W3-1 Autonomic Nervous System - Cholinergic Drugs

Front 1

Basic steps in neurotransmission: sites of drug action

Back 1

1. Uptake of precursors
2. Synthesis of transmitter
3. Uptake/ transport of transmitter into vesicles
4. Degradation of surplus transmitter
5. Depolarization by propagated action potential
6. Influx of Ca in response to depolarization
7. Release of transmitter by exocytosis
8. Diffusion to postsynaptic membrane
9. Interaction with postsynaptic receptors
10. Inactivation of transmitter
11. Reuptake of transmitter or degradation products by nerve terminals
12. Uptake of transmitter by non-neuronal cells
13. Interaction with presynaptic receptors

Front 2

Major neurotransmitters in the body

Back 2

1. Acetylcholine
2. Dopamine
3. GABA (gamma-aminobutyric acid)
4. Glutamate
5. Glycine
6. Norepinephrine
7. Serotonin

Front 3

Acetycholine - role

Back 3

1. Used by the spinal cord neurons to control muscles
2. Used by many neurons in the brain to regulate memory.
3. Excitatory: most instances

Front 4

Dopamine - role

Back 4

Produces feelings of pleasure
Inhibitory usually

Front 5

GABA

Back 5

Major inhibitory neurotransmitter in the brain

Front 6

Glutamate

Back 6

Most common excitatory neurotransmitter in the brain

Front 7

Glycine

Back 7

Used mainly by neurons in the spinal cord.
Always inhibitory

Front 8

Norepinephrine

Back 8

Neurotransmitter and a hormone
Peripheral nervous system: part of the fight-flight response
Brain: neurotransmitter regulating normal brain processes
Excitatory usually, but inhibitory in a few brain areas

Front 9

Serotonin

Back 9

Inhibitory in pain pathways in the spinal cord

Front 10

Ways that drugs interfere with neurotransmission

Back 10

1. Increasing number of impulses
2. Release NT from vesicles with or without impulses
3. Block reuptake or block receptors
4. Produce more or less NT
5. Prevent vesicles from releasing NT

Front 11

What nervous system does autonomic belong to?

Back 11

Peripheral nervous system (PNS)

Front 12

What does autonomic control?

Back 12

1. Conveys all the outputs from CNS to rest of the body
- Except the motor innervation to skeletal muscle
1. Heart
2. Blood vessels
3. Smooth muscles
4. Glands

2. Regulates the involuntary function of the body
i. Smooth muscle tone - Contraction and relaxation of vascular and visceral smooth muscle
ii. The heart rhythm and force
iii. All exocrine (skin, salivary, lacrimal) and certain endocrine (renin from kidneys) secretions
iv. Energy metabolism (particularly in liver and skeletal muscle) e.g. digesting a meal and maintaining BP

Front 13

What are the two systems that belong to the autonomic?

Back 13

1. Sympathetic
2. Parasympathetic
Can not work alone

Front 14

Autonomic nervous system (ANS): Sensory receptors -> sensory neurons -> CNS (Integration) -> Preganglionic autonomic Efferent neurons (motor neurons)
-> ??????????????????
-> Effector organ

Back 14

GANGLIA

Front 15

Autonomic nervous system - Roles

Back 15

1. Maintain homeostasis
2. Most organs receive dual innervaton (some exceptions)
3. In general, opposing actions of the two systems balance one another
4. A rise in parasymp activity is accompanied by a fall in sympathetic activity (some exceptions)

Front 16

Some general rules of ANS neurotransmission - All motor nerve fibers leaving the CNS release ACh -> nicotinic receptors

Back 16

True

Front 17

Some general rules of ANS neurotransmission - All postganglionic PS fibers release ACh -> muscarinic receptors - T/F?

Back 17

True

Front 18

Some general rules of ANS neurotransmission - All postganglionic sympathetic fibers release NA -> a & b receptors - T/F?
What is the exception?

Back 18

True
Except sweat glands - ACh->muscarinic receptors

Front 19

Parasympathetic
1. Origin
2. Innervation
3. Autonomic ganglia
4. Length of fibers
5. Ratio of preganglionic to postganglionic fibers
6. Response
7. Chemical transmitter at autonomic ganglia
8. Chemical transmitter at the postganglionic nerve ending

Back 19

1. Craniosacral
2. Cardiac muscle, smooth muscle, glands, viscera
3. Near or within the wall of the effector
4. Preganglionic (lomg)
Postganglionic (short)
5. Branching of minimal
6. Discrete
7. ACh
8. ACh

Front 20

Sympathetic
1. Origin
2. Innervation
3. Autonomic ganglia
4. Length of fibers
5. Ratio of preganglionic to postganglionic fibers
6. Response
7. Chemical transmitter at autonomic ganglia
8. Chemical transmitter at the postganglionic nerve ending

Back 20

1. Thoracolumbar
2. Cardiac muscle, smooth muscle, glands, viscera
3. Near the CNS
4. Preganglionic (short)
Postganglionic (long)
5. High degree of nerve branching
6. Diffuse
7. ACh
8. NA (most cases)
Adrenaline and NA (adrenal medulla)
ACh (sweat glands)

Front 21

Most organs receive dual innervation, what the the exceptions - Only sympathetic?

Back 21

1. Sweat glands
2. Salivary glands
3. Adrenal medulla
4. Kidney
5. Pilomotor muscles

Front 22

Most organs receive dual innervation, what the the exceptions - Only parasympathetic?

Back 22

1. Most blood vessels
2. Ciliary muscle of the eye
3. Bronchial smooth muscle

Front 23

Cholinergic transmission - What is it?

Back 23

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Front 24

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Back 24

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Front 25

Parasympathetic nervous system

Back 25

1. REST & Digest: Conserves energy and restores body resources
2. Dec HR
2. Inc GIT activity
3. Inc digestive enzyme secretion
4. -> Inc Digestion abd Absorption

Front 26

Sympathetic nervous system

Back 26

1. Fight or Flight: Dominates during stress and emergency situations
2. Inc HR and BP
3. Inc blood sugar conc
4. Inc blood flow to skeletal and cardiac muscles
5. Dec blood flow to skin and internal organs
6. Mobilizes energy stores
7. Dilates pupil and bronchioles

Front 27

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Back 27

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Front 28

Cholinergic transmission - What chemical transmitter has both muscarinic and nicotinic effects?

Back 28

ACh

Front 29

Muscarinic effects

Back 29

Closely resembles PS stimulation

Front 30

Nicotinic effects

Back 30

1. Stim of all autonomic ganglia
2. Stim of voluntary muscle
3. Adrenaline secretion from adrenal medulla

Front 31

Nicotinic ACh receptors -
1. What are they?
2. What activates and blocks?
3. What types?

Back 31

1. Ligand gated ion channel - rosette like pentameric structure -> rapid inflow of cations -> depolarization -> AP
2. Selectively activated by nicotine and blocked by tubocurarine or hexamethonium
3. NM type: Muscle type - stim by PTMA and blocked by tubocurarine
NN type: Ganglion type - stim by DMPP and blocked by hexamethonium

Front 32

Nicotinic ACh receptors - Types
1. Location
2. Mechanism of signal transduction
3. Functional response

Back 32

NM type - Muscle type
1. Skeletal muscle NMJ, mainly postsynaptic
2. Excitatory; increase cation permeability (Na, K)
3. Skeletal muscle contraction

Front 33

Nicotinic ACh receptors - Types
1. Location
2. Mechanism of signal transduction
3. Functional response

Back 33

NN type - Ganglion type
1. Autonomic ganglia, mainly postsynaptic
2. Excitatory, increase cation permeability (NA, K)
3. Secretion of catecholamines
Excitation of postganglionic neurons

Front 34

Muscarinic receptors -
1. What are they?
2. Types

Back 34

1. G-protein coupled receptors
2. M1-M5
- M1, M3, M5 -> Gq protein -> Activation of PLC -> IP3/DAG -> Inc Ca & PKC
- M2, M4 -> Gi protein -> Inhibition of AC -> Dec cAMP -> Dec. Ca conductance

Front 35

ACh receptors - Muscarinic - Types

Back 35

M1: Neuronal
M2: Cardiac
M3: Glandular

Front 36

Muscarinic agonists
1. What effects?
2. What are they?
3. Structure
4. Name a few

Back 36

1. Parasympathomimetic drugs
2. A quaternary ammonium group
3. An ester group: susceptible for hydrolysis by cholinesterase
4. ACh
Carbachol
Methacholine
Bethanechol
Muscarine
Pilocarpine
Oxotremorine

Front 37

Muscarinic agonists - Pharmalogical effects

Back 37

1. Cardiovascular
- Blood vessels - DIlate
- Heart rate - Slow
- BP -Dec.
2. GIT
- Tone - Inc.
- Motility - Inc.
- Sphincters - Relaxed
3. Glands
- Inc. salivary, lacrimal, intestinal and sweat secretion
4. Eye
- Pupil constricts and dec. accommodation

Front 38

Muscarinic agonists - Major clinical use

Back 38

1. Glaucoma and to reverse the effects of mydriatics
- ACh, Pilocarpine, Carbachol
2. Xerostomia
- 5-10mg pilocarpine -> Inc. parotid, subman and sublingual secretions
- Max flow rates in 30 min, return to baseline in about 3 hrs
- 3 times daily
- Salivatory stimulatory effects depends on residual salivary gland function
- No sig effects on BP, HR, or cardiac function at these doses
- Sweating (common), chills, nausea, and dizziness also reported
- Cevimeline more selective for M1&M2 (fewer adverse effects)
- Oral fluid, saliva substitutes

Front 39

Muscarinic agonists - Adverse effects

Back 39

DUMBELS
1. DIarrhea
2. Urination
3. Miosis
4. Bronchoconstriction
5. Excitaion
6. Lacrimation
7. Salivation

Front 40

Slide 36

Back 40

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Front 41

What products results from hydrolysis of ACh?

Back 41

1. Choline
2. Acetate

Front 42

Give one example of drug that acts as cholinesterase blockers?

Back 42

1. Reversible
- Edrophonium
- Neostigmine
- Physostigmine
- Pyridostigmine
- Donepezil
- Rivastigmine
- Galantamine
2. Irreversible
- Ecothiophate

Front 43

Mechanisms of reversible vs irreversible AChE inhibitors

Back 43

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Front 44

Anticholinesterases - Edrophonium

Back 44

1. Quaternary alcohol
2. REversible binding by electrostatic forces and hydrogen bonds to the active site
3. Prevent access to ACh
4. No covalent bond involved, therefore enzyme-inhibito complex is short-lived (2-10mins)

Front 45

Anticholinesterases - Neostigmine and Physostigmine

Back 45

1. Carbamate esters
2. Covalent bonds
3. Longer time to be hydrolyzed (30min-6hrs)

Front 46

Anticholinesterases- Organophohsphates

Back 46

1. Irreversible AChE inhibitor - Ecothiophate
2. Phosphorylates the active site: binds covalently via its phosphate group to serine-OH group at the active site
-> loss of alkyl group (aging)
-> impossible for enzyme reactivators (PAM) to break the bond between the remaining drug and the enzyme
-> Permanently inactivates the enzyme
-> Restoration requires synthesis of new enzyme molecules

Front 47

AChE: Pharmacological effects-CNS

Back 47

- Excitation -> convulsions (low dose)
- Depression - unconsciousness - respiratory failure (high dose)

Front 48

AChE: Pharmacological effects - Effect of autonomic cholinergic synapses

Back 48

1. Inc salivary, lacrimal, bronchial, GIT secretions
2. Inc peristaltic activity
3. Bronchoconstriction
4. Bradycardia, hypotension
5. Miosis
6. Dec. intraocular pressure

Front 49

AChE: Pharmacological effects - Effect on NMJ

Back 49

1. Inc strength of contraction
2. Fibrilation of muscle fiber
3. High does -> depolarise NM blockade
4. Reversal of tubocurarine effect
5. Improved transmission in myasthenia gravis

Front 50

AChE: Pharmacological effects - Demyelination of nerves

Back 50

Weakness and sensory loss

Front 51

AChE: Pharmacological effects - Cholinesterase activators
What is the name?
What does it do?

Back 51

1. Pralidoxime (PAM)
2. Reactivates ChE once blocked by organophosphates

Front 52

Muscaricnic agonists - Clinical uses

Back 52

1. Glaucoma (pilocarpine and physostigmine)
2. Postoperative ileus - congenital megacolon
3. Postoperative urinary retention - neurogenic bladder
4. Reflux oesophagitis
5. To reverse the actions of non depolarizing NMJ blockers
6. Myasthenia Gravis
7. Alzheimer's disease
8. Atropine poisoning

Front 53

Organophosphate poisoning
1. Signs and symptoms
2. What to do

Back 53

1. Signs and symptoms
- Salivation
- Sweating
- Bronshoconstriction
- Vomiting
- Diarrhoea
- Depolarizing NMJ blockade
2. What to do
- Maintain vital signs
- Decontaminate
- High dose atropine

Front 54

Muscarinic antagonists
1. Another name
2. What are they?
3. Structure
4. Names

Back 54

1. Parasympatholytic drugs
2. Competitive antagonists
3. Usually contain ester and basic group in the same relationship as ACh
4. Atropine
- Scopolamine
- Ipratropium
- Tropicamide
- Cyclopentolate
- Pirenzepine
- Darifenacin

Front 55

Muscarinic antagonists - Pharmacological effects

Back 55

1. Inhibition of secretions
2. Effects on heart rate
3. Effects on eye
4. Effects on GIT
5. Effects on other smooth muscles
6. Effects on CNS

Front 56

Muscarinic antagonists - Pharmacological effects -

Back 56

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Front 57

Muscarinic antagonists - Pharmacological effects

Back 57

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Front 58

Muscarinic antagonists - Pharmacological effects

Back 58

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Front 59

Muscarinic antagonists - Pharmacological effects

Back 59

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Front 60

Muscarinic antagonists - Pharmacological effects

Back 60

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Front 61

Muscarinic antagonists - Pharmacological effects

Back 61

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Front 62

Muscarinic antagonists - Atropine

Back 62

1. In opthalmology, to produce mydriasis and cycloplegia prior to refraction
2. To treat spastic disorders of GI and lower urinary tract
3. To treat organophosphate poisoning
4. To suppress respiratory secretions prior to surgery

Front 63

Muscarinic antagonists - Scopolamine

Back 63

1. In obstetrics, with morphine to produce amnesia and sedation
2. To prevent motion sickness

Front 64

Muscarinic antagonists - Ipratropium

Back 64

Tx of asthma

Front 65

Muscarinic antagonists - Pirenzipine

Back 65

Peptic ulcer

Front 66

Muscarinic antagonists - Darifenacin

Back 66

Urinary incontinence

Front 67

Muscarinic antagonists - Tropicamide/Cyclopentolate

Back 67

Ophthalmology use, short acting than atropine

Front 68

Adverse effects of muscarinic antagonists

Back 68

1. Blurred vision
2. Confusion
3. Mydriasis
4. Constipation
5. Urinary retention

Front 69

Cholinergic blocking agents - Dental practice

Back 69

1. Do not overhead dental light into eyes (Photophobia)
2. Monitor heart rate and qualities before tx
3. Make sure the walkway is unobstructed (blurred vision)
4. Examine oral cavity for caries, candidiasis, periodontal
5. Oral health education
- Chronic dry mouth: Home F products on a daily basis
- Xylitol gum - stim saliva for anti-caries effect

Front 70

Neuromuscular junction (NMJ) blockers
1. What do they do?
2. Structure
3. Used clinically

Back 70

1. Block the cholinergic transmission between motor nerve endings and nicotinic receptors on the neuromuscular endplate of skeletal muscle.
2. Structural analogues of ACh
- Act either as antagonists -> non-depolarizing type
- Or agonist -> depolarizing type at receptors on the endplate of the NMJ.
3. During surgery for complete muscle relaxation, without using higher doses of anaesthesia

Front 71

Classification of muscle relaxants according to mechanism of action

Back 71

1. Depolarizing: Succinylcholine
2. Nondepolarizing:
- Pancuronium
- Atracurium
- Cisatracurium
- Doxacurium
- Vecuronium
- Pipecurium
- Mivacurium
- Rocuronium

Front 72

Muscle relaxants: Non depolarizing agents

Back 72

1. Also called competitive or stabilizing agents
2. Compete with ACh at the NMJ
3. Blocks the effects of ACh -> muscle paralysis and flaccidity
4. Can be counteracted clinically by AntiChE drugs
5. Initial muscle weakness quickly changes to flaccid paralysis

Front 73

Muscle relaxants: Non depolarizing agents

Back 73

1. First muslces affected are those innervated by cranial nerves (eyes, face and neck)
2. Followed by Limb, Abdomen, Trunk, Intercostals and diaphragm
3. Recovery usually in reverse order

Front 74

Muscle relaxants : Can non depolarizing agents affect mental status or pain?

Back 74

NO because they do not cross BBB

Front 75

Muscle relaxants: Use of non depolarizing agents

Back 75

Intermediate and prolonged muscle relaxatoin
1. Facilitated intubation
2. Muscle relaxation for surgery
3. Continued mechanical ventilation
4. Prevent additional injury (penetrating globe injuries)

Front 76

Muscle relaxants: Depolarizing agents - Suxamethomium/Succinylcholine - Biphasic effect

Back 76

1. Phase1:
- Acts like ACh and depolarizes the synaptic membranes of the mucle
- Not deactivated by AChase
- Causes muscle fasiculations, followed by muscle paralysis and flaccidity
2. Phase 2: Not seen except in high concentrations
- Causes receptor site blockade and continued paralysis

Front 77

Muscle relaxants - Succinylcholine

Back 77

1. Only clinically available agent
2. Bisfunctional agonist - two cholines esterified to a central dicarboxylic acid.
3. Resistant to AChE, but susceptible to plasma ChE
4. Binds to nicotinic receptors in skeletal muscle
- Initial spasm: due to maintained depolarisation at end-plate since the drugs act as agonists
- Paralysis: due to inactivation of voltage-sensitve Na channels by over-depolarisation

Front 78

Muscle relaxants - Succinylcholine - Uses

Back 78

Rapid endotracheal intubation during the induction of anaestheis
Electroconvulsive shock tx

Front 79

Muscle relaxants - Succinylcholine - Adverse effects

Back 79

1. Malignant hyperthermia
2. Apnoea
3. Hyperkalemia