Autonomic Nervous System Neuropharmacology Flashcards
What are the mechanism by which ANS drugs act? (3)
- Direct Agonist
- Antagonist
- Indirect Agonist/Antagonist
ANS drugs that act to mimick NT action at receptor level are ?
Direct Agonist
ANS drugs that act to block NT action at receptor level are ?
Antagonist
What is the MOA of Indirect Agonist/Antagonist ANS drugs?
Change normal action of NT.
Indirect Agonist/Antagonist ANS drugs change normal action of NT, in what ways do they/can they do this?
- Synthesis of NT.
- Storage and release of NT.
- Inactivation of NT following release. (*Less clinically useful because they affect all synapses for that particular NT regardless of which specific postsynaptic receptor subtype is present.)
Most clinically useful are drugs that act at the ____ (post or pre?) -synaptically at specific receptor subtypes as agonists or antagonists
POST!
Between a direct agonist and a direct antagonist ANS drug, which one is more clinical useful?
antagonist!
More clinically useful, act post-synaptically at specific receptor subtype
Botulinum toxin*: ____1____ ACh release
Black Widow Spider toxin*: ____2____ ACh release
- blocks
2. increases
What are the two subtypes of Cholinergic Receptors?
Nicotinic Receptors
Muscarinic Receptors
ligand gated, alter ionic permeability are the actions of what type of Cholinergic Receptors?
Nicotinic Receptors:
G-protein coupled receptors, alters enzyme activity are the actions of what type of Cholinergic Receptors?
Muscarinic Receptors:
Nicotinic Receptors: ?
ligand gated, alter ionic permeability
Muscarinic Receptors: ?
G-protein coupled receptors, alters enzyme activity
Gq → ____1___ PLC
Gi → ___2____ AC
- increase
2. decrease
What [M] subtype is associated with Gq and what type of cell/organs are they on?
M1 = neuronal, GI glands
M3 = exocrine glands, smooth muscle
What [M] subtype is associated with Gi and what type of cell/organs are they on?
M2, M4 = heart, CNS
What are the direct acting Muscarinic Cholinergic Receptor Agonists?
Choline Esters:
- Acetylcholine*: not used, rapid hydrolysis by AChE
- Bethanechol*: synthetic analog of ACh, resistant to AChE
Parasympathetic Alkaloids:
- Pilocarpine*
What are the Nicotinic Neuronal (ganglionic) Receptor Agonists
- Nicotine* → increase BP, HR, vasoconstriction, increase GI motility, arousal, euphoria, increased attention
Prolonged or toxic dose can cause antagonism due to persistent depolarization → renders membrane unresponsive - Acetylcholine*
What is the MOA of Muscarinic Cholinergic Receptor Antagonists?
antagonize ACh, reversible (competitive) inhibitors (aka anticholinergic and antimuscarinic)
What are the Muscarinic Cholinergic Receptor Antagonists?
Alkaloids:
- Atropine*
- Scopolamine*
Semi-Synthetic Agents: higher selectivity of antagonism particularly parasympathetic function (bladder especially).
- Oxybutynin*, Ipratropium*What is the overall MOA of Acetylcholinesterase Inhibitors?
Indirect agonist?
List the Acetylcholinesterase Inhibitors. (4)
- Physostigmine
- Neostigmine, Pyridostigmine
- Edrophonium
- Organophosphates (nerve gas, insecticides) act indirectly to inhibit acetylcholine esterase → too much acetylcholine
nerve gas, insecticides are what type of Acetylcholinesterase Inhibitors?
Organophosphates
List the adrenergic agonist drugs:
- Epinephrine
- Pseudoephedrine
- Norepinephrine
- Phenylephrine
- Clonidine
- Isoproterenol
- Albuterol
- Dobutamine
- Dopamine
List the adrenergic antagonist drugs:
- Doxazosin
- Propranolol, Timolol = Non-selective B1 and B2
- Metoprolol, Atenolol = B1 cardioselective (only at lower doses)
- Labetalol, Carvedilol
What adrenergic antagonist drug is non-selective for beta1 and beta 2?
Propranolol, Timolol
What adrenergic antagonist drug is beta1 cardio-selective? (only at lower doses)
Metoprolol, Atenolol
What part of the CNS does: Reflex changes in blood pressure, sweat production and micturition.
Spinal cord
What part of the CNS does: Centers for control of blood pressure and respiration
Medulla oblongata
What part of the CNS does: Principal locus of integration; controls body temperature, water balance, carbohydrate metabolism, sexual reflexes, emotional responses.
Hypothalamus
What part of the CNS does: Volitional changes and conditioned autonomic responses.
Cerebral cortex
Sympathetic neurons release what NT in the effector organs?
NE
What is the neurotransmitter at the sympathetic ganglion?
acetylcholine (ACh)
What is the NT at the parasympathetic ganglion?
ACh
Parasympathetic neurons release what NT in the effector organs?
ACh
What branch of the ANS innervates blood vessels?
SNS ONLY!
Predominant (basal) tone exerted by which branch of the ANS?
PNS
Responses directed to single organ system –> ___?___ activation produces discrete, localized discharges
PNS
What are the physiologic responses in “Rest and Digest” for the:
- CV
- GI
- Bladder and Rectum
- Pupil
- Slowing of heart rate –> decreased blood pressure.
- Stimulation of GI motility and secretions.
- Emptying of bladder and rectum.
- Pupil constriction - focus (accommodation) for near vision.
TRUE or FALSE?
Nicotinic receptors can be found at Bronchial smooth muscle?
FALSE!!!
Nicotinic receptors can be found at all of the following sites:
- Adrenal medullary cells
- Parasympathetic ganglia
- Skeletal muscle end plates
- Sympathetic ganglia
Activation of [M] receptors in the CV results in what?
Decreased heart rate and AV conduction rate, reduced atrial contractility
Vasodilation - indirect effect mediated via generation of nitric oxide, then cGMP –> decreased blood pressure
NOTE: These muscarinic receptors are NOT innervated - activation of the PNS does NOT result in vasodilation.
Activation of [M] receptors in the Respiratory system results in what?
Respiratory: Bronchial muscle contraction, stimulation of glands
Activation of [M] receptors in the GI Tract results in what?
GI Tract: Increase in secretory and motor activity - most sphincters relaxed
Activation of [M] receptors in the GU Tract results in what?
Genitourinary tract: Relax sphincter muscles, contract detrusor muscle, thus promote voiding.
Activation of [M] receptors in the Eye results in what?
Contraction of circular muscle miosis (pupil constriction)
Ciliary body focuses lens for near vision accommodation
Outflow of aqueous humor (tension on trabecular meshwork increases flow into Canal of Schlemm) IOP
Which of the following drugs causes vasodilation that can be blocked by atropine?
Metoprolol Bethanechol Doxazosin Labetalol Nitroglycerin
Bethanechol
[N_N] receptor activation in the ganglia results in what?
Cardiovascular: Chiefly sympathetic effects - moderate vasoconstriction, tachycardia, elevated blood pressure
GI / urinary tract: Parasympathetic effects = nausea, vomiting, diarrhea, urination
[N_N] receptor activation in the CNS results in what?
Mild alerting effect, tremor, emesis, respiratory stimulation
Activates “reward” pathway in limbic system contributing to addiction potential
Convulsions can occur at toxic doses
“Fight or Flight”/SNS activation does what to:
- HR/BP
- blood flow/management
- bronchioles/pupils
- blood glucose
- Accelerated heart rate = increased blood pressure
- Shift of blood from skin-splanchnic regions to skeletal muscles
- Dilation of bronchioles and pupils
- Rise in blood glucose
What adrenergic receptors are at cutaneous, mucous membranes, splanchnic vessels and what is the physiological results?
Cutaneous, mucous membranes, splanchnic vessels = [Alpha-1]
Vasoconstriction mediated via 1 receptors, contributes significantly to increase in total peripheral resistance
What adrenergic receptors are at Skeletal muscle vasculature and what is the physiological results?
Skeletal muscle vasculature = [Alpha-1 and Beta-2]
Vasoconstriction (Alpha-1) or vasodilation (Beta-2) can occur
Beta-2 receptor activation increases blood flow to muscle and decreases total peripheral resistance
What adrenergic receptors are at Renal vasculature and what is the physiological results?
Renal vasculature = [D1 and Alpha-1]
Vasodilation via D1 receptors balanced by constriction via α1 receptors (dose-dependent effect of dopamine)
What adrenergic receptors are at Heart and what is the physiological results?
Direct effects on heart are largely mediated by [Beta-1] receptors
SA node: Increase in heart rate (positive chronotropy)
AV node: Increase in conduction velocity
Atrial - ventricular cardiac muscle: Increase in force of contraction (positive inotropy)
What adrenergic receptors that control Blood Pressure and what are the physiological results?
α1: Vasoconstriction –> increase TPR and BP –> reflex bradycardia occurs.
β1: Increased heart rate / force of contraction –> increase CO and BP.
β2: Vasodilation –> decreases TPR and BP –> reflex tachycardia occurs.
What adrenergic receptors are in JGA cells (kidney) and what is the physiological results?
Juxtoglomerular cells: Increased renin release via [α1] receptors.
What adrenergic receptors are at the Respiratory Tract and what are the physiological results?
Respiratory Tract:
Bronchial smooth muscle: Bronchodilation via [β2] receptors.
Upper respiratory tract mucosal blood vessels: Constriction via [α1] receptors.
What adrenergic receptors are in the GI tract and what is the physiological results?
Gastrointestinal Tract: Smooth muscle
Indirect relaxation via presynaptic [α2] receptors inhibiting release of ACh and ACh-mediated muscle contraction.
Direct relaxation via by [β2] - [β3] receptors on smooth muscle.
What adrenergic receptors are at Uterine smooth muscle and what is the physiological results?
Uterine smooth muscle: Relaxation via [β2] receptors.
What adrenergic receptors are at Uretal sphincter and what is the physiological results?
Uretal sphincter, bladder base, prostate: Contraction via α1 receptors –> Increase continence.
What adrenergic receptors are at bladder wall musculature and what is the physiological results?
Bladder wall musculature: Relaxation via [β2]-[β3] receptors promoting urinary continence.
What adrenergic receptors for ejaculation and what is the physiological results?
Ejaculation: Via α1 receptor activation in vas deferens, seminal vesicles, and prostate.
What adrenergic receptors for the radial pupillary dilator muscle and what is the physiological results?
Radial pupillary dilator muscle: Constriction via [α1] receptors –> mydriasis (dilation).
Aqueous humor –> intraocular pressure (IOP) - balance between production and outflow)
Major effect: Increased production via ___1___ receptors (increases IOP)
Minor effect: Increased outflow via ___2___ receptors vasoconstriction of ocular vessels (decreases IOP)
- beta receptors
2. Alpha-1 receptors
What adrenergic receptors are in skeletal muscle and what is the physiological results?
Skeletal Muscle [β2]
[β2] receptors located on extrafusal fibers and muscle spindles.
Activation associated with marked tremor - dose-dependent enhancement of muscle spindle discharge.
Liver: Increased glycogenolysis via what adrenergic receptors –>increased blood glucose
[β2]
Fat cells: Increased lipolysis (fat breakdown) via what adrenergic receptors?
[β3]
Pancreas β cells
Decreased insulin secretion via what adrenergic receptors? (major effect)
Increased insulin release via what adrenergic receptors?
Pancreas β cells
Decreased insulin secretion via [[α2] receptor (major effect).
Increased insulin release via [β2] receptors.
