Pharmacology: Cholinergic Antagonists
Cholinergic Antagonist are also called
What do Cholinergic Antagonists due?
bind to cholinoceptors, but do not trigger the usual receptor mediated intracellular effect.
3 Families of antagonists:
neuromuscular blocking agents
What are the adverse effects commonly observed with cholinergic antagonists?
What are muscarinic blockers
selectively block muscarinic receptors of all the parasympathetic nerves.
Parasympathetic innervation are interrupted and actions of sympathetic stimulation are left unopposed
binds to the muscarinic synapses of the parasympathetic nerves
No action at skeletal neuromuscular junctions or autonomic ganglia.
ex: atropine and scopolamine block muscarinic receptors causing inhibition of all muscarinic functions
also block innervating salivary and sweat glands
mydriasis and cycloplegia
bronchodilators, adjuncts to general anesthesia.
Antimuscarinic undesirable effects
Antimuscarinic contraindication and types of drugs
Contraindicated for: glaucoma, G.I. tract atony.
What are neuromuscular-blocking agents
interfere (blocks) with transmission of efferent impulses to skeletal muscles.
used as skeletal muscle relaxants adjuvants in anesthesia during surgery, intubation, and various orthopedic procedures
What are ganglionic blockers
binds to nicotinic receptors of the sympathetic and parasympathetic ganglia
(Nicotonic are cholinergic receptors that form ligand-gated ion channels in the plasma membranes on the postsynaptic side of the neuromuscular junction. As ionotropic receptors, are directly linked to ion channels and do not use second messengers)
Use limited by severe side effects.
Drugs: Trimethaphan, Hexamethonium.
cholinergic agonists have useful or limited therapeutic capabilities?
limited usefulness therpauetically
cholinergic antagonists (blockers) are beneficial or not beneficial for clinical situations?
Beneficial because they do not block nicotonic receptors, the antimuscarinic drugs have little to no actions at skeletal neuromuscular junctions (NMJ) or autonomic ganglia
What is Atropine as an antimuscarinic agent?
a tertiary amine belladonna alkaloid with high affinity for muscarinic receptors
prevents acetylcholine from binding to muscarinic receptors
acts both centrally and peripherally
What is Atropine as an antimuscarinic agent
action lasts 4 hours (except placed topically in eye where it can last for days)
neuroeffector organs have varying sensitivity o atropine
inhibatory effects are on bronchial tissue and secretion of sweat glands and saliva
Atropines actions on?
Atropine on eyes
blocks cholinergic activity on eye, resulting in mydriasis (dilation of pupils)
unresponsiveness to light
cyclopegia (inability to focus for near vision
patients with narrow angle glaucoma, intraoccular pressure may rise dangerously
Atropine on Gastrointestinal (GI)
active isomer = l-hyoscyamine
antispasmodic to reduce activity of GI tract
Atropine and scopolamine
not promoted for peptic ulcer healing
slight hydrochloric acid
reduce saliva secretion
Atropine on Urinary System
reduce hypermotility of urinary bladder
occasionally used in enuresis (involuntary voiding of urine) among children
Atropine on Cardiovascular
produces divergent effects;
low dose = decrease cardiac rate (bradycardia) due to blockade of M1 receptors on the inhibitory prejunctional (presynaptic) neurons which permitted the increase of ACh release
Higher doses (1mg) = M2 receptors on SA node are blocked and cardiac rate increases
toxic levels will dilate cutaneous vasculature
Atropine on Secretions
blocks salivary glands, producing dry effect on the oral mucous membranes called xerostomia
inhibition of secretions by sweat glands can elevate body temperature; dangerous for children and elderly
Atropine Therapeutic uses on eye
topically, it exerts both mydriatic and cycloplegia effects
short activing antimuscarinics cyclopentolate and tropicamid have replaced atropine due to the prolonged mydriasis (7-14 days vs 6-24 hours)
may induce acute attack of eye due to sudden increases in eye pressure with narrow angle glaucoma
Atropine Therapeutic on GI tract
active isomer l-hyoscyamine
used as an antispasmodic agent to relax GI tract and bladder
Antidote for Cholinergic Agonist
Treatment of overdoses of cholinesterase inhibitor insecticides and certain types of mushroom poisoning and organophosphate
may need massive amounts for long period of time to counteract
also blocks excess ACh resulting from acetylcholinesterase inhibitors such as physostigmine
Atropine Therapeutic on Antisecretory
block secretions in upper and lower respiratory tract prior to surgery
partially metabolized by liver
eliminated (excreted) by urine
half-life 4 hours
Atropine adverse reactions
Depending on Dose. may cause
Effects on CNS
delirium -> depression, collapsation of circulatory or respiratory system and death
dangerous to children, because of sensitive side effects and rapid increase in body temperature
What should you use to overcome atropine toxicity?
low doses of cholinesterase inhibitors(pysostigmine) overcome atropine toxicity
What is Scopolamine as an antimuscarinic agent
another tertiary amine plant alkaloid, produced peripheral effects similar to atropine
has greater action on CNS (unlike atropine) and longer duraction of action compared to atropine
What are Scopalamines actions?
most effective anti motion sickness drugs
unusual effects on blocking short term memory
produces sedation (unlike atropine) but higher doses produces excitement
euphoria and susceptible to abuse
What are Scopalamines Therapauetic uses & Pharmacokinetics/adverse effects
prevention of motion sickness and blocking short term memory
its much more effective prophylactically for motion sickness
amnesic action makes it important in anesthetic procedures
Have similar to Atropine
What are Ipratropium and Tiotropium?
Inhaled are quaternary derivatives of atropine
approved as bronchodilators for maintenance treatment of bronchospasm associated with COPD
both chornic and emphysema
pending for Asthma patients because they are unable to take adrenergic agonist because of positive charges, thus drugs do not enter systemc circulation or CNS
Tiotropium = administered once daily, major advantage over ipratropium
Ipratropium = four times daily dosing.
What are Benztropine and trihexyphenidyle
treat parkinsons disease though replaced by levodopa and carbidopa
are useful as adjuncts with other antiparkinsonian agents to treat all types of parkinsonian syndromes
-antipsychotic induced extrapyramidal symptoms
geriatric patients who cannot tolerate stimulants
What are Tropicamide and cyclopentolate
similar to atropine as othalmic solutions for mydriasis and cycloplegia
duration of action shorter than atropine
Tropicamide may produce myadriasis for 6 hours
Cyclopntolate may produce myadriasis for 24 hours
treatment of overactive urinary bladder.
blocking muscarinic receptors in bladder, intravesicular pressure is lowered so bladder capacity increases and fequency of bladder contraction reduced
side effect: dry mouth, constipation, and blurred vision
Oxybutylin (transdermal/topical patch) better tolerated because less dry mouth and more widely accepted
What are Ganglionic blockers
They block the entire output of the autonomic
nervous system at the ganglionic nicotinic receptors (parasympathetic and sympathetic)
not effective neuromuscular antagonist; thus block entire output of antonomic nervous system at the nicotonic receptor
non-depolarizing competitive antagonnists (except for nicotine)
produce atony of bladder and GI tract, cycloplegia, xerostomia, and tachycardia
Overall, rarely used therapeutically but served as a tool in experimental pharmacology
Nicotine (Ganglionic Blocker)
cessation of smoking.
is a poison without therapeutic benefit and deleterious to health
depolarizes autonomic ganglia = stimulation than paralysis of ganglia
are complex and result from increased release of neurotransmitters that effect both sympathetic and parasympathetic
Nicotine stimulatory effects
Dopamine = pleasure, appetite supression (lowers body weight)
Norepinephrine = arousal, appetite suppression
Acetylcholine = arousal, cognitive enhancement
Glutamate = Learning, memory enhancement
Serotonin - Mood modulation, appetite suppression
Beta Endorphin = Reduction of anxiety and tension
GABA = Reduction of anxiety and tension
Nicotine physiological system response
increased BP and cardiac rate (due to release of transmitter from adrenergic terminals and form the adrenal medulla)
increased peristalsis and secretion
Higher dose = blood pressure fall (due to ganglionic blockade and activity in GI and bladder muscarture ceases)
What is Mecamylamine and Trimethaphan (Ganglionic Blocker)
competitive nicotine blockade of ganglia and
Mecamylamine = Treatment of moderately-severe hypertension
Trimethaphan = Treatment of short term hypertension
Role of different ions in cellular excitation and inhibition
A neuronal, heart or a muscle cell is negative inside and positive outside so the potential difference across the cell membrane is about -75 mV.
Calcium influx causes the release of both types of
neurotransmitters, excitatory as well as inhibitory
Excitatory neurotransmitters are:
Increase the influx of sodium inside the cell, thus depolarizing the cell that helps in propagation of
Inhibitory neurotransmitters are:
increase the influx of chloride ions thus hyperpolarizing the cell that does not allow the current to move forward.
increase the efflux of potassium thus again
hyperpolarizing the cell that does not allow the current to move forward
Neuromuscular blocking drugs
block cholinergic transmission between
-motor nerve endings
-nocotinic receptors on neuromuscular endplate of
either antagonist (nondepolarizing) or agonist (depolarizing) receptors on endplate of NMJ
Neuromuscular blocking drugs
clinically useful during surgery for complete muscle relaxation without higher anesthetic doses
facilitating tracheal intubation
What are second group of Neuromuscular blocking drugs
second group = central muscle relaxants used to control spastic muscle tone
diazapam, binds to gama aminobutyric acid (GABA)
dantrolene, acts directly on muscle by interfering release of calcium from sarcoplasmic reticulum
baclofen, acts at GABA receptors in CNS
first drug capable of blocking the skeletal NMJ was?
Curare, native South American hunters of Amazon region used to paralyze prey
Nondepolarizing Competitive blocker Tubocurarine
ultimately purified and introduced into clinical practice in 1940s.
prototype agent no longer available in US
Benefits of neuromuscular blocking agents?
significantly increased safety of anesthesia, because less anesthetic required to produce muscle relaxation, allowing patients to recover quickly and completely after surgery
Higher dose = respiratory paralysis and cardiac depression which increases recovery time
What are Neuromuscular blocking mechanism of actionn at low dose
nondepolarizing neuromuscular blocking drugs interact with nicotinic receptors = prevention of ACh binding
preventing depolarization of muscle cell membrane and inhibit muscular contraction
compete w/o stimulation, they are called competitive blockers
actions overcome by increasing concentration of ACh in synaptic gap: Cholinesterase inhibitors include:
low dose, muscle will respond direct electrical stimulations from peripheral nerve to varying degrees
What are Neuromuscular blocking mechanism of action at high dose?
block ion channels of endplate with leads to further weakening of neuromuscular transmission
reducing AChE inhibitors to reverse actions of nondepolarizing muscle relaxants
Neuromuscular blocking drug actions
Blockade of muscles of face and eye followed by the
fingers, limbs, neck and trunk (respiratory system).
Effects for 20 min - 2 hr
Small rapidly contracting muscles of face and eyes fingers
Recovery comes from REVERSE MANNER starting with diaphragm. Last is face and eyes
Histime releasing Actracurim = fall in BP, flushing, and bronchoconstriction
Neuromuscular therpaeutic uses
For muscle relaxation with adjuvant drugs in
surgical anesthesia. Given parenterally, do not
cross blood brain barrier.
orthopedic surgery (fracture alignment and dislocation)
All injected intravenously because of their uptake via oral absorption (minimal)
two or more quaternary amines; making it bulky and orally ineffective
very poor membrane penetration and does not cross blood brain barrier
Roll of Pancuronium as a Neuromuscular pharmacokinetic
Five times more potent than tubocurarine,
does not release release histamine. It is the prototypic drug for many is the prototypic drug for many new drugs such as
Atracurium (metabolized to laudanosine; causing seizures)
Rocuronium (steroid drug deacetylated in liver)
Vecuronium (steroid drug deacetylated in liver)
These drugs heavily used as adjuncts in anesthesia during surgery to relax skeletal muscles.
Agents safe with minimal side effects
spontaneously degrades in plasma
only nondepolarizing neuromuscular blocker whose dose does not need to be reduced in patients with renal failure
used in multisystem organ failure because its metabolism is independent of hepatic or renal function
used in mechanical bentilation of critically illed patients
Vagolytic increased heart rate
Drug interactions with Neuromusclar blocking drugs:
help overcome nondepolarizing neuromuscular blockers
if increased dose, it can cause a depolarizing block with elevated ACh concentration at end plate membrane
Drug interactions with Neuromusclar blocking drugs
Halogenated hydrocarbon anesthetics
halothane acts to enhance neuromuscular blockade by exerting a stabilizing action at NMJ
Drug interactions with Neuromusclar blocking drugs:
inhibit ACh release from cholinergic nerves by competing with CA ions
Drug interactions with Neuromusclar blocking drugs:
Calcium Channel blockers
increase neuromuscular blocking of competitive blockers
as well as depolarizing blockers
work by depolarizing plasma membrane of muscle fibers
more resistant to degradation by AChE, thus more persistent depolarization of muscle fibers
only depolarizing muscle relaxant used today
attaches to nicotinic receptor and acts like ACh to depolarize the junction
ACh instantly destroyed by AChE, Succinylcholine remains attached to the receptor for longer time and providing constant stimulation of the receptor
Duration of Action of Succinylcholine
depends on diffusion from motor endplate and hydrolysis by plasma pseudocholinesterase
How does Depolarization work for Succinylcholine?
causes opening of sodium channel associated with nicotinic receptors causing depolarization of receptor (phase 1)
Phase I: twitching of muscle (fasciculation)
Sodium Channels Open
Continued binding renders receptor incapable of transmitting further impulses thus in time depolarization gives way to gradual repolarization as sodium channel closes (blocked)
Phase II: resistance to depolarize and flaccid paralysis
Paralysis (respiratory muscles are paralyzed last)
broken down by plasma pseudocholinesterase = short duration action
Metabolized rapidly by plasma
Muscle fasciculations followed by paralysis.
given by continuous i.v. infusion.
Succinylcholine Therapeutic Action
rapid onset and short duration of action
rapid endotracheal intubation during induction of anesthesia (rapid action essential if aspiration of gastric content is to be avoided during intubation)
electroconvulsive shock therapy
brief duration of action (several minutes) rseults from redistribution of rapid hydrolysis by plasma pseudocholinesterase
given continuous infusion to maintain a longer duration effect
What are the adverse effects for Succinylcholine?
Succinylcholine Adverse effect: Hyperthermia
With halothane, causes malignant
hypyperthermia in genetically
susceptible people (with muscular rigidity, metabolic acidosis, tachycardia, and
MH is treated with dantrolene (blocks Ca2+ release, reduces heat production and muscle tone).
Succinylcholine Adverse effect: Apnea
patient genetically deficient in plasma cholinesterase or who has an atypical form of the enzyme can lead to prolonged apnea d/t paralysis of diaphragm
rapid release of potassium prolong apnea in patients with electrolyte imbalance
What drugs should be avoided when on Succinylcholine?
Diuretics (Congestive Heart Failure)
Succinylcholine Adverse effect: Hyperkalemia
increases potassium release from intracellular stores
dangerous in burn patients and patients with massive tissue patients in which potassium is rapidly lost within cells