Lectures: ANS 1-4 Flashcards
Autonomic system which is REQUIRED for life
Parasympathetic (“rest and digest”)
drugs that modulate Acetycholine usually affect which steps of signaling?
- NT binding to post-synaptic Receptor
2. Acetycholine degradation (in synapse)
Autonomic vs. somatic system organization
+ adrenal pathway
Autonomic: 2 neurons to target (CNS—>ganglion —> target)
* Adrenal: CNS —> adrenal medulla to circulation
Somatic: 1 neuron to target
Acetylcholine = NT for what parts of ANS
- ganglionic neurotransmitter
- parasympathetic post-ganglionic to target tissue NT
* 3. Also: somatic NT to target tissue
Most drugs affecting cholinergic signaling act on:
- Receptor site for ACh
2. ACh degradation in synapse
Nicotinic cholinergic receptors
Ionotropic ligand-gated cation channel,
open when depolarized.
* neuronal subunits (ganglia and adrenal medulla): alpha, beta
* NMJ subunits: alpha, beta, gamma, delta/epsilon
–> mediate neurotransmission at
1. ganglionic synapse of symp, parasymp
2. adrenal medulla
3. neuroeffective (target) synapse for sympathetic ANS
Muscarinic Cholingergic receptor
metabotropic, serpentine GPCR
5 subunits: M1, M2, M3, (M4 & M5 = in brain)
* drugs act on all subtypes equally!
–> mediate neurotransmission at “neuroeffective” (target) synapse of parasymp. ANS
norepinephrine
primary NT at neuroeffective (end/target) synapse of sympathetic ANS
sympathetic stimulation of adrenal medulla
- signaled to adrenal medulla by ACh (nicotinic R)
- adrenal medulla releases epinephrine into blood
- -> acts throughout body (endocrine signaling)
pattern of adrenergic signaling
- NE synthesis
- uptake into storage vesicles
- release NE (as NT)
* 4. NE binds to R
* 5. NE removal = Reuptake - metabolism of NE by COMT
* drugs mostly act on starred steps
pattern of cholinergic signaling
- synthesis of ACh
- storage in vesicles
- release ACh (as NT) into synapse
* 4. ACh binds to R
* 5. ACh removal = Degradation - ACh recycling
* drugs mostly act on starred steps
post-ganglionic sympathetic special case NTs/exceptions:
Sympathetic post-ganglionic neurons that do NOT use NE as NT
- sweat glands = ACh
- some vascular sm. muscle in skeletal muscle = ACh
- renal vascular sm. muscle = Dopamine
* Also: some tissues have mAChRs but No Parasymp. input
main/functional differences between Sympathetic and Parasympathetic pathways
Sympathetic:
- NE = reuptake at synapse
- High integration (activates all target organs at 1x)
- ganglia near spinal cord (long POST-ganglionic neurons)
Parasympathetic:
- ACh = degraded at synapse
- low integration (activation to targets = separate/individual)
- ganglia near targets (long PRE-ganglionic neurons)
Homeostatic reflexes
autonomic signaling influenced by info relayed to CNS integration central by the (original) ANS effector/target.
(multiple feedback loops)
- important for determining secondary effects of drugs*
ie: altering BP initiates feedback loops to heart, etc.
Target tissues w/ muscarininc ACh Rs
Parasympathetic: cardiac (decrease HR), sm. muscle (vasodilate), exocrine glands, endothelial cells
Sympathetic: sweat glands (activate)
tissues w/ nicotinic ACh Rs
somatic/voluntary: skeletal muscle (activation)
tissues w/ alpha adrenergic Rs
sympathetic: vascular smooth muscle (vasoconstrict)
tissues w/ beta adrenergic Rs
(sympathetic)
Beta-1 and 2: cardiac muscle (increase contractility & HR)
* beta-2: skeletal muscle vasculature (dilate)
Direct-acting Cholinergic Agonists
- Acetycholine
- Carbechol
- Bethanechol (m)
- Cevilmeline (m)
- Pilocarpine (m)
AcetylcholineEsterase (AChE) inhibitors
(= indirect cholinergic agonists)
- Echothiophate *irreversible
- Edrophomium
- Neostigmine
- Physostigmine
* less effect at non-firing sites (where normally no active signaling)
Cholinergic agonists (types, characteristics)
aka: cholinomimetics, Useful locally (eye, bladder, NMJ); bad side effects if given systemically. Types: direct, indirect, organophosphate antidote
non-selective ACh agonists
Direct: (2/5) acetylcholine & carbechol
Indirect: (all 4)
echpthiophate, edrophonium, neostigmine, and physostigmine
cholinergic agonists DURATION of ACTION
- Seconds: ACh
- Hours:
a) Bethanechol, Carbechol, Edrophonium
b) Cevimeline, Piloocarpine (indirect binding)
c) neostigmine, physostigmine - Days: Echothiophate
main effects of direct, non-selective cholinergic agonists
Heart: low [ ] –> reflex increase contractility,
high [ ] –> bradycardia
Vasc: vasodilate
GI: increase motility & salivation
Resp: bronchoconstriction, increase secretions
Eye: miosis
Urinary: increase voiding ** also: increase sweating! **
“DUMBBELSS”
side effects from any/all cholinergic agonists... D: diarrhea U: urination M: miosis Bx2: bronchospasm, bradycardia E: excitation (of sk. mm/fasciculations) L: lacrimation Sx2: sweating, salivating
cyclospasm
excessive accomodation (marked ciliary contraction) * may be from cholinergic agonists
miosis
reduction in pupil size due to circular muscle contraction
* may be induced by cholinergic agonists
accomodation
contraction of the ciliary muscle for near vision,
helps decrease intraocular pressure by facilitating outflow of aqueous humor
* may be induced by cholinergic agonists
Glaucoma
condition of increased intraocular pressure
damages retina and optic nerve –> restrict visual field/blindness.
Types = “open-“ or “closed-angle.”
Meds: #1 pilocarpine (for emergencies)
or echothiophate, timolol, prostaglandins
Sjogren’s Syndrome
autoimmune destruction of secretory glands in eyes & mouth,
- -> dry eyes/mouth, organ dysfunction (renal, lungs, vasc., etc)…
- primary = alone, secondary = w/ CT disease
Meds: pilocarpine, Cevimeline
Atonic/neurogenic bladder & ileus
disruption of normal GI motility/urination,
bc of: labor/delivery & surgery (–> opioid analgesics)
* may occur w/ megacolon
–> lack of: peristalsis, detrusor m. tone, sphincter tone
Meds: bethanechol, neostigmine
Myasthenia Gravis
autoimmune disease causing loss of nACh Rs @ NMJ only
(not at ANS ganglia)
–> muscle weakness, esp. w/exercise; ptosis/facial mm. weak
Meds:
1. Edrophonium: Dx and evaluate dosing
2. neostigmine: long-term management
Anti-cholinergic overdose
ie: atropine, tri-cyclics (anti-depressants), some plants (belladonna, jimson weed)
- -> hallucinations, hyperthermia (esp. in children)
* Antidote: physostigmine (AChE inhibitor)
Organophosphate poisoning (OR cholinergic overdose)
ie: pesticides/insecticides, nerve gases, echothiophate
- -> Sx depend on dose:
low: DUMBBELSS, med: tight chest, can’t walk, invol. urination;
high: loss of consciousness, seizures, death
* Antidote: Pralodoxime (#1), atropine
muscarinic AChR antagonists
- block receptor binding, non-selective*
1. atropine
2. ipratropium
3. scopolamine
nicotinic AChR antagonists
block receptor binding
Ganglionic blockers:
1. mecamylamine 2. trimethaphan (3. Nicotine)
Neuromuscular blockers:
1. cisatracurium 2. rapacuronium 3. succinylamine
4. tubocurarine (5. nicotine)
relative CNS distribution of Muscarinic cholinergic antagonists
- scopolamine (HIGHest)
- atropine (~high)
- Ipratropium (low)
general effects of cholinergic antagonists
Induce: “Blind, hot, red, mad”
(mydriasis/cycloplegia, increase temp, confusion/hallucination/delirium… dysregulation & death)
Block: “SLUD” = salivation, lacrimation, urination, defecation
mydriasis
increase in pupil size due to radial muscle contraction,
induced by nicotinic cholinergic antagonists
(block ciliary muscle contraction (= parasymp)
==> radial m. = unopposed)
*useful for eye exams
drugs to treat asthma
#1. epinephrine/beta-2 agonists 2. ipratropium ( 2nd choice, if don't tolerate B-2 agonists well) Also: cysteine-leukotriene inhibitors
COPD (chronic obstructive pulmonary disorder)
chronic, irreversible airflow obstruction and cilia loss
– emphysema (SOB) and chronic bronchitis (increased mucus production and cough)
Meds:
ipratropium or epinephrine/beta-2 agonists
depolarizing blockade
when a receptor is so continuously occupied that post-synaptic membrane stops responding (desensitization)
aka: ganglionic OR neuromuscular effect (depends on where)
– too much agonist ==> antagonistic function,
passes 1. (agonist effect) to cause 2. (antagonist effect).
ie: nicotine on nicotinic AChRs
Neuromuscular blockers
= nAChR antagonists that f(x) at NMJ.
Non-depolarizing antagonists:
(*at low [ ], can be out-competed by AChE inhibitors)
1. cisatracurium 2. rapacuronium 3. tubocurarine
Depolarizing agonist (functionally antagonistic, neurom. effect)
4. succinylcholine
phases of depolarizing neuromuscular blockers:
Phase I: “prolonged depolarization,” acts like agonist.
- fasciculations and flaccid paralysis
* response augmented by AChE inhibitors (even more ACh to flood Rs)
Phase II: gradually repolarize, but resistant to depolarization,
* not affected by AChE inhibitors
pharmacokinetic characteristics of neuromuscular blockers
- low distribution to CNS (highly polar)
- administer by IV (inactive if taken orally)
- vary in onset time and duration of action*
timing of neuromuscular blocker action (onset/offset)
Onset:
Succinylcholine (fastest, 1 min.) < Rapacuronium < Cisatracurium < Tubocurarine (slowest, 6 min.)
Duration of Action:
succinycholine (shortest, 5 min.) < rapacuronium < tubocurarine < cisatracurium (longest, 1 hr.)
tubocurarine metabolism pattern
(a neuromuscular blocker)
excreted in urine unchanged,
- terminate action w/ re-distribution.
rapacuronium metabolism pattern
(a neuromuscular blocker)
metabolized by Liver,
– action prolonged w/ hepatic disease
succinylcholine metabolism pattern
(a neuromuscular blocker)
metabolized by esterases,
– action prolonged if low levels pseudocholinesterase
(aka: plasma cholinesterase/butylcholinesterase;
made in liver but located in plasma)
cisatracurium metabolism pattern
(a neuromuscular blocker)
metabolized spontaneously
– no specific disease influences on duration of action
effects of neuromuscular blockers on cardiovascular system
Tubocurarine: inhibit cholinergic transmission at adrenal medulla
–> hypotension, *reflex: tachycardia
Succinylcholine: low = parasymp. stim., high = symp. stim.
–> bradycardia (low); hypertension & tachycardia (high)
Rapacuronium/Cisatracurium: none.
Major side effects of Neuromuscular blockers:
- hyperkalemia
- malignant hyperthermia
- increase intra-ocular and GI pressures, muscle pain
