Autonomic Pharmacology Flashcards
Where (generally) is autonomic outflow to the CV system regulated?
medulla
Where is afferent baroreceptor information received?
nucleus tract solitarii (NTS)
Where is parasympathetic outflow regulated?
dorsal motor nucleus of the vagus
Where is sympathetic outflow regulated?
rostral ventrolateral medulla (RVLM)
Which neurotransmitter is used in inhibitory neurons in the ventrolateral medulla?
GABA
How does efferent parasympathetic outflow reach the CV system?
vagus nerve
Where does sympathetic outflow from the RVLM to the CV system travel?
IML of the spinal cord
What is the major neurotransmitter of both sympathetic and parasympathetic preganlionic neurons?
ACh
What is the major NT of postganglionic sympathetic fibers?
NE
What is the major exception to postganglionic sympathetic fiber regulation?
Sweat glands (ACh)
What NT mediates parasympathetic postganglionic fibers?
ACh
Where is epi found?
adrenal medulla, CNS, para-aortic bodies
How is ACh synthesized?
acetyl CoA + choline, catlayzed by choline acetyltranferase
What is usually the rate-limiting step in ACh synthesis?
transport of choline into the cell
What agent blocks the neuronal release of ACh?
botulinum toxin
Which enzyme catalyzes the rapid hydrolysis of ACh in the synaptic cleft?
acetylcholinesterase, ACh->choline + acetic acid
What is pseudocholinesterase?
non-specific cholinesterase found in plasma but not in RBCs or cholinergic neurons
How are catecholamines (NE, Epi, Dopamine) synthesized?
How do people with dopamine ß-hydroxylase deficiency present?
lifelong orthostatic hypotension, ptosis, exercise intolerance
How do local synaptic concentrations of catecholamines modulate their own release?
Interact with presynpatic α2-receptors to reduce release of NE
Interact with presynaptic β2-receptors to increase release of NE
What happens to released catecholamines (termination of action)?
- retaken up into the neuron via NE transporter
- taken up by extraneuronal tissue
- washed into the extracellular fluid and into the circulation
How are catecholamines broken down?
MAO converts them into their corresponding aldehydes
COMT converts epi and NE into metanephrine and normetanephrine
Describe the action of carbidopa
inhibits peripheral dopa decarboxylase to prevent formation of peripheral dopamine when treating Parkinson’s
What intracellular mechanisms result from β-adrenoreceptor stimulation?
Gs activates adenylyl cyclase to synthesize cAMP
What intracellular mechanisms result from alpha 2 adrenoreceptor or muscarinic M2 stimulation?
Gi binds to GTP, inhibiting adenylyl cyclase
What intracellular mechanisms result from alpha1 adrenoreceptor stimulation?
activation of membrane-bound phospholipase C
PLC hydrolyzes PIP2, resulting in the formation of DAG and IP3
IP3 causes release of Ca2+ from intracellular stores
α1 adrenoreceptor effects of NE
mydriasis
arteriolar constriction (vasoconstriction)
viscous salivary secretion
pilomotor erection
bladder sphincter contraction
α2 adrenoreceptor effects of NE
reduced sympathetic outflow (medulla oblongata)
vasoconstriction
viscous salivary secretion
platelet aggregation
β1 adrenoreceptor effects
increase HR
increase contractility
increase renin release
β2 adrenoreceptor effects
arteriolar dilation
bronchial relaxation
uterine relaxation
What are the major α1 agonists?
phenylephrine
NE
(epinephrine, dopamine)
What are the indications for phenylephrine use?
hypotension
nasal congestion
What are the α1 antagonists?
phentolamine
phenoxybenzamine
prazosin
What are the characteristics of phentolamine?
competitive, short-acting α-antagonist
What are the indications for phentolamine?
to determine whether a given level of HTN is catecholamine-mediated
help diagnose pheochromocytoma
Major side effects of phentolamine
arrythmias
angina pectoris
hypotension
abdominal cramping
What are the characteristics of phenoxybenzamine?
noncompetitive, long-acting α-antagonist
Indication for phenoxybenzamine
medical management of pheochromocytoma
Major side effect of phenoxybenzamine
hypotension
What class of drugs is prazosin?
α1-selective antagonist
Prazosin indications
hypertension
CHF
Which adrenoreceptor mediates feedback-inhibition of NE release?
presynaptic α2 receptors
α2 agonists
clonidine
methyldopa (α-methylnorepinephrine)
Vascular effects of high and low doses of α2 agonists
Low: Redcuce sympathetic outflow to the CV system
High: May stimulate peripheral postsynaptic vascular α2-receptors, vasoconstriction
α2 antagonist
yohimbine
yohimbine effects
block α2-receptors in the medulla: increase sympathetic outflow
block α2-receptors in the periphery: enhance NE release
Isoproterenol drug class
non-selective β agonist
Isoproterenol effects
increased contractility
increased HR
dilate arterioles
increased likelihood of premature beats/arrythmias
Dobutamine drug class
relatively β1-selective agonist
Dobutamine indications
pulmonary edema
coronary bypass post-op
What is ephedrine used for?
weight loss, therapy of asthma, nasal decongestant, adjunct therapy for myasthenia gravis
Where are muscarinic receptors located?
- tissues innervated by postganglionic parasympathetic neurons
- presynaptic noradrenergic and cholinergic nerve terminals
- vascular endothelium
- CNS
Where are nicotinic receptors located?
- sympathetic and parasympathetic ganglia
- adrenal medila
- neuromuscular junction of skeletal muscle
- CNS
Important selectivity of muscarinic receptor subtypes
M2: heart
M3: bladder, GI tract
What are the subtypes of nicotinic receptors?
NM mediates skeletal muscle stimulation
NN mediates stimulation of the ganglia of the ANS
muscarinic agonists
ACh, bethanechol, methacholine, pilocarpine
Muscarinic effects of ACh
contraction of iris sphincter (miosis) and ciliary muscle (accomodation)
bradycardia (SA node)
reduced conduction velocity (AV node)
bronchial muscle contraction
increased GI motility and secretion
bladder contraction
What are the clinical uses of muscarinic agonists?
open-angle glaucoma (pilocarpine)
urinary retention
gastroparesis
Sjögren’s syndrome
diagnosstic testing of pulmonary function (methacholine)
What is the classical muscarinic antagonist?
atropine
What is atropine derived from?
Deadly nightshade, Jimson weed
What are the clinical uses of muscarinic agonists?
bradycardia
excessive secretion
pupillary dilatation
preanesthetic medication (intubation)
neurocardiogenic syncope
Side effects of muscarinic agonists
constipation, xerostomia, hyphidrosis, mydirasis, glaucoma, tachycardia, etc.
Effects of nicotine
stimulates ganglionic nicotinic receptors, enchancing both sympathetic and parasympathetic neurotransmission (low doses)
What effect does nicotine have at high doses?
some antagonism at nicotinic receptors
NM blockers
tubocararine (nondepolarizing)
succinylcholine (depolarizing)
reversible cholinesterase inhibitors
physostigmine (enters CNS)
neostigmine (does not enter CNS)
parathion
malathion
physostigmine muscarinic side effects
nausea, pallor, sweating, bradycardia
(add anticholinergic drugs which do not cross BBB)
uses of cholinesterase inhibitors
myasthenia gravis
• open-angle glaucoma
• overdose reversal
• Insecticide
• Poor GI motility
• parasympathetic failure • chemical warfare
What is pralidoxime used for?
counteracts cholinesterase inhibtor intoxication by reactivating the cholinesterase enzyme
irreversible cholinesterase inhibitors
insecticides (organophosphates), sarin (war gas)
Clinical manifestations of cholinesterase inhibitor intoxication
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