Download Lecture 3 – intro to ANS drugs – cholinergic

Lecture 3

Autonomic nervous system
 Sympathetic
 Parasympathetic

Nerve impulses and synapses
 Axon terminal
 Synapse
 Receptors on the effector organ

Basic arrangement of nerves:
 CNS  nerve  ganglion  nerve  effector
organ
 Preganglionic and postganglionic nerves
▪ Preganglionic parasympathetic and preganglionic
sympathetic
▪ Postganglionic para and postganglionic sympa
Preganglionic
Postganglionic
Parasympa
Acetylcholine (long)
Acetylcholine (short)
Sympa
Acetylcholine (short)
Noradrenaline or
dopamine (long)
Ganglionic receptor
Effector receptor
Parasympa =
Cholinoceptors or
cholinergic receptors
Nicotinic receptor
Muscarinic receptor
Sympa = Adrenoceptors or
adrenergic receptors
Nicotinic receptor
Muscarinic, Adrenaline,
noradrenaline or
dopamine receptors

5 key features of neurotransmitter function,
which can be targets for pharmacotherapy
 Synthesis
 Storage
 Release
 Termination of action
 Receptor effects

Acetylcholine (Ach)
 Produced in the nerve axon body and stored in the
axon terminal
 Synthesized from acetyl-CoA + choline (via enzyme
choline acetyltransferase or ChAT)
▪ Acetyl CoA comes from the mitochondria (Krebs)
▪ Choline is absorbed by the nerve cell from outside thru a
transporter called choline transporter (CHT)
▪ Blocked by a research drug called Hemicholiniums
 Once synthesized, Ach is transported to vesicles by a
vessicle associated transporter (VAT)
▪ Blocked by a research drug called vesamicol

Acetylcholine (Ach)
 Release of neurotransmitter is dependent on
calcium entry into the nerve axon
▪ Once an action potential (nerve impulse) reaches the
terminal end of the axon, calcium channels open.
▪ This promotes vesicles to merge with the axonal
membrane to release contents into the synapse
▪ Release can be blocked by botolinum toxin

Acetylcholine (Ach)
 Once released, Ach binds with cholinoceptors on
the effector organ = effect
 Ach is then deactivated by AChe
(acetylcholinesterase)
▪ Very rapidly
▪ Split into acetate and choline
▪ Choline is then recycled back into the nerve axon

Noradrenaline or Norepinephrine
 Synthesis
▪ Starts as a tyrosine molecule, eventually modified into
dopa  dopamine  norepinephrine  epinephrine
▪ Conversion of tyr to dopa inhibited by drug metyrosine
 Storage
▪ Stored in vesicles via transporter VMAT (vesicular
monoamine transporter)
▪ Blocked by drug reserpine = depletion of adrenergic stores

Noradrenaline or Norepinephrine
 Release
▪ Similar to cholinergic release = nerve impulse stimulates
opening of Ca++ channels
 Termination of action
▪ 2 processes:
▪ Simple diffusion away from the receptor site (with eventual
metabolism in the plasma or liver)
▪ Reuptake into the nerve terminal by NET (norepinephrine
transporter)
 Blocked by drugs such as cocaine and tricyclic antidepressants
(TCAs) = increased neurotransmitter activity in the synapse

NANC or nanadrenergic, noncholinergic
neurons
 Some parts of the ANS does not follow the usual
classification
 May use a combination of adrenergic and
cholinergic receptors and transmitters
 May use other substances (ex. nitric oxide,
cholecystokinin, enkephalins, serotonin,
somatostatin, etc.)

ANS = sympa and parasympa
 Multifactorial and multilevel interactions
 Ex. blood pressure or mean arterial pressure
(MAP)
▪ MAP = CO x TPR
▪ CO = SV x HR
 SV = Venous return = blood volume = affected by oral intake
and kidneys
▪ TPR = arterial diameters
▪ Give norepinephrine (a potent vasoconstrictor) in small
doses = promote vasoconstriction and slightly increased
HR  increase BP
▪ But the TPR will induce the parasympa to HR (via vagus nerve
and baroreceptors in the carotid body)
▪ Therefore = there will be an BP with a corresponding HR,
despite the direct action of NE to the heart

Historically, plant derivatives, muscarine
(mushroom Amanita muscaria) and nicotine
(tobacco), were applied or ingested, which
produced parasympathetic effects.
 Receptors were termed muscarinic or nicotinic

Usually has a diffuse action (due to wide
spread presence of cholinergic receptors)
 Selectivity of action may be achieved via:
▪ Modifying the drug for specific receptors
▪ Modifying route of administration = ex. eye drops
Type of receptor
Location
Muscarinic
Nicotinic
G protein-linked
(stimulates 2nd
messenger system)
Nerves, CNS, heart,
smooth muscle,
glands
Ion channel
Skeletal muscle
(NMJ), CNS
Preganglionic
nerves
Receptor Type
M1
M2 (Cardiac M2)
Location
Nerves
Heart, nerves, smooth muscle
M3
M4
M5
Glands, smooth muscle, endothelium
CNS
CNS
NM
NN
Skeletal muscle (NMJ)
CNS, postganglionic cell body,
dendrites

Direct acting agents bind to and activate
muscarinic or nicotinic receptors
 Acetylcholine, methacholine, carbachol,
bethanechol

Indirect acting agents inhibit
acetylcholinesterase
 Neostigmine, carbaryl, physostigmine,
edrophonium

Pharmacokinetics
 Permanently charged = hydrophilic
▪ Poorly absorbed into the CNS
 Rapidly metabolized by Ach-ase (AChe)
▪ Ach = very rapidly metabolized
▪ Need to give a very large amount and injected very quickly to
produce an effect
▪ Modified drugs are more resistant to Ach-ase
metabolism, and therefore longer duration of action
▪ Methacholine < Carbachol < Bethanechol

Pharmacodynamics
 MOA:
▪ activates muscarinic receptors on effector organ
▪ Inhibits release of neurotransmitters on nerve terminals with
muscarinic receptors
▪ In effect, promote parasympa activity and inhibit sympa
activity
▪ Muscarinic receptors activate the 2nd messenger cascade (ex.
IP3 and DAG cascade)
▪ Nicotinic receptors opens up Na+ and K+ channels causing
depolarization of the nerve cell or NMJ, producing
contraction of the muscle

Pharmacodynamics
▪ Special activity at nicotinic receptors during prolonged
exposure to agonists
▪ Prolonged agonist occupancy of the nicotinic receptor will
eventually stop its activity (ex. the muscle initially contracts then
relaxes despite exposure to the agonist)
▪ Continued presence of the nicotinic agonist prevents electrical
recovery of the postjunctional membrane = “depolarizing
blockade” (receptor becomes insensitive to more agonist
concentrations)
▪ Receptor eventually becomes desensitized to agonist and is
becomes more difficult to be reversed (useful in muscle relaxant
drugs = ex. succinylcholine)
Choline Ester
Acetylcholine
chloride
Methacholine
Carbachol
Bethanechol
Susceptibility to
cholinesterase
++++
Muscarinic
Nicotinic
action
action
+++
+++
+
Negligible
Negligible
++++
++
++
None
+++
None

Organ System Effects
 Eye
▪ Pupillary constriction and accomodation
 Cardiovascular system
▪ Reduction in peripheral vascular resistance
▪ Decreased HR
 Respiratory system
▪ Bronchoconstriction and increased glandular activity

Organ System Effects
 Gastrointestinal
▪ Increase secretory and motor activity of the gut
 Genitourinary
▪ Promote voiding
 Secretory glands
▪ Stimulate sweat, lacrimal, nasopharyngeal glands

Organ System Effects
 Central Nervous System
▪ Muscarinic receptors =
▪ role in cognition, learning
▪ hunger
▪ Nicotinic receptors =
▪ release of other transmitters (ex. glumatate, serotonin, GABA,
etc)
▪ Chronic exposure can lead to desensitization and greater release
of dopamine in the mesolimbic system
 Contributes to the mild alerting and addictive qualities of
cigarette smoking
Organ
Response
Eye
Iris muscle (pupils) Contraction (miosis)
Ciliary muscle
Accomodation (near
vision)
Heart
Organ
Response
Lungs
Bronchial muscle
constriction
Bronchial glands
stimulation
GI Tract
SA node
rate (chrontropy)
Motility
Increase
Atria
inotropy
Sphincters
Relax
AV node
conduction velocity
(dromotropy)
Secretion
Stimulation
Ventricles
Mild inotropy
Blood vessels
Salivary glands
Dilation (EDRF)
Constriciton (at very
high doses)
Stimulate
Urinary bladder
Detrusor muscle
Trigone &
sphincter
Sweat glands
Contract
Relax
Stimulate
Act by inhibiting acetylcholinesterase = increasing or
prolonging Ach activity on the synapse
 3 groups

 Alcohols with quaternary ammonium group
▪ Edrophonium
 Carbamic acid esters with quaternary or tertiary
ammonium groups
▪ Carbamates (Ex. neostigmine, pyridostigmine, physostigmine)
 Organic derivatives of phosphoric acid
▪ Organophosphates (ex. echothiophate) and thiophosphates
(malathion)

Pharmacokinetics
 Carbamates
▪ Generally hydrophilic, and therefore poor absorption in
lungs and gut and skin
 Organophosphates
▪ Generally hydrophilic, but more lipid soluble than
carbamates = better absorbed in skin, gut and lungs
▪ Potentially more dangerous to humans, but can kill more insects
▪ Relatively shorter half-life in the environment than carbamates

Pharmacokinetics
 Thiophosphates
▪ More lipid soluble = better drug absorption
▪ Must be activated in the body to produce an effect
▪ Easily metabolized into inactive products among birds
and mammals, but not in insects and fishes
▪ Makes it potentially more safe to humans.

Pharmacodynamics
 MOA: Inhibits Ach-ase
 Alcohols
▪ Reversibly bind with Ach-ase, preventing binding with Ach.
▪ Effect is of short duration (5-15min)
 Carbamates
▪ Covalently bonds with Ach-ase. = longer duration (30min6hours)
 Organophosphates
▪ Phosphorylates with Ach-ase = extremely stable bond =
(duration, ≥100hours)
Uses
Alcohols
Edrophonium
Carbamates
Neostigmine
Pyridostigmine
Physostigmine
Organophosphates
Echothiophate
Myasthenia gravis,
ileus, arrythmias
Approximate
duration of action
1-15min
Myasthenia gravis
MG
Glaucoma
0.5-2 hours
3-6 hours
0.5-2 hours
Glaucoma
100 hours

Organ System Effects
 CNS
▪ Produce mild alertness
 Eye, respiratory tract, GIT, urinary
▪ Similar to cholinergic drug effects
 Cardiovascular system
▪ Can increase activity on both para and sympa ganglia
▪ Heart = negative chronotropic, dromotropic and inotropic effects
▪ Blood vessels lack cholinergic innervation.  sympathetic response
 vascular constriction  increase in blood pressure
▪ NET effect = HR, CO, TPR = BP
▪ At toxic doses, there will be severe bradycardia = hypotension

Organ System Effects
 Neuromuscular Junction (NMJ)
▪ At low doses = intensify action of Ach at the NMJ =
increase muscular contractions. May help treat muscle
weakness in myasthenia gravis
▪ Moderate doses = may produce fasciculations of the
muscle unit (ex. tonic-like seizure)
▪ High doses = prolonged relaxation (neuromuscular
depolarizing blockade, as in succinylcholine)

Treatment for
 Diseases of the eye (Glaucoma)
 Gastrointestinal and urinary tract (motility
problems, postoperative atony, neurogenic
bladder)
 Neuromuscular junction (myasthenia gravis)
 Alzheimer’s disease

Excess of parasympathetic effects
 Nausea, vomiting, diarrhea, urinary urgency, salivation,
cutaneous vasodilation, bronchial constriction, seizures,
coma, death

Nicotine overdose
 Fatal dose is 40mg, or 1 drop of the pure liquid (in essence
is the amount in 2 cigarettes)
▪ Destroyed by heat, and exhaled
 Chronic smoking = behavioral therapy, nicotine patch,
nasal spray or inhaler
▪ New drug Varenicline = prevents release of dopamine in the
thalamus = reduce the rewarding/addicting sensation
▪ Side effects = nausea, insomnia, anxiety, depression, suicidal
ideation

Pesticide/Insecticide overdose
(organophosphates)
 “Muscarinic excess” = miosis, salivation, sweating,
bronchial constriction, vomiting, diarrhea,
convulsions, coma, muscle and respiratory
depression
 Treatment = atropine

Used during warfare = “nerve gas”


Also called parasympatholytic
Cholinoceptor antagonists
 Nicotinic antagonists
▪ Ganglion blockers = little clinical significance (because of its
very broad effects)
▪ NMJ blockers = muscle relaxants
 Muscarinic antagonists
▪ Atropine = basic drug
▪ Synthetic drugs = developed for more specific and less toxic
effects
▪ Tertiary = 3rd generation (pirenzepine, dicyclomine, trpicamide,
benztropine)
▪ Quaternary = 4th generation (propantheline, glycopyrrolate,
tiotropium)

Atropine
 Found from the plant Atropa belladona (“deadly
nightshade”)
 Generally well absorbed
▪ Tertiary drugs enter the CNS readily (more lipid soluble)
▪ Quaternary drugs less lipid soluble (less absorbed in the GUT
and CNS) = more peripheral activity
 Elimination: 2 phases
▪ Rapid phase = t½ 2 hours
▪ Slow phase = t½ 13 hours
▪ Excreted mainly in the urine

Atropine
 MOA = reversible blockade of cholinomimetic
actions at muscarinic receptors (may be overcome
by large doses of Ach)
 Inverse agonists = stop the muscarinic receptor
from being active

Organ System Effects
 CNS
▪ Mild CNS effect
▪ Treatment for tremors in Parkinson’s disease
▪ Due to relative excess of cholinergic activity (due to decreased
dopamine activity in the brain)
 Eye
▪ Used by ophthalmologists to examine the eye
▪ Mydriasis (pupil dilation)

Organ System Effects
 Cardiovascular
▪ Stimulates SA node = tachycardia
▪ Shortens AV node conduction = tachycardia
▪ Blood vessels have minimal innervations from
parasympa = mild effect on BP
▪ NET effect = HR but normal BP
 Respiratory
▪ Mild bronchodilation and reduce bronchial secretions
▪ Useful during inhalational anesthetics

Organ System Effects
 Gastrointestinal
▪ Decrease salivary, stomach and intestinal secretions
▪ Decreased peristalsis = prolonged GI time
 Genitourinary
▪ Relaxes urinary bladder = slows voiding
 Sweat glands
▪ Decreases sweating = may affect temperature
regulation, called atropine fever


Parkinson’s disease (in combination with
dopamine drugs)
Motion sickness
 Due to cholinergic activation of vestibular nerves (ear)
 Scopolamine best used to treat motion sickness
For eye exam
Preparation for pre-operative patients who will
need inhalational anesthetics
 Asthma


 Ipratropium = bronchodilation and decreased
secretions

Reversing bradycardia
 Acute myocardial infarction and resuscitation

Gastrointestinal
 Peptic ulcer disease, diarrhea


Antidote for nerve gas and organophosphate
poisoning and some types of mushroom
poisoning
Hyperhydrosis (excessive sweating)

Symptoms: dry mouth, mydriasis,
tachycardia, hot and flushed skin, agitation
and delirium
 “dry as a bone, blind as a bat, red as a beet, mad
as a hatter”