L5 Autonomic pharmacology: cholinergic and anti cholinergic drugs

一、Human Nervous System

Controls and coordinates functions throughout the body
Nervous System
- Central Nervous System (Brain, Spinal cord)
- Peripheral Nervous System (cranial (颅) + spinal nerves + sense organs)
  - Somatic (regulates activities under voluntary control)
  - Autonomic (regulates activities under involuntary control)

Organization of nervous system

Nervous network

Peripheral nervous system(PNS)
- Autonomic nervous system(ANS): ANS: not directly under conscious control
  - (sympathetic and parasympathetic)
- Somatic nervous system: Somatic :under conscious control (movement)
Central nervous system (CNS)

Chemical transmission (neurotransmitters: cholinergic and adrenergic)

ganglion is a nerve cell cluster or a group of nerve cell bodies located in the autonomic nervous system

1. More details on ANS

The autonomic nervous system (ANS) is a division of the peripheral nervous system that influences the function of internal organs

a control system that acts largely unconsciously and regulates bodily functions such as the heart rate, digestion, respiratory rate, pupillary response, urination, and sexual arousal.

The sympathetic nervous system: the “fight or flight“ system; “quick response mobilizing system“

The parasympathetic nervous: the “rest and digest“ or “feed and breed” system; “more slowly activated dampening system“

ANS often work in conjunction with SNS which provides voluntary control

ganglion is a nerve cell cluster or a group of nerve cell bodies located in the autonomic nervous system
Sympathetic and parasympatheic are anotomic designations: independent of types of transmitter chemicals, or the kind of effect evoked by nerve activity (excitatory vs inhibitory)
- parasympathetic system does not have extra ganglions
- Ganglions are mainly used by sympathetic systems

ANS: Neurotransmitter &receptors

Parasympathetic: Always use Ach as neurotransmitter

二、Neurotransmitters

Receptors

Classification of neurotransmitter receptors of ANS

Cholinoceptors
Adrenoceptors
Dopamine receptors

Mechanisms of action

G-protein-coupled receptor(GPCR)
ligand-gated ion channels (Nicotic)

1. GPCR and G protein

2. Ligand-Gated Channels

The nicotinic acetylcholine receptor

The open of channel results in the flow of ion and thereby alters the electrical potential across the membrane

The natural ligands including N-acetylcholine, excitatory amino acids (glycine, glutamate, etc), γ-GABA (Cl-, chlorine)

All of these agents are synaptic transmitters

3. Acetylcholine receptor

Muscarinic acetylcholine receptors

M1 M2 M3 M4 M5

Nicotinic acetylcholine receptors

N1 N2

M1,M3,M5– Gq protein to induce IP3 and DAG

M2,M4- Gi protein to inhibit cAMP, opening K+ channel

N receptor: ion-channel, opening Na+ channel depolarization

Muscarinic acetylcholine receptors(mAChR,M1,3,5)

Location: CNS, stomach, salivary gland et al.

Muscarinic acetylcholine receptors(M2,4)

Location: heart, gastrointestinal(GI) smooth muscle, CNS

Nicotinic acetylcholine receptors (nAChR,N-R)

ligand-gated ion channel, 5 subunits
16 different subunits: α(9)/β(4)/γ/δ/ε
nAChR: 3 main types—muscle type/ganglion type/CNS type
- mostly in the central nervous system , except:
  - transmit outgoing signals from the presynaptic to the postsynaptic cells within the sympathetic and parasympathetic nervous system,
  - found on skeletal muscle that receive acetylcholine released to signal for muscular contraction.

Nicotinic acetylcholine receptors(N-R)

Receptors & locations

Direct effect of autonomic nerve activity on some organ systems

Receptor type in parasympathetic system: all muscarinic acetylcholine receptor

acetylcholine(Ach)

Cholinergic fibers

All preganglionic autonomic fibres
All postganglionic parasympathetic fibres
A small number of postganglionic sympathetic fibres

VAT: vesicle-associate transporter
VAMP: vesicle-associated membrane proteins
SNAP: synaptosomal nerve-associated proteins

1. Cholinoceptor-activating drugs

Objectives

To know classification of cholinoceptor-activating and cholinesterase-inhibiting drugs, chemical structures and mechanism of action
To understand major pharmacological effects and therapeutic applications
To understand major adverse reactions

Cholinergic nerves and receptors

Classification of drugs

Cholinomimetic agents

Cholinoceptor-activating(direct)
Cholinesterase inhibitors(indirect)

The direct-acting drugs

(1) Chemistry & pharmacokinetics

Chemical structures:
- Esters of choline: acetylcholine. methacholine, carbacholine…
- Alkaloids: muscarine, nicotine
M,N receptor agonists: acetylcholine, carbacholine
M receptor agonists: pilocarpine

Alkaloid, any of a class of naturally occurring organic nitrogen-containing bases.

(2) Absorption, distribution, Metabolism

Choline esters: poorly absorbed, poor in CNS-hydrophlic

poorly absorbed: the molecules are polar and charged, hard to pass through the cell membrane

Alkaloids: easy to absorbed, nicotine> muscarine –neurotoxic (mushrooms)

(3) Pharmacological effects

Eyes

miosis (瞳孔过小) (M3-R)
reduced intraocular pressure (secondary effect)
accommodation spasm (M3-R)

Miscellaneous secretary glands (M3-R)

Miscellaneous secretary glands (M3-R)

Respiratory system

contract smooth muscle in bronchial tree (M3-R→Ca2+)
stimulate secretion of tracheobronchial mucosa (M3-R→Ca2+)

Cardiovascular system mainly Reduces heart rate (M2)

Increase potassium ion concentration
- atrial muscle
- sinoatrial muscle
- atrioventricular nodes
decrease hyperpolarization-activated current
slow inward calcium current

Vasodilation and blood pressure

M3 R in endothelial cells → relax smooth muscle

Gastrointestinal(GI) tract

Secretion of salivary(M3-R), gastric(M1-R), gut glands(M3-R)
Motility of GI smooth muscle(M3-R)
Sphincters of GI → relaxation

Genitourinary tract (M3-R)

Contraction of detrusor urinary + Relaxation of trigone and sphincter muscles of the bladder
- To promote voiding
Uterus is less sensitive to M-receptor agonists

(4) Clinical uses

Stomach, bowel, urine retention: (bethanechol)

Salivary secretion: (pilocaine)

2. The indirect-acting drugs

(anticholinesterase agents ,such as neostigmine, physostigmine)

Quanternary ammonium group
2.carbamic acid
organophosphates

3. Cholinesterase inhibitors

(anticholinesterase agents ,such as neostigmine, physostigmine)

Organophosphate-based choplinesterase inhibitors

Well absorbed
Causing skeletal muscle paralysis in miniutes

Cholinesterase: mechanism of action

4. Pharmacodynamics

Mechanisms of Action

Pharmacological actions

Similar to that of the direct-acting drugs on the eye, the cardiovascular and gastrointestinal systems, and the skeletal muscle neuromuscular junction

antimuscarinic drug intoxication

Physostigamine (counteracting atropine and tricyclic antidepressants)

glaucoma

physostigamine

5. Cholinoceptor-blocking drugs

Classification of drugs

Anticholinergic Drugs

M-cholinergic receptor blockers(Muscarinic antagonist)
- atropine-like alkaloids
- synthetic and semisynthetic substitutes for belladonna alkaloids
N-cholinergic receptor blockers (antinicotinic)
- neuromuscular blocking drugs
- ganglionic blocking drugs
  - Very rare used in clinical practice

For Atropine

Mechanism of action

Competitively antagonize M-R mediated effects of Ach. High selective drug for M receptors
Therefore the atropine increase heart rate and relax the lung.