaucoma because of its undesired nicotinic activity
What receptors does bethanechol act on?
Is it hydrolyzed?
What is its use?
(1) Muscarinic, agonist
(2) Not hydrolyzed
(3) Ideal drug because not hydrolyzed and selective for muscarinic receptors, so used to treat paralytic ileus (peristalsis in small intestine stops) and bladder atony (muscle in bladder stops functioning)
What causes paralytic ileus and bladder atony?
3
(1) Peritoneal infections
(2) Surgery
(3) Very young or old age
What receptors does pilocarpine act on?
What is its use?
(1) Muscarinic
2) Used to treat glaucoma (causes contraction of longitudinal ciliary muscle) and xerostomia (low saliva production
What are the adverse effects of cholinergic agonists?
(1) Less serious - activation of muscarinic receptors on non-target tissues
(2) More serious - “cholinergic crisis” due to drug overdose, leading to SLUD (salivation, lacrimation, urination, and defecation
What are anticholinesterases?
Rapidly reversible inhibitors (5): Noncovalent inhibitors (2) Covalent inhibitors (3)
Slowly reversible inhibitors (3)
(8 total)
Noncovalent inhibitors
(1) Edrophonium
(2) Donepezil
Covalent inhibitors (carbamates)
(3) Physostigmine
(4) Neostigmine
(5) Carbaryl
Slowly reversible inhibitors (organophosphates)
(6) Echothiophate
(7) Parathion
(8) Soman
What is the mechanism of action of acetylcholinesterases?
4
(1) Acetylcholine acetylates oxygen of hydroxyl group on serine residue in active site of acetylcholinesterase, (2) releasing choline, then (3) water molecule de-acetylates acetylcholinesterase to produce (4) acetate
What is the mechanism of action of edrophonium?
Edrophonium positions itself in active site of acetylcholinesterase, preventing acetylation of -OH group
What is the use of edrophonium?
Diagnosis of Myasthenia Gravis - if injection of edrophonium improves grip strength, Myasthenia Gravis diagnosis likely
What is the mechanism of action of donepezil?
Binds reversibly to amino acid residues in acetylcholinesterase active site
What is a use of donepezil?
Treatment of Alzheimer’s
What drugs are carbamates and what is their mechanism of action?
(1) Physostigmine, neostigmine, and carbaryl
(2) Carbamates carbamylate OH group of serine residue in the active site of acetylcholinesterase (similar to acetylation by Ach) but decarbamylation takes minutes to hours, resulting in inhibition
What is a use of physostigmine? What is its downside?
(1) Treats glaucoma by inhibiting acetylcholinesterase, leading to contraction of the longitudinal ciliary muscle
(2) Can’t be administered systemically because it crosses the blood brain barrier
What are two uses of neostigmine? What is its advantage over physostigmine?
(1) Treatment of Myasthenia Gravis by increasing Ach levels at the neuromuscular junction
(2) Used in combination with bethanecol to treat paralytic ileus and bladder atony
(3) Advantage: does not cross blood brain barrier so can be used systemically
What drugs are organophosphates? What is their mechanism of action?
(1) Echothiophate, parathion, and soman
(2) Organophosphates phosphorylate OH group of serine residue in active site of acetylcholinesterase (similar to acetylation by Ach) but dephosphorylation takes hours to days
What is a use of echothiophate? Does it age?
(1) Treatment of glaucoma
(2) No aging
What is a use of parathion? Does it age?
(1) Pesticide
2) Ages over time (2-PAM antidote effective before aging occurs
What is soman? Does it age?
(1) Volatile nerve gas
(2) Ages instantly so cannot be treated with reactivators
What is “aging” in organophosphates?
When alkyl groups of organophosphates spontaneously break off from phosphorylated acetylcholinesterase, leading to irreversible inhibition
What is 2-PAM?
2-PAM is a reactivator that pulls organophosphate off serine hydroxyl of acetylcholinesterase, acting as an antidote to parathion poisoning
Note: ineffective after parathion has aged
What are cholinergic blockers?
Muscarinic blockers (4):
Natural alkaloids (2)
Synthetic quaternary amines (1)
Synthetic tertiary amines (1)
Ganglionic blockers (1) (4 total)
Muscarinic blockers:
Natural alkaloids
(1) Atropine
(2) Scopolamine
Synthetic quaternary amines
(3) Ipratropium
Synthetic tertiary amines
(4) Benztropine
Ganglionic blockers
(5) Mecamylamine
What is atropine? What does it cause?
Atropine is a muscarinic blocker that decreases parasympathetic tone
What are some uses of atropine?
4
(1) Prevent saliva production during oral surgery
(2) Bronchodilation/reduction in mucus production
(3) Suppress urination to treat urinary urge incontinence
(4) Antidote for cholinergic crisis
(5) Used with 2-PAM for organophosphate intoxication or alone for carbamylation
What is an advantage of scopolamine over atropine?
Acts in brain as antiemetic (treat motion sickness and vomiting)
What is ipratropium?
Muscarinic blocker that is used to treat asthma because it is easily volatilized
What is benztropine?
Muscarinic blocker that is used to treat Parkinson’s
What is the mechanism of action of mecamylamine?
Blocks nicotinic receptors in sympathetic and parasympathetic ganglia
What is the clinical effect of mecamylamine?
Acts on both sympathetic and parasympathetic ganglia, but since parasympathetic innervation typically dominates, this is what gets blocked (thus mecamylamine lowers systolic and diastolic BP)
What is an adverse effect of mecamylamine?
Orthostatic hypotension
