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Types of cholinergic receptors
Nicotinic and muscarinic
Effects of nicotinic receptors
Stimulates the autonomic ganglia and skeletal muscle receptors
Effects of muscarinic receptors
Stimulates end-organ effector cells in bronchial smooth muscle, salivary glands and sinoatrial node
Nicotinic receptors blocked by..?
Muscle relaxants
Muscarinic receptors blocked by...?
Anticholinergic drugs i.e atropine
Goal of reversing neuromuscular blocakde
Maximize nicotinic transmission and minimize muscarinic side effects
Muscarinic side effects of cholinesterase inhibitors
PBB SP
Pupil constriction
Bradycardia
BRonchospasm
Secretion
Peristalsis

CNS
-DIffuse excitation (only for physostigmine)  
Ophthalmo
-Pupillary constriction  
CVS
-Bradycardia, may progress to sinus arrest (more likely if heart transplant > 6 months earlier [reinnervated])  
Pulmonary
-Bronchospasm, increased bronchial secretions  
GI
- Increase glandular secretions (salivary, parietal), and peristaltic activity (esophageal, gastric and intestinal)
- May cause peri-op bowel anastomotic leakage, nausea/vomiting, and fecal incontinence
3 groups of anti-cholinesterases
1) Easily reversible inhibition (edrophonium)
2) Formation of a carbamylated enzyme complex (neostigmine/pyridostigmine/physostigmine)
3) Irreversible inactivation by organophosphorus compounds
Edrophonium  
Chemical structure
Phenolic quarternary amine (limited lipid solubility)
Edrophonium  
Mode of action
Because lack a carbamate group, it forms non-covalent bonding to acetylcholinesterase enyme (forms hydrogen bond)
Edrophonium  
Potency compared to neostigmine
10% as potent as neostigmine
Edrophonium

Uses
1) Reverse muscle block
2) Distinguish between myasthenic crisis (muscle power improved) and cholinergic crisis (clinical picture worsened)  [Dose 2-10 mg]
Edrophonium  
Effects of low lipid solubility
- Not absorbed after oral administration
- Does not cross BBB/placenta
Edrophonium  
Dose
0.5 - 1.0 mg/kg
Edrophonium  
Onset of action
1-2 min (fastest of all anti-cholinesterases)
Edrophonium  
Duration of effect
-Shortest duration of effect of all anti-cholinesterases
- Don't use low dose, because longer-acting muscle relaxants may outlast effects of edrophonium
-High doses prolong effect to > 1 hour
Edrophonium  
Efficacy compared to neostigmine
- Not as effective as neostigmine at reversing intense neuromuscular block
- More effective at reversing mivacurium block
Edrophonium  
Muscarinic effects comparison
- Less muscarinic effects than neostigmine/pyridostigmine at equipotent doses
Edrophonium  
Use with anti-cholinergics
- Because muscarinic efffects less, needs only half the amount of anti-cholinergics (0.014 mg atropine per 1 mg of edrophonium, 0.007 mg per 1 mg of edrophonium)
- Atropine and edrophonium's onset of action almost similar, so give together
- Glycopyrrolate slower, so give few minutes before to avoid bradycardia
Edrophonium  
Metabolism
- Most excreted unchanged in urine; rest undergo glucuronidation in liver and subsequent excretion in bile
Neostigmine  
Chemical structure
- Consists of a carbamate moeity (forms convalent bonding to acetylcholinesterase) and a quartenary ammonium group (renders the molecule lipid-insoluble, so cannot pass BBB)
Neostigmine   
Uses
1) Reverse non-depolarizing muscle relaxants  
2) Treatment of myasthenia gravis (15-30 mg orally, lasts 4 hours)  

3) Treatment of urinary bladder atony, paralytic ileus (prokinetic agent)
Neostigmine   
Dose
0.05 mg/kg IV
Neostigmine  
Onset of action
5-10 min
Neostigmine  
Duration of action
Lasts > 1 hour, peaks at 10 min
Neostigmine  
Effects in children/elderly
- More rapid onset, need smaller dose
- Duration of effect prolonged in geriatric patients
Neostigmine  
Anti-cholinergic
- Glycopyrrolate 0.2 mg per 1mg of neostigmine
- Atropine 0.4mg per 1mg of neostigmine  
- Onset of action of glycopyrrolate similar to neostigmine, and assoc. with less tachycardia than with atropine, so better to give glycopyrrolate with neostigmine ( if give with atropine, will cause initial tachycardia, then late bradycardia as atropine duration of action 40 min; neostigmine 60 min)
Neostigmine  
Effects in pregnancy
- Crosses placenta, causing fetal bradycardia
- So better to give atropine in pregnant patients given neostigmine
Neostigmine  
Pharmacokinetics
- Poorly absorbed from gut, low oral bioavailability
- Minimally protein-bound
- Low volume of distribution
Neostigmine  
Metabolism
- Partially metabolized in liver
- 55% excreted unchanged in urine
Pyridostigmine  
Chemical structure
- Similar to neostigmine, except the quartenary ammonium is incorporated into the phenol ring
Pyridostigmine  
Similarities with neostigmine
- Forms covalent bond with acetylcholinesterase and is lipid insoluble
Pyridostigmine  
Potency
20% as potent as neostigmine
Pyridostigmine  
Dose
0.1 - 0.4 mg/kg
Pyridostigmine  
Onset of action
10-15 min (slower than neostigmine)
Pyridostigmine  
Anticholinergic
- Glycopyrrolate 0.05 mg per 1 mg
- Atropine 0.1 mg per 1 mg  
- Glycopyrrolate preferred, as slower onset better matches pyridostigmine, causing less tachycardia (although still slower onset than pyridostigmine, so still have mild tachy)
Pyridostigmine  
Excretion
- 75% excreted unchanged
- Relies on renal excretion more than neostigmine
Physostigmine  
Chemical structure
- Tertiary amine, has a carbamate group but no quartenary ammonium
- So, is lipid soluble and is the only cholinesterase inhibitor that freely passes the BBB
Physostigmine  
WHy not useful as NDMB reversal
- Because of lipid solubility, and CNS penetration

Physostigmine  
Uses
- Treatment of central anti-chlinergic toxicity caused by overdose of atropine/scopolamine
- Reverses some of the CNS depression and delirium assoc. with BZD and volatile anesthetics
- Can prevent post-op shivering (0.04 mg/kg)
- Partially antagonizes morphine-induced respi depression; but effects transient and need repeated doses
Physostigmine  
Metabolism
- In contrast to other cholinesterase inhibitors, physostigmine is almost completely metabolized by plasma esterases, so renal excretion not important
Organophosphorus compounds
- Highly toxic, mainly used as insecticides or nerve gas
- Very lipid-soluble; rapidly absorbed through skin  
MOA
-Esteratic site of AChE is phosphorylated by organophosphorus compounds, causing inhibition of AChE
- Complex formed is very stable and unlike carbamate esters, is resistant to hydrolysis/reactivation
- Also inhibits pseudocholinesterase   - Toxic manifestation include nicotinic and muscarinic effects, autonomic instability, and initially central excitationprogressing to depression, coma and apnea
Anti-cholinergics  
Chemical structure
- Esters of an aromatic acid plus an organic base
Anticholinergics   
Mode of action
- Ester linkage binds to acetylcholine receptor, competetively blocks binding by ACh and prevents receptor activation
Anticholinergics  
General pharmacology
- In clinical doses, only muscarinic receptors blocked by clinically used anticholinergic drugs   
- Extent of anti-cholinergic effect depends on degree of baseline vagal tone
Anticholinergics   CNS effects

- Causes wide range of CNS effects, ranging from stimulation (excitation, restlessness, hallucinations) to depression (sedation, amnesia), depending on drug and dose
- Physostigmine crosses the BBB, so can reverse these actions
Anticholinergics  
Ophthalmic effects
- Mydriasis (pupillary dilation) and cyclopegia (inability to accomodate to near-vision)  
- May cause acute angle-closure glaucoma (rare, contraindicated in these patients)
Anticholinergics  
CVS effects
- Blocks muscarinic receptors in sinoatrial node, causing tachycardia (this effect useful to reverse bradycardia from vagal reflexes i.e baroreceptor/oculocardiac reflex, peritoneal stimulation)  
- May have atrial arrhythmia
- Little effect on ventricles/peripheral vasculature
- Large doses can cause dilation of cutaneous blood vessels (atropine flush)
Anticholinergics  
Respi
- Inhibits secretions of respi tract mucosa, from nose to bronchi
- Relaxes bronchial smooth muscle, reducing airway resistance and increasing anatomic dead space
Anticholinergics  
GI
- Reduced salivary/gastric secretions
- Reduced intestinal motility and peristalsis, prolonging gastric emptying time
- Reduced LES tone
- Anticholinergics not useful in prevention of aspiration penumonia
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