Pharmacology: Pharmacology: Cholinergic Antagonists Flashcards

cholinergic blockers
parasympatholytics
anticholinergic

bind to cholinoceptors, but do not trigger the usual receptor mediated intracellular effect.

3 Families of antagonists:
Muscarinic blockers
ganglionic blockers
neuromuscular blocking agents

blurred vision
confusion
mydriasis
constipation
urinary retension

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

produce
mydriasis and cycloplegia
motion sickness
bronchodilators, adjuncts to general anesthesia.

Xerostomia
blurred vision
tachycardia
anhidrosis
urinary retention,
glaucoma

Contraindicated for: glaucoma, G.I. tract atony.

Drugs:
Atropine,
scopolamine
ipratropium

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

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.

limited usefulness therpauetically

Beneficial because they do not block nicotonic receptors, the antimuscarinic drugs have little to no actions at skeletal neuromuscular junctions (NMJ) or autonomic ganglia

a tertiary amine belladonna alkaloid with high affinity for muscarinic receptors

prevents acetylcholine from binding to muscarinic receptors

acts both centrally and peripherally

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

eye
GI
Urinary System
Cardiovascular
Secretions

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

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
ocular accomodation
micturition (urination)

reduce hypermotility of urinary bladder

occasionally used in enuresis (involuntary voiding of urine) among children

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

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

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

active isomer l-hyoscyamine
used as an antispasmodic agent to relax GI tract and bladder

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

block secretions in upper and lower respiratory tract prior to surgery

readily absorbed,
partially metabolized by liver
eliminated (excreted) by urine
half-life 4 hours

Depending on Dose. may cause

dry mouth
blurred vision
"sandy eyes"
tachycardia
urinary retention
constipation

Effects on CNS
restlessness
confusion
hallucination
delirium -> depression, collapsation of circulatory or respiratory system and death

dangerous to children, because of sensitive side effects and rapid increase in body temperature

low doses of cholinesterase inhibitors(pysostigmine) overcome atropine toxicity

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

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

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

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.

delivered inhalation

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

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

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

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

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

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)

competitive nicotine blockade of ganglia and

Mecamylamine = Treatment of moderately-severe hypertension

Trimethaphan = Treatment of short term hypertension

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

Acetylcholine
Glutamate

Increase the influx of sodium inside the cell, thus depolarizing the cell that helps in propagation of
the current.

Glycine
GABA
increase the influx of chloride ions thus hyperpolarizing the cell that does not allow the current to move forward.

adenosine
opioids
increase the efflux of potassium thus again
hyperpolarizing the cell that does not allow the current to move forward

block cholinergic transmission between
-motor nerve endings
-nocotinic receptors on neuromuscular endplate of
skeletal muscle

either antagonist (nondepolarizing) or agonist (depolarizing) receptors on endplate of NMJ

clinically useful during surgery for complete muscle relaxation without higher anesthetic doses

orthopedic surgery

facilitating tracheal intubation

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

Curare, native South American hunters of Amazon region used to paralyze prey

ultimately purified and introduced into clinical practice in 1940s.

prototype agent no longer available in US

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

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:
neostigmine
pyridostigmine
edophonium

low dose, muscle will respond direct electrical stimulations from peripheral nerve to varying degrees

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

ex. Tubocurarine

Blockade of muscles of face and eye followed by the
fingers, limbs, neck and trunk (respiratory system).
Effects for 20 min - 2 hr

Paralyziation:
Small rapidly contracting muscles of face and eyes fingers
neck
trunk muscle
intercostal muscles
diaphragm

Recovery comes from REVERSE MANNER starting with diaphragm. Last is face and eyes

Histime releasing Actracurim = fall in BP, flushing, and bronchoconstriction

For muscle relaxation with adjuvant drugs in
surgical anesthesia. Given parenterally, do not
cross blood brain barrier.

intubation
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

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)
Cisatracurium
Doxacurium
Mivacurium
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

neostigmine
physostigmine
pyridostigmine
edrophonium

help overcome nondepolarizing neuromuscular blockers
if increased dose, it can cause a depolarizing block with elevated ACh concentration at end plate membrane

halothane acts to enhance neuromuscular blockade by exerting a stabilizing action at NMJ

gentamicin
tobramycin

inhibit ACh release from cholinergic nerves by competing with CA ions

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

Succinylcholine

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

depends on diffusion from motor endplate and hydrolysis by plasma pseudocholinesterase

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.

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

Inject intravenously
brief duration of action (several minutes) rseults from redistribution of rapid hydrolysis by plasma pseudocholinesterase

given continuous infusion to maintain a longer duration effect

Hyperthermia
apnea
Hyerkalemia

With halothane, causes malignant
hypyperthermia in genetically
susceptible people (with muscular rigidity, metabolic acidosis, tachycardia, and
hyperpyrexia).

MH is treated with dantrolene (blocks Ca2+ release, reduces heat production and muscle tone).

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

Digoxin
Diuretics (Congestive Heart Failure)

increases potassium release from intracellular stores
dangerous in burn patients and patients with massive tissue patients in which potassium is rapidly lost within cells