introduction to autonomic drugs: cholinergic agents · pdf filedirect acting agents bind to...

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 oradrenergic 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, noncholinergicneurons

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

Muscarinic Nicotinic

Type of receptor G protein-linked (stimulates 2nd

messenger system)

Ion channel

Location Nerves, CNS, heart, smooth muscle, glands

Skeletal muscle (NMJ), CNSPreganglionic nerves

Receptor Type Location

M1 Nerves

M2 (Cardiac M2) Heart, nerves, smooth muscle

M3 Glands, smooth muscle, endothelium

M4 CNS

M5 CNS

NM Skeletal muscle (NMJ)

NN 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-asemetabolism, 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 sympaactivity

▪ 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 Susceptibility to cholinesterase

Muscarinicaction

Nicotinicaction

Acetylcholinechloride

++++ +++ +++

Methacholine + ++++ None

Carbachol Negligible ++ +++

Bethanechol Negligible ++ 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 Organ Response

EyeIris muscle (pupils) Contraction (miosis)

LungsBronchial muscle constriction

Ciliary muscle Accomodation (near vision)

Bronchial glands stimulation

Heart GI Tract

SA node rate (chrontropy) Motility Increase

Atria inotropy Sphincters Relax

AV node conduction velocity (dromotropy)

Secretion Stimulation

Ventricles Mildinotropy Urinary bladder

Blood vessels Dilation (EDRF)Constriciton (at very high doses)

Detrusor muscleTrigone &

sphincter

Contract

Relax

Salivary glands Stimulate Sweat glands 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 (30min-

6hours)

Organophosphates▪ Phosphorylates with Ach-ase = extremely stable bond =

(duration, ≥100hours)

Uses Approximate duration of action

AlcoholsEdrophonium

Myasthenia gravis, ileus, arrythmias

1-15min

Carbamates

Neostigmine Myasthenia gravis 0.5-2 hours

Pyridostigmine MG 3-6 hours

Physostigmine Glaucoma 0.5-2 hours

OrganophosphatesEchothiophate 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 cholinomimeticactions 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”