Cholinergic Drugs on anesthesia practice

Cholinergic Pharmacology

Digenes Herreo-Senz, Ph.D.Pharmacology and Toxicology

School of MedicineUniversity of Puerto Rico

Cholinergic Pharmacology

Refers to the effects of the neurotransmitter acetylcholine.

Cholinergic pharmacology is centered on the properties of the neurotransmitter ACh, and the pathways throught which ACh exerts its effects in the body.

The functions of cholinergic pathways generally involveA. Neuromuscular junctionB. The autonomic nervous system (ANS) C. Central nervous system (CNS)

Synthesis and Hydrolysis of Acetylcholine

Synthesis

Hydrolysis

The rate-limiting step of ACh synthesis is the uptake of choline into the neurons.

Cholinergic Receptors

Nicotinic Receptors Muscarinic receptors

Parasympathetic Nervous System

CNS

Neuromuscular Junction (M)

Sympathetic Ganglions (N)

CNS

Acetylcholine Synthesis, Storage, Release and Degradation Pathways, and Pharmacological Agents that Act on these Pathways

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Nicotinic Receptors: ligand-gated ion channels

Muscarinic Receptors:G-protein-coupled receptors that alter signaling pathways.

Drugs that enhance or inhibit Cholinergic Transmision

secretion

The overall effect of ganglionic blockade depend on the relative predominance of sympathetic and parasympathetic tone at the various end-organs

(profuse perspiration)

Cholinesterase Inhibitors

Clinical uses: Pharmacological reversal of nondepolarizing

neuromuscular blockade. Diagnosis and treatment of myasthenia gravis.

autoimmune disorder of the neuromuscular junction the body creates antibodies against its own nicotinic

acetylcholine receptors in the neuromuscular junctions. This disorder affects 50 to 125 people per million population,

and there are approximately 25,000 reported cases in the United States.

MG is characterized by muscular weakness and fatigability. In MG, there is reduced interaction between acetylcholine and its

postsynpatic receptor, so that variable and fatigable neuromuscular transmission ensue.

Symptoms of MG tend to fluctuate throughout the day and under different environmental and physiological conditions

Death or severe impairment due to the disease is rare, and most patients are able to live normal lives.

Myasthenia gravis (MG)

In myasthenia gravis the antibodies bind the acetylcholine receptor and cause it to be cleared from the surface of the muscle

(no activation of the receptor or destruction of the muscle.)

Myasthenia gravis(anti-acetylcholine receptors)

Cholinesterase Inhibitors

The primary use is to reverse nondepolarizing muscle blockade.

Mechanism of Action of Cholinesterase Inhibitors

Neuromuscular transmission depends on ACh binding to nicotinic receptors on the motor plate.

Nondepolarizing muscle relaxants are antagonist of ACh on the nicotinic receptors.

Pharmacological reversal of the blockade uses the cholinesterase inhibitors

1. diffusion from the synaptic cleft2. redistribution3. metabolism and 4. excretion

of nondepolarizing muscle

Spontaneous reversal of the blockade depends on:

Mechanism of Action Cholinesterase inhibitors indirectly increase the amount of

ACh available to compete with the nondepolarizing agents, thereby reestablishing normal neuromuscular transmission.

Cholinesterase inhibitors inactive the acethylcholinesterase by reversibly biding to the enzyme.

The stability of the bond influences the duration of action: Edrophonium: short half life (electrostatic biding and

hydrogen biding) Neostigmine and pyridostigmine: longer half life

(covalent biding) The clinical duration of cholinesterase inhibitors is

probably most influenced by the rate of drug disappearance from the plasma

Mechanism of action other the cholinesterase inactivation may contribute to the restoration of neuromuscular function:Edrophonium: appears to enhance the acetylcholine liberation.Neostigmine: has a weak agonist effect on nicotinic receptors

Excessive doses of cholinesterase inhibitors paradoxically potentiate a nodepolarizing neuromuscular blockade.Neostigmine: high doses may cause Ach channel blockade.

Cholinesterase inhibitors prolongs the depolarization blockade of succinylcholine A) increases motor end plate depolarization B) the inhibition of pseudocholinesterase activity (neostigmine> pyridostigmine)

Mechanism of Action

General Pharmacological Characteristics

Cardiovascular receptors Muscarinic effects: HR, conduction velocity

(disrythmias), contraction: vagal-like bradycardia that can progress to sinus arrest.

Pulmonary receptors Muscarinic stimulation: bronchospasm (smooth muscle

contraction) respiratory tract secretions

Cholinesterase inhibitors affect more than the nicotinic receptor of the neuromuscular junction.

The agents can act at cholinergic receptors of several other organ systems

Cerebral Receptors Physiostignina crosses the BBB and cause diffuse

activation of the EEG by stimulating muscarinic and nicotinic receptors within de CNS


Gastrointestinal receptors Muscarinic stimulation: peristaltic activity: esophageal,

gastric, and intestinal glandular secretions: salivary, parietal

Unwanted muscarinic side effects are minimized by prior or concomitant administration of anticholinergic medications such as atropine sulfate or glycopyrrolate.

The duration of action: similar among the AChE inhibitors Elimination: Hepatic metabolism (25-50%) and renal

excretion (50-75%) Any prolongation of action of a nondepolarizing muscle

relaxant from renal or hepatic insufficiency will probably be accompanied by a corresponding increase in the duration of action of a AChE inhibitor.

The time required to fully reverse a nondepolarizing block depends on :Choice and dose of AChE inhibitor The muscle relaxant The extent of the blockade before reversal.


Neostigmine The effect are usually apparent in 5-10 min and last more

than 1 h. Pediatric and elderly patients appear to be more sensitive

to its effects, experiencing amore rapid onset and requiring a smaller dose.

It crosses the placenta resulting in fetal bradycardia. Atropine better choice as anticholinergic agent in pregnant

patients receiving neostigmine. Used to treat myasthenia gravis, urinary bladder atony, and

paralytic ileus (intestinal blockage; no peristalsis) . Side effects include nauseas, vomiting, fecal incontinence,

and atropine-resistant bradycardia at higher doses.


Pyridostigmine Structurally similar to neostigmine, lipid insoluble, and has

a covalent binding with AChE Potency: Neostigmine >>Pyridostigmine>>Edrophonium

Onset of action is slower than that of neostigmine and its duration of action is slightly longer(>2h).

Glycopyrrolate or atropine must be administered to prevent bradycardia.

Glycopyrrolate is preferred because its slower onset of action matches that of pyridostigmine, resulting in less tachycardia

Treatment of myasthenia gravis


Edrophonium The most rapid onset of action (1 o 2 min) and the shorter

duration of effect of any of the AChE inhibitors. Patients at the extremes of age are not more sensitive to

edrophonium reversal. May be more effective than neostigmine in reversing the

mivacurium blockade. Muscarinic effects less pronounced than those of neostigmine

or pyridostigmine requiring only half the amounts of anticholinergic agent.

Recommended anticholinergic: Atropine It is not useful for maintenance therapy of myasthenia gravis

because of its short duration of action.


Physostigmine Lipid soluble; freely passes the BBB The lipid solubility and CNS penetration limit its usefulness as

a reversal agent for nondepolarizing blockade. Effective in the treatment of central anticholinergic toxicity

caused by atropine or scopolamine. It reverses some of the CNS depression and delirium associated

with use of benzodiazepines and volatile anesthetics. Effective in preventing postoperative shivering. Partially antagonizes morphine induced respiratory depression

(morphine reduces Ach release in the brain)


Cont.

Other muscarinic effects: excessive salivation, vomiting, and convulsion.

Almost completely metabolized by plasma esterases, so renal excretions is not important.

Used for glaucoma treatment (second choice after policarpine) overdoses of atropine, phenothiazines, and TCA Intestinal and bowel atony

Adverse effects: ConvulsionsMuscle paralysis secondary to overstimulations Catarats Generalized excessive cholinergic stimulation

PhysostigmineGeneral Pharmacological Characteristics

TCA: tricyclic antidepressants

Anticholinergic DrugsOr

Antimuscarinic drugs

Drugs that block muscarinic receptorsAntagonists of muscarinic receptors

Anticholinergic Drugs

Drugs that block muscarinic receptors

Antimuscarinic drugs

The clinical use of this drugs in anesthesia relate to their effects on the CV, respiratory, cerebral, GI and other organ systems.

Mechanism of action

Competitively block binding of acetylcholine and prevents muscarinic receptors activation.

The cellular effects of ACh, in muscarinic receptors, which are mediated through second messenger (cGMP), are inhibited.

Cardiovascular Effects

Blockade of muscarinic receptors in the sinoatrial node results in tachycardia.

Effect especially useful in reversing bradycardia due to vagal reflexes (baroreceptor reflex, peritoneal reflex, oculacardiac relex).

HR: The mechanism may be a weak peripheral agonist effect.


Cardiovascular effects

Facilitation of conduction through the atrioventricular node, shortens the P-R interval on the electrocardiogram and often decreases heart block caused by vagal activity.

atrial arrhythmias and nodal rhythms occasionally occur.

Large doses can result in dilation of cutaneous blood vessels (atropine flush)


Respiratory effects Inhibit the secretions of the respiratory tract mucosa, from

the nose to the bronchi.

Bronchodilation: relaxation of the bronchial smooth musculature reduces airway resistance and increases anatomic dead space.

These effect are particularly pronounced in patients with chronic obstructive pulmonary disease of asthma.


Cerebral Effects

Effects ranging from stimulation to depression, depending on drug choice and dosage.

Stimulation may present as excitation, restlessness, or hallucinations (toxic doses)

Depression can cause sedation and amnesia. Physiostigmina reverses these actions.


Ophtalmic effects

Midriasis (pupillary dilatation) and cycloplegia (an inability to accommodate to near vision)

Do not dilates eyes of a patient who has narrow-angle glaucoma: acute crisis due to closure of the canal of Schlemn

ThermoregulationInhibition of sweat glands may lead to a rise in body temperature (atropine fever)


Gastrointestinal Effects salivary secretions gastric secretions (large doses) intestinal motility and peristalsis prolonged gastric emptying time

pressure of lower esophageal sphincter Anticholinergic drugs are not very advantageous in the

prevention of aspiration pneumonia.

Genitourinary effects ureter and bladder tone as a result of smooth muscle

relaxation (lead to urinary retention) urinary retention, particularly in elderly men with prostatic hypertrophy.


Atropine (alkaloid) Potent effects on the heart and bronchial smooth muscle

and is the most efficacious anticholinergic for treating bradyarrhythmias.

Due to tachychardia, myocardial oxygen demand and oxygen supply (warning for patients with coronary artery disease may not tolerate ).

Atropine has been associated with mild postoperative memory deficits, and toxic doses are usually associated with excitatory reactions.

Atropine should be used cautiously in patients with narrow-angle glaucoma, prostatic hypertrophy or bladder-neck obstruction.

Toxic effects: dry mouth, inhibition of sweating, tachycardia and cutaneous vasodilatation, blurring of vision, hallucination and delirium

Scopolamine

Alkaloid More potent antisialagogue that atropine. Causes greater CNS effects that atropine. Clinical doses produce drowsiness and amnesia,

although restlessness and delirium are possible. Prevent motion sickness. Avoid in patients with closed-angle glaucoma (high

ocular effects). Toxic effects: same as atropine

Glycopyrrolate

Because the quaternary structure , can not cross the BBB. Potent inhibition of salivary gland and respiratory tract

secretions.

HR after IV administration Glycopyrrolate has longer duration of action that atropine

(2-4 h versus 30 min after IV administration)

Drug interaction: Antihistamines, phenothiazines, tricyclic antidepressants,

antipsycotics When given with muscarinic blocking agents, cause ADDITIVE

antimuscarinic effects, resulting in increased effects Physostigmine effectively reverses central anticholinergic toxicity

Central Anticholinergic SyndromePlease, read the Case discussion : Central anthicholinergic Syndrome (pag 240 text book, chapter 11)

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Cholinergic Drugs on anesthesia practice