By Qingwei Zhang Olivia STRUCTURE ANS RECAP CHOLINOMIMETICS CHOLINOCEPTOR AGONISYS CHOLINOCEPTOR ANTAGONISTS NEUROMUSCULAR JUNCTION BLOCKING DRUGS ANS Recap SALIVARY GLANDS Thick viscious secretion ID: 774951
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Slide1
Cholinergic drugs & NMJ blockers
By Qingwei Zhang (Olivia)
Slide2STRUCTURE
ANS RECAP
CHOLINOMIMETICS (CHOLINOCEPTOR AGONISYS)
CHOLINOCEPTOR ANTAGONISTS
NEUROMUSCULAR JUNCTION BLOCKING DRUGS
Slide3ANS Recap
Slide4SALIVARY GLANDS
Thick, viscious secretion
Copious, watery secretion
SKIN
Piloerection
Increased sweating (C)
HEART
rate and contractility
rate and contractility
GASTROINTESTINAL
motility and tone;
Sphincter contraction
motility and tone;
secretions
BLOOD VESSELS
Constriction
(skin, mucous membranes and splanchnic area)
EYE
Dilatation (Pupil)
Constriction (Pupil)
Contraction (Ciliary Muscle)
TRACHEA AND BRONCHEOLES
Dilates (Ad)
Constriction
LIVER
Glycogenolysis
Gluconeogenesis
ADIPOSE
Lipolysis
KIDNEY
Increased renin secretion
URETERS AND BLADDER
Relaxes detrusor; constriction of
trigone
and sphincter
Contraction of detrusor; relaxation of
trigone
and sphincter
BLOOD VESSELS
(skeletal muscle) Dilatation
PRINCIPAL TARGETS AND FUNCTIONS OF THE AUTONOMIC NERVOUS SYSTEM
Dark Blue = sympathetic
Brown = parasympathetic
C = sympathetic cholinergic
Slide5PNS
SNS
ACh
ACh
ACh
NA
ACh
ACh
Adrenal
medulla
A & NA via bloodstream
ACh
ANS
Skeletal muscle
Motor neurone
Effector
organ
Effector
organ
e.g. sweat gland
ACh
Effector
organ
Effector
organ
Muscarinic
Nicotinic
The Autonomic Nervous System
2 types of receptors:
Slide6Nicotinic Receptors(Type 2) Ligand gated ion channels
MUST HAVE 2a units Muscle type: 2α β δ ε Ganglion (‘neuronal’) type: 2α 3β
a
α
β
ACh
ACh
Na
+
K+
Slide7Muscarinic Receptors3 subtypes – G-protein coupled
M1: Salivary glands Stomach CNSM2: HeartM3: Salivary glands Bronchial/visceral SM Sweat glands Eye
α
γ
β
M1 & M3 have excitatory effects -
G
q
IP
3
DAG
M2 have inhibitory effects -
G
i
cAMP
Slide8Synthesis, Release & Metabolism of Acetylcholine
Acetyl CoA
+
Choline
Choline
acetyltransferase
ACh
+ CoA
ACh
ACh
ACh
Receptor
Postsynaptic cell
Choline + Acetate
2
1
Ca
2+
Action Potential
3
Acetylcholinesterase
4
Presynaptic cell
Slide9Cholinesterase – 2 types
Acetylcholinesterase (‘True’)Highly selective for AchVery rapid hydrolysis All cholinergic synapses
ButyrylcholinesterasePlasma and most tissues Broad substrate specificity (e.g. suxamethonium)Genetic variation
H
3C
O
O
+
N
CH
3
CH
3
CH
3
Serine
OH
**Uses OH group to hydrolyse
Ach
breakdown**
Slide10A. Cholinomimetics
Slide11SALIVARY GLANDS
Copious, watery secretion
SKIN
Increased sweating (C)
HEART
rate and contractility
GASTROINTESTINAL
motility and tone;
secretions
EYE
Constriction (Pupil)
Contraction (Ciliary Muscle)
Lacrimatioon
TRACHEA AND BRONCHEOLES
Constriction
URETERS AND BLADDER
Contraction of detrusor; relaxation of trigone and sphincter
Brown = parasympathetic
C = sympathetic cholinergic
Remember: At rest, PNS dominates…
Slide12LO1: Explain how (a) directly acting and (b) indirectly acting cholinomimetic drugs produce their biological actions and state why the former are more selective in their actions
Slide13Acetyl CoA
+
Choline
Choline
acetyltransferase
ACh + CoA
ACh
ACh
ACh
Receptor
Postsynaptic cell
Choline + Acetate
2
1
Ca
2+
Action Potential
3
Acetylcholinesterase
4
Presynaptic cell
1. DIRECT:
↑ Exogenous agonists
2. INDIRECT:
↑ Endogenous
ACh
by ↓breakdown by
AchEsterase
Direct agonists are selective for specific receptor types/subtypes
AchEsterase
is present in all cholinergic synapses
Slide14LO2: Muscarinic receptor agonists: Identify and explain the clinical uses and pharmacokinetic properties of muscarinic receptor agonists.
Slide15Directly Acting Cholinomimetic Drugs(Typical agonists at muscarinic receptors)
Choline esters - BETHANECHOLPk: M3 selective, orally active, t1/2 ≈ 3-4h (resistant to degradation) limited brain access- Uses: Assist bladder emptying and gastric motility after surgery
Alkaloids
-
PILOCARPINE
Pk:
Non-selective, t
1/2
≈ 3-4h, good lipid solubility
- Use:
Glaucoma
Slide16LO3: Anticholinesterases: Identify the explain the clinical uses and pharmacokinetic properties of anticholinesterase drugs.
Slide17Indirectly Acting Cholinomimetic Drugs(Increases normal [ACh] by inhibiting ACHesterase)
Reversible - PHYSOSTIGMINE- Competes with ACh at the active site, t1/2 ≈ 30 minsDonates carbamyl blocking group (hydrolysis of this is slow - mins)Uses: Glaucoma, Atropine poisoningNeostigmine Reverse non-depolarising NM BlockTreat Myaesthenia gravis
Irreversible
-
ECOTHIOPATE
Organophosphate compounds
Rapidly reacts with active site to leave a
large phosphate blocking group
Stable and resistant to hydrolysis
May require new enzymes (Days/weeks)
Uses: Glaucoma (Prolonged
DofA
)
Slide18EFFECTS OF ALL CHOLINOMIMETICS
(Indirect + Direct)
Covers previous 2 LOs
REFLECT MUSCARINIC ACTIVATION AS PNS DOMINATES AT REST
CNS EFFECTS
SKELETAL EFFECTS (Toxicity, NMJ blockade)
Slide191. Muscarinic Effects: Eye
Contract ciliary muscle (near accommodation)Contract sphincter pupillae (miosis, aqueous humour drainage via canals of Schlemm ↓IOP)Lacrimation
Slide20Slide212. Muscarinic Effects: CVS
Heart: Decreases HR, less atrial contraction
Reduced CO
Vasculature: Decreases TPR
(M3r vascular endothelial cells
+NO production VSM relaxation)
Clinically relevant, less used in physiology (SNS control)
= DROP IN BP
Slide223. Muscarinic Effects: Non-Vascular Smooth Muscle Contraction
Lung:
Bronchoconstriction
Gut:
Increased peristalsis (motility)
Bladder:
Increased bladder emptying
Slide234. Muscarinic Effects: Exocrine Glands
Digestion:
Salivation
Increased
gastro-intestinal
secretions (
HCl
)
Increased
bronchial
secretions
Increased sweating (SNS-mediated)
Slide245. Muscarinic Effects: the CNS
Non-polar
anticholinesterases (e.g. physostigmine; nerve agents) can cross the
blood brain barrier
Low doses:
Excitation
with possibility of convulsions
High doses:
Unconsciousness
,
respiratory depression
,
death
Slide25Side Effects (++ PNS)
Sweating
Impaired/blurred vision
Bradycardia
Hypotension
Respiratory difficulty/Arrest
GI disturbance/pain
Slide26LO4: Anticholinesterase poisoning: Recognise the signs and symptoms of anticholinesterase poisoning and explain how it may be treated.
Slide27Effects of ANTICholinesterase DRUGS:
Low dose
Enhanced
muscarinic activity (therapeutic)
Moderate dose
++
transmission at
ALL
autonomic ganglia (
nAChRs
)
High dose (toxic)
++ muscarinic activity
Depolarising block
at autonomic ganglia & NMJ
CNS effects (dose dependent)
Slide28Muscarinic Effects: the CNS
Non-polar
anticholinesterases (e.g. physostigmine) can cross the
blood brain barrier
Low doses:
Excitation
with possibility of convulsions
High doses:
Unconsciousness
,
respiratory depression
,
death
Slide29Organophosphate Poisoning
Treatment:
IV Atropine (Anti-muscarinic);
artificial respiration;
Within a couple of hours: pralidoxime (iv)
Phosphorylated enzyme ‘ages’ within few hours
Slide30SBA Question 1
Anticholinesterase drugs have the ability to increase activity at which synapses within the autonomic nervous system?
A: All autonomic synapses
B: Pre- and post-ganglionic parasympathetic synapses
C: Pre- and post-ganglionic sympathetic synapses
D: Post-ganglionic parasympathetic synapses only
E: Pre-ganglionic sympathetic synapses only
Answer?
Slide31SBA Question 2
Anticholinesterase drugs can be used to treat which of the following conditions?
A: Asthma
B: Glaucoma
C: Hypotension
D: Motion Sickness
E: Peptic Ulcer Disease
Answer?
Slide32Which of the following is a symptom of anticholinesterase poisoning?A) Pupil constrictionB) BronchodilationC) ConstipationD) Reduced sweatingE) NMJ blockade
SBA Question 3
Slide33SBA Question 4
Which of the following drugs has efficacy for the muscarinic acetylcholine receptor?
Acetylcholine
Atropine
Acetyl-cholinesterase
Adrenaline
Acetate
Slide34SAQ 1
How do irreversible anticholinesterases cause respiratory problems? Explain in terms of:
The lungs
CNS
Voluntary Muscles
Slide35CNS: Non-polar anticholinesterases can cross BBB
at high doses =high [
Ach
], which affects unconsciousness and leads to decreased respiration control
Lungs: (M3r) Increased bronchial secretions and SM constriction
size of the lumen decreasing
less air reaching the lungs
Voluntary muscle – cause contraction and possibly resulting in a depolarising block at very high [
ACh
],
flaccid paralysis (NMJ Block). This would decrease respiratory muscle activity
Slide36B. Cholinoceptor Antagonists
Slide37LO1: Cholinergic blockade:
Identify the consequences of
cholinoceptor
blockade
and list the main clinical uses and unwanted effects of muscarinic
cholinoceptor
antagonists.
Slide38NICOTINIC RECEPTOR ANTAGONISTSGanglion blocking drugs
Affects the system that dominates(i.e. at rest = PNS)Mechanisms of action:Blocks receptor ± channel poreChannel pore bloackage Use-dependent block (↑ agonist present = more accessible channel)Incomplete block (ion leakage)
Slide39SALIVARY GLANDS
Copious, watery secretion
HEART
rate and contractility
GASTROINTESTINAL
motility and tone;
secretions
EYE
Constriction (Pupil)
Contraction (Ciliary Muscle)
TRACHEA AND BRONCHEOLES
Constriction
URETERS AND BLADDER
Contraction of detrusor; relaxation of
trigone
and sphincter
Brown = parasympathetic
Slide40Effects of Ganglion blocking drugs
Increases HR (PNS Blockade)
Hypotension (Vasodilation)
At rest, SNS dominates the following areas:
SNS tone in BVs
Renin secretion by kidney
Increasing blood volume
Downstream agents e.g. ATII (vasoconstrictor)
Blockade of the above leads to vasodilation and loss of blood volume (diuresis)
ANTI-HYPERTENSIVE drugs
Hexamethonium
1
st
Anti-hypertensive
(Blocks receptor and channel)
Trimetaphan
Hypotension during surgery, short acting
(Blocks receptor only)
Slide41NB:
Therapeutic drugs:
intermolecular forces; surmountable by increasing [
ACh
]
Only targets ANS
Toxins
e.g. -bungarotoxin: irreversible, covalent block
Affects ANS + Skeletal muscles
Paralyses diaphragm and respiratory muscles
Slide42MUSCARINIC RECEPTOR ANTAGONISTS
NB: both can cause CNS effects as they can cross the BBBAtropine; Normal dose – Little effectToxic dose - Mild restlessness Agitation(Less M1 selective)Hyoscine; Normal dose – Sedation, amnesiaToxic dose – CNS depression or paradoxical CNS excitation (associated with pain) (Greater permeation into CNS – more lipid soluble; more M1 selective)
Slide43Clinical Uses
1)
Opthalmology
: Retina examination
Tropicamide blocks PNS constriction of pupils
pupil dilation
2) Pre-surgery:
Block PNS bronchoconstriction – anaesthetic has better access
Reduce saliva and GI secretions – prevent aspiration
Counteract HR decrease (many anaesthetics lower HR - dangerous)
Sedation:
Hyoscine
3) Motion sickness
Hyoscine patch blocks transmission of sensory-mismatch to vomiting centre
Slide444) Parkinson’s DiseasePatho: loss of dopaminergic neuronsActivation of M4r inhibits D1rBlockage of M4r inhibition increases dopaminergic transmission
Slide455) Asthma/Obstructive airway disease
Blocks PNS bronchoconstriction
Atropine
Ipratropium bromide
(quaternary nitrogen group, +
vely
charged)
Adv:
lower doses required, limited systemic SE
6) Irritable bowel syndrome
(hyperactive gut)
Blocks (M3r-mediated) gut motility + tone, secretions
Slide46Hot as hell - sweating, thermoregulationDry as a bone - secretionsBlind as a bat - cyclopegiaMad as a hatter - CNS disturbance
Unwanted effects of Muscarinic antagonists
Slide47LO2: Atropine poisoning: identify the signs and symptoms of atropine poisoning and explain how it may be treated
Atropine poisoning:
Symptoms: prev. slide on SE
Treat with
Physostigmine
(Anticholinesterase)
- Increases [
Ach
], which outcompetes antagonist
Slide48Acetyl Co A
+
Choline
ACh + Co A
ACh
ACh
ACh
ACh
Receptor
Effector cell
Ca
++
Action potential
Binds SNARE
complex
[Not covered by LO]: Other
Parasympatholytics
Botulinum Toxin
Slide49SBA QUESTION 5
Which of the following effects would be observed at rest after treatment with a ganglion blocking drug?
Increased heart rate
Pupil constriction
Bronchodilation
Detrusor contraction
Increased gut motility
Slide50Which of the following is not an effect of ganglion blockade at rest?A) ConstipationB) Dilated pupilsC) VasoconstrictionD) HypotensionE) Bronchodilation
SBA QUESTION 6
Slide51Which of the following drugs would you administer to treat an atropine overdose?BethanecholEcothiopateHyoscinePhysostigminePralidoxime
SBA QUESTION 7
Slide52Which of the following is a side effect of atropine (a muscarinic antagonist)?A) Abdominal crampsB) Dilated pupilsC) BronchoconstrictionD) Increased sweatingE) Increased urinary frequency
SBA QUESTION 8
Slide53SBA QUESTION 9
Bromocriptine is an M3 selective muscarinic agonist. Which of the following is the most suitable use for the drug?
A) To aid bladder emptying
B) Sedative
C) To treat motion sickness
D) To treat atropine poisoning
E) Antiarrhythmic medication
Slide54SAQ 2
List three effects of muscarinic antagonists. (3 marks)What is the effect of a muscarinic antagonist on the respiratory system? (2 marks)Atropine and ipratropium bromide are both muscarinic antagonists. Based on their structure (below), which drug is more ideal to use as an inhaled drug for asthma, and why? (3 marks)List two other clinical uses for muscarinic antagonists (2 marks)
Ipratropium Bromide
Atropine
Slide55C. Neuromuscular Junction Blockers
Slide561. Neuromuscular Junction: Identify the neurotransmitter at the skeletal neuromuscular junction and the receptor type on which it acts.
Ach activation of nAChr on motor end-plate (centre of muscle fibres)Graded EPPIf EPP is sufficient (above threshold) AP is generatedMuscle contraction
Slide57Neuromuscular blocking drugs: list the clinical uses, mechanism of action, pharmacokinetics and unwanted effects of neuromuscular blocking agents
Slide58NM blocking drugs…
DO:
Target depolarisation of motor-end-plate
Acts on post-synaptic receptors (ganglionic
nAChr
)
Lead to muscle paralysis (stops withdrawal from pain sensation)
DO NOT:
AFFECT CONSCIOUSNESS (not GA) or PAIN SENSATION (not analgesic)
ALWAYS
ASSIST RESPIRATION
Until the drug is INACTIVE (excreted/metabolised) or ANTAGONISED
Slide59LO1a: Tubocurarine: define the nature of the antagonism of tubocurarine on the effects of acetylcholine (
ACh
) at the motor end-plate
Slide60Non-depolarising (Competitive nAChr Antagonists)
TUBOCURARINE 4° AMMONIUM COMPOUND (ALKALOID)70 - 80% BLOCK NECESSARY EPP insufficient for APFlaccid Paralysis (Relaxed)
RECOVERY
ORDER OF
PARALYSIS
EXTRINSIC EYE MUSCLES (DOUBLE VISION)
SMALL MUSCLES OF FACE, LIMBS, PHARYNXRESPIRATORY MUSCLES
ATRACURIUM – same but shorter duration of action (15 min)
Slide61EFFECT OF TUBOCURARINE ON NM TRANSMISSION
Slide62TUBOCURARINE
Uses:
During surgery:
1) Relaxation of skeletal muscles (less GA)
2) Permit artificial ventilation
Pharmacokinetics:
Route of administration: IV (Highly charged so can’t absorb from gut)
Cannot cross BBB or placenta (less SE, used in
Obs
/
Gyn
)
Longer duration: 1-2 hours
Not metabolised, excreted in unchanged form (70% Urine, 30% Bile)
If Renal/Hepatic impairment
use
Atracurium
(spontaneous hydrolysis in 15 mins)
Slide63LO1b: Explain how the log dose curve showing the response of skeletal muscle to increasing concentrations of Ach would be altered in the presence of tubocurarine
Slide64TUBOCURARINE SIDE EFFECTS
Ganglion BlockadeHistamine release from mast cellsBlockade of respiratory muscles
Tachycardia ( Arrythmia)Hypotension BronchospasmExcessive secretions (bronchial, salivary)Apnoea (ASSIST RESPIRATION)
TPR
VASODILATION
VAGAL GANGLIA BLOCKADE
REFLEX
REVERSED BY ANTICHOLINESTERASES e.g.
NEOSTIGMINE
(overcomes competitive block)
(Give Atropine at same time to prevent ++ PNS)
Slide65Depolarising (nAchr Agonists)SUXAMETHONIUM
Extended endplate depolarisation depolarisation blockSimple terms: ^^ACh in synapse overstimulates nAChr shutdown Fasciculations FLACCID PARALYSISPHARMACOKINETICSRoute of administration: IV (Highly charged so can’t absorb from gut)Short duration - 5 MINMetabolised by pseudocholinesterase (Liver and plasma)Uses:Endotracheal intubation ECT – muscle relaxant
Two ACH attached together
Slide66SUXAMETHONIUM SIDE EFFECTS
Post-operative muscle pain (contractions)
Bradycardia (direct M2 action on heart)
Hyperkalaemia
Ventricular arrhythmias/cardiac arrest
AVOID in soft tissue injury/burns: DEINNERVATION SUPERSENSITIVITY
INTRA-OCULAR PRESSURE (++Intraocular muscles)
AVOID in eye injuries/glaucoma
Slide67SBA QUESTIOn 10
Which drug would you use to reverse the effect of
tubocurarine
(a non-depolarising NMJ blocker)?
A) Nicotine
B) Atropine (muscarinic antagonist)
C) Neostigmine (reversible anticholinesterase)
D) Ecothiopate (irreversible anticholinesterase)
E)
Suxamethonium
(depolarising NMJ blocker)
Slide68The clinical use of neuromuscular blocking drugs will most likely involve interference with which of following physiological processes?A: Kidney functionB: ConsciousnessC: Body temperature regulationD: Pain sensationE: Respiration
SBA
QUESTIOn
11
Slide69SBA QUESTIOn 12
Which of the following effects would be observed with a non-depolarising neuromuscular block?
A: Initial muscle fasciculations
B: Irreversible
nAChR
blockade
C: The block would be enhanced by anti-cholinesterase drugs
D: A flaccid paralysis
E: Increased arterial pressure
Slide70SAQ 3
Graph showing effects of a muscarinic receptor agonist, on airway smooth muscle contraction in utero. Explain how the co-administration of (a) atropine [3] or (b) physostigmine [3] affect the graph.
Slide71a) Atropine:
(Competitive muscarinic antagonist)
Curve would shift to the right
(Increasing [agonist] can outcompete the atropine for the muscarinic receptor binding site
maximum tissue response can be reached but greater [agonist] required
curve remains at same height
b) Physostigmine:
Reversible anticholinesterase
less [agonist] has greater effect as no longer broken down curve shifts to the left
Depolarising block formed
therefore leading to no more tissue response
the maximum tissue response being lower
Slide72THANKS FOR LISTENING
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