AChEs and anticholinergics A Barnes

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AChEs and anticholinergics A Barnes Powered By Docstoc
					Anticholinesterases
         &
 Anticholinergics
   ANZCA Part 1 Course
          Learning Objectives
     - ANTICHOLINESTERASE          IX      - ANTICHOLINERGIC
UGS1.General Instructional         DRUGS1.General Instructional
ectivesAn understanding of the     ObjectivesAn understanding of the
 rmacology of anticholinesterase   pharmacology of the anticholinergic
gs and their clinical              drugs and their clinical
 lications2.Required Abilitiesa.   applications2.Required Abilitiesa.
classify the anti-cholinesterase   To describe the pharmacology of
gs in relation to mechanism of     acetylcholine and the muscarinic
onb. To compare and contrast       and nicotinic receptorsb. To
 pharmacodynamics and              compare and contrast the
 rmacokinetics of neostigmine,     pharmacodynamics and
ophonium, pyridostigmine and       pharmacokinetics of atropine,
 sostigminec. To describe the      hyoscine and glycopyrrolatec. To
 erse effects of                   describe the effects of overdosage
 cholinesterase agents             of anti-cholinergic drugs and its
To outline the effects and         management
               Acetylcholine
Neurotransmitter                       O

Quaternary ammonium ester        CH3 – C – O – CH2 – CH2 – N(

Synthesized in the nerve axoplasm from
                coenzyme
holine + acetyl-coenzyme A then
                          storage-
ackaged into vesicles for storage
ocations
  1. autonomic ganglia
  2. parasympathetic postganglionic nerve
  endings
  3. sympathetic postganglionic n endings
  (sweat glands and some blood vessels in
  muscle)
Produces muscarinic or nicotinic actions
epending on receptor
Hydrolysed to choline and acetate by
cetylcholinesterase (AChE)
   Acetylcholine Receptors
atic Muscle                                  <   Nicotinic
                             Nicotinic
sympathetic                              <   <   Muscari
                             Nicotinic
            Most nerves                  <   <   Adrener
mpatheti                     Nicotinic
 c         Sweat glands                  <   <   Muscari
                             Nicotinic
           Adrenal medulla               <
       Nicotinic receptors
          gated
 Ligand-gated ion channels
 Membrane proteins with 5 subunits
2α, β, δ, ε)
      selective
 non-selective ion channel
 ACh must bind both α to open
 hannel
 influx of ion (e.g. Na) → MEPPs
→threshold and voltage-  -gated Na
                   depolarization
 hannels open →depolarization
 NMJ: Ca release from SR
→muscle contraction
     Muscarinic receptors
G protein coupled receptors
7 transmembrane loops coupled to
econd messenger systems, coupled
 ion channels
5 subtypes: M1-M5
Odd receptors (M1,3,5) →→activate
hospholipase C and release intracell.
a
Even receptors (M2,4) →→act via Gi to
 gulate adenylate cyclase and inhibit
       sensitive
oltage-sensitive Ca channels
              receptor subtypes
                  M1             M2                M3           M4      M5


                 CNS             Heart             CNS          CNS     CNS
               Stomach            CNS         Salivary glands   Heart
                             Airway smooth   Airway sm muscle
ocation                          muscle           Muscle
                                                 Vascular
                                                endothelium

                                                Salivation
                                              Bronchodilation
                                               Vasodilation
cal effects   H+ secretion    Bradycardia                        ?       ?
Nicotinic vs Muscarinic
                NMJ




http://www.youtube.com/watch?v=ZscXOvDgCmQ
   Anticholinesterase drugs
 ChE hydrolyses ACh
 nticholinesterase drugs antagonize AChE
 acilitate speed of recovery from sk muscle
 ects of NMBDs
Not specific for NMJ→auautonomic cholinergic
 ects
                        for
 lso may be used in rx fo Myasthenia Gravis
 d glaucoma
 ding to HOW they antagonize AChE

 versible Inhibition
ROPHONIUM
 rsible inhibition through electrostatic attachment to the anionic site on the enzym
 ilised by H-bonding at esteratic site

rmation of carbamylated enzyme complex
OSTIGMINE, PYRIDOSTIGMINE, PHYSOSTIGMINE
 rsible inhibition of AChE by acting as competitive substrates
 amate esters transfer a carbamate grp to AChE at esteratic site
 E now unable to hydrolyse ACh until the bond dissociates
 amylated AChE has t1/2 15-30mins

eversible Inactivation
GANOPHOSPHATES
                                  stable
 bine with AChE at esteratic site→stable inactive complex
 ires synthesis of new AChE which may take several hrs or not occur at all
enolic quaternary amine
 2-10mg
                      0.7mg/kg
versal of NMB 0.5-0.7mg/kg
 rmacodynamics
 es: Tensilon test and ddx be between myasthenic crisis v
 inergic crisis
OA: reversible inhibition
                 autonomic
 reased ACh →autonomic cholinergic effects
 rmacokinetics
 not PO
                                      0.9-.3L/kg
 low lipid solubility, fast onset, Vd 0.9
      16
  12-16 times less potent cf neostigmine (less musc
  effects)
?uncertain
                            ster
uaternary amine and an este of an alkyl carbamic acid
O 15mg tabs of neostigmine bromide
                            g/ml
ear soln for injection 2.5mg/m of neostigmine metilsulf
 ed dose combo with 0.5mg glycopyrronium
                               0.05-0.07mg/kg
  dose for reversal of NDMR 0.05
armacodynamics
                              of
ses: reversal of NDMRs; rx o MG, paralytic ileus and
 ary retention
OA: reversible inhibitor of AChE by formation of
bamylated enzyme, hydrolysed slower than ACh
 ccumulation of ACh
olongs duration of suxamethonium
                  Clinical Effects
 S
 ycardia (with fall in CO)
 eases refractory period of myocardium
eases conduction time
  doses → hypotension (centrally mediated)
ESP
eases bronchial secretions
  cause bronchoconstriction
NS
 etal muscle contraction
  doses may block NMJ transmission via direct effect and accumulation of ACh
sis
 T
eased salivation
ers oesophageal and gastric tone, gastric acid production and GI motility
  cause N+V
U
eases ureteric peristalsis
 her
              Neostigmine
armacokinetics
                                       1-2%
 poor oral absorption, bioavailability 1
  highly ionized, doesn’t cross BBB significantly
   6-10%protein bound
   Vd 0.4-1L/kg
  predominant metabolism by plasma esterases to
 ternary EtOH
   some hepatic metab and biliary excr may occur
      67%
  50-67% of dose excr in urine
                  11.1ml/min/kg
   clearance 5.7-11.1ml/min/kg
   t1/2 15-80mins
                       decreased
   renal impairment →decreased cl, increased t1/2
           Pyridostigmine
armaceutical
uaternary amine
ainly used in Rx of Myasthenia gravis
armacodynamics
nger DOA and reduced autoutonomic SE and slower onse
 eostigmine
OA: carbamylated enzyme complex with AChE
 ersible)
armacokinetics
 esn’t cross BBB
            Physostigmine
armaceutical
rtiary amine structure
armacodynamics
 ed in anticholinergic poisoning
OA: forms carbamylated enz  enzyme with AChE (reversibl
armacokinetics
gh lipid solubility (crosses BBB)
ell absorbed orally
 Comparative Pharmacology
o significant pharmacokinetic differences
                        a]
 ter bolus, peak [plasma and decline during 5-
mins (edrophonium, neo eostigmine, pyridostigmin
                  1.4L/kg
- Vd rang of 0.7-1.4L/kg
- t1/2 60-120mins
- cl 8-16mL/kg/min
                      mainly dt differences in
fferences in potency ma
armacodynamics
at. ammonium grp (neo, edroph., pyridostigmine) = poorly lipid soluble
                                     ophosphates) highly lipid soluble and rea
tiary amines (physostigmine and organop
orbed across mucous membranes, GIT →  →CNS effects

Vd
ge Vd of quaternary ammoniums dt extensive tissue storage in liver/kidneys

nset of action
              2
rophonium 1-2 mins (?dt possible presynaptic effects)
ostigmine 7-11mins
ridostigmine 16mins

 OA
ficult to determine
                                  30mins
lf time of carbamylated enzyme 15-30mins (much shorter than t1/2 of the
cholinesterase drugs (60-120mins)
   the absence of renal function, hepatic metabolism
  ounts for:
    - 50% of a dose neostigmine
    - 30% of a dose edrophonium
    - 25% of a dose pyridostigmine
                                      3-
  incipal metabolite of neostigmine = 3
droxyphenyltrimethylammonium (1/10 activity)
                                         3-hydroxy-N-
  incipal metabolite of pyridostigmine = 3
 thylpyridinium (no activity)
drophonium undergoes conjugation to edrophoium
 curonide (inactive)
                             d
hysostigmine is hydrolyzed at its ester linkage and ren
  r is of minor importance
Renal Clearance
nticholinesterase drugs actively secreted in tubules
ccounts for 50% elimination of neostigmine
ccounts for 75% elimination of edrophonium and
idostigmine
 /2 greatly prolonged by renal failure
  hysostigmine not used
 dministered during sponontaneous recovery from
MB
                       ferred agent when >90%
 eostigmine is the prefer
 tch depression is to be antagonised
 nce AChE is maximally inhibited, further
 ticholinesterase drug does not further
 tagonize the NDMB
when twitch height recovered to >10%, the
 ticholinesterase is more likely to produce
edictable effect.
  fficacy may be inhibited by
           Adverse Effects
1. Autonomic cholinergic effects
- decreased HR and CO
- increased bronchial secretions
- increased salivation, GI motility and emetic

                  rinic
2. Overdose→muscarin and nicotinic effects
CNS and periphery
  muscarinic              nicotinic            CNS
  miosis, difficulty      skeletal muscle      confusion, ataxia,
  focusing, salivation,   weakness to overt    seizures, coma,
  bronchoconstriction,    paralysis, apnoea,   depression of
  bradycardia,                                 ventilation
  abdominal cramps,
  Limitations of Neostigmine
 ecovery from NM blockade r   e relies on a relative increase
                              J to
ACh (cf NDMR) at the NMJ t overcome the competitive
 ckade
 nce AChE is maximally inhibited by neostigmine, no
                               an
 her dose of neostigmine can enhance this inhibition. i.e
he concentration of NDMR is still high, efficacy of
ostigmine is limited
 o flexibility in terminating NM blockade early
eads to problems of incompl    plete reversal and residual
                              cant
 ck which may pose significa airway issues in recovery
tudy by Debaene and colleg    egues in 2003 Anesthesiology
 orted a 45% incidence of po  postoperative residual block i
 ients arriving in the PACU
                          veoli,
 pidly absorbed across alveo skin and GI tract (highly
d soluble)
sually inhaled / dermal absorption
 oss BBB →intense CNS eff  effects ( autonomic instability
 al excitation progressing to depression, coma and
noea
X:
 ropine +/- pralidoxime (AChE reactivator)
            70mcg/kg
 ropine 35-70mcg/kg IV administered every 3  3-10mins
il muscarinic symptoms disaisappear (no effect on nicotin
mptoms)
                          er
 alidoxime 15mg/kg IV over 2 mins reverses effects at
otinic receptors (rpt 20mins if sk muscle weakness
                            ith
dministered concurrently with anticholinesterase drugs
 ng reversal of NMB to prevent muscarinic cholinergic
 cts
                          eceptors with very little activi
 tagonists at muscarinic rece
 icotinic receptors
                          terase
ster onset cf anticholinestera drug to minimise induc
dycardia
ugs of choice:
ropine
ycopyrrolate
 oscine
ropine and hyoscine are naturally occuring tertiary
 nes (central effects)
                    Effects
 ntisialagogue effects
ycopyrrolate and Hyoscine >Atropine

Sedative and amnesic effects
                         cine
 werful effects when hyoscin combined with morpine

Prevents reflex bradycardia
 ed as rx and prophylaxis e.g atropine as premed to bl
 locardiac reflex in squint surgery
             Side effects
CNS toxicity
                       syndrome: restlessness,
entral anticholinergic syn
tation, somnolence, con onvulsions and coma (es
               Rx
h atropine) →Rx physostigmine 1   1-2mg IV
 Reduced LOS tone →? increased reflux (not i
 ctice)
Tachycardia
Mydriasis + cycloplegia (visual impairment)
Pyrexia dt inhibition of sweat secretion
Excessive drying
 ncreased physiological deadspace 20  20-25%
maceutical
loid derived from scopolia carniolica
 mic mixture (L-hyoscine is active)
ative effects

macodynamics
 tionally given with IM opioids as premed for PONV
A: competitive antagonism of ACh at muscarinic receptors
S depressant (twilight sleep and amnesia)
antispasmodic, prevention of motion sickness
 ced bronchial secretions, mild bronchodilator and stimulates ventilation

macokinetics
  oral absorption (bioavail 10%)
 absorbed s/c or IV
  protein bound
2L/kg
 nsive metabolism in liver → scopine and scopic acid
 ter DOA cf atropine
 armaceutical
                    Atropine
 kaloid from atropa belladonna
 rtiary amine (ester of tropic acid and tropine)
                         atropine
acemic mixture, only L-atropine is active
00mcg/mL IV or tablets
                0.02mg/kg
ose is 0.015-0.02mg/kg OR half neostigmine dose
 armacodynamics
 ses:
                          op
    1. dry secretions pre-op (antisialagogue)
    2. rx of bradycardia dt increased vagal tone
                             ffects of anticholinesterase
    3. counter muscarinic effe
    agents
    4. CPR
 OA: competitive antagonism of ACh at muscarinic
                   EffECTS
CVS (M2, M3)
 - initial bradycardia, then increased HR
 - increase CO, little change in BP
RESP (M2, M3)
 duced secretions
 duced laryngospasm
 onchodilation
creased RR
CNS
ss cholinergic crisis cf hyoscine
ss sedation
GIT
ild antiemetic
 : rapid intestinal absorption
 : 50%protein bound, Vd 2-    -4L/kg
   crosses BBB and placenta
                            tissues to tropine and trop
  : hydrolysed in liver and tis
 d
 : 94% excreted in urine

When administered with neostigmine → initial
 hycardia dt faster onset of action
             Glycopyrrolate
armaceutical
uaternary ammonium compound
 nthetic
ear soln for injection with 0.2mg/mL
armacodynamics
                                    anti-secretory action
nticholinergic; especially profound anti
OA: competitive antagonism of ACh at peripheral
scarinic receptors
                    10mcg/kg
ose: 0.2-0.4mg (4-10mcg/kg in paeds)
eak effect 3mins after IV
chycardia only when dose >0.2mg
 otective against bradycardias dt oculocardiac reflex
 golytic effects last 2-3hrs
RESP
gnificant and prolonged bronchodilator effects
creases phys deadspace
CNS
 able to cross BBB (headache and drowsiness are
mmon)
ster PACU recovery cf atropine
  effect on pupil size / accommodation
GIT
                            sts
 werful antisialogogue (lasts 8hrs, 5 times more potent
 apid redistribution (90% out of plasma in 5mins)
                     fetal
 rosses placenta →fetal tachycardia
Vd 0.2-0.64L/kg

hydroxylation and oxidation in liver, very little
ransformation

urinary excretion 85%, bile 15%, 80% unchanged
 earance 0.89L/min
 /2 0.6-1.1hrs

                             ine,
 en combined with neostigmin less tachycardia and bett
                            chieved with glycopyrolate cf
 pression of secretions is achi
        Comparison of agents

                                            Smooth                Dec
                        Anti-
            Sedation              Inc HR    Muscle    Mydriasis    Ga
                     sialagogue
                                           Relaxation             Sec



opine          +         +        +++         ++         +



pyrrolate      0        ++         ++         ++         0
        Anticholinergic S.E
dry mouth

difficulty with micturition

nhibition of sweating
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                       Glycopyrrolate stops perspiration of overall body, face, hands,
                       armpits etc.

                       Glycopyrrolate is Doctor and Dermatologist recommended.
                  Overdose
dry mouth
blurred vision with photophobia
 achycardia
skin dry and flushed
 ash may appear over face, neck and upper chest
 ncreased body temperature (inhibited sweating)
                           slightly increased dt central
minute ventilation may be sl
imulation
                          s and
skeletal muscle weakness a orthostatic hypotension
 icotinic receptor block)
                           ma
Fatal Events: seizures, com and medullary ventilatory
entre paralysis
small children are especially vulnerable
    Central anticholinergic syndrome
 ropine can enter CNS p   producing this syndrom
ymptoms: restlessness, hallucinations,
mnolence and unconsciousness
 ay be mistaken as delayed recovery from
aesthesia
  blockade of muscarinic receptors and
mpetitive inhibition of ACh in CNS
 ycopyrrolate has been implicated
                        d soluble tertiary amine)
X: physostigmine (lipid s
 60mcg/kg IV - may need repeating every 1    1-2h
                         ine
drophonium, neostigmin and pyridostigmine
                     SAQs
March 2001, 2004

Compare and contrast neostigmine and the organophosphorus
compounds.
The pass rate for this question was 64 %. The question asked for a
comparison and contrast between two drugs and it was essential for
candidates to have addressed both agents to achieve a pass mark
and not discuss only one of the agents.
It was imperative to define the actions of these drugs and describe
the mode of binding with some explanation of their durations of
action. An explanation of their actions, clinical effects and the fact
that neostigmine does not cross the blood brain barrier unlike
organophosphates was considered important to the answer.
Candidates who were able to give detailed explanation of the
binding characteristics of these agents and how that influenced their
duration of action, pharmacodynamic profile and clinical applications
attained higher marks. It was considered that a general comment
such as neostigmine being short acting and organophosphates
being long acting, without detailed explanation, was inadequate to
pass
ministering neostigmine postoperatively (68%)
This question examined the pharmacology of neostigmine, a drug that is
being used in anaesthesia on a daily basis. An adequate description of
adverse effects was therefore expected for candidates to obtain a pass
mark.
The main points should include a discussion on the accumulation of
acetylcholine at muscarinic (at low dose) and nicotinic (at higher dose)
receptor sites after administration of neostigmine.
The muscarinic effects are severe and hence the co  co-administration of
antimuscarinic agent is important. The most worrying adverse effects are
bradyarrhythmia with hypotension. Bronchoconstriction, salivation,
tracheobronchial hypersecretion, postoperative nausea and vomiting, and
enhanced peristalsis (and potential damage on bowel anastomosis) should
be mentioned.
Additional marks were awarded for including potential drug interaction with
                                  .
suxamethonium and mivacurium. Marks were a      also awarded for depolarizing
block after excessive doses of neostigmine. No credit was given for
description of neuromuscular monitoring.
                            e the
arm97A12: Briefly describe t pharmacological action
                           ith
he anticholinesterases with reference to edrophonium
ostigmine and the organophophosphorous compounds.
 cate the similarities and differences with the 3 drugs

				
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Description: AChEs and anticholinergics A Barnes