Antimuscarinic Agents and nicotinic block Flashcards
What are the muscinarinic receptor antagonists
Tertiary amine esters - atropine, scopolamine, hyoscyamine and homatropine; these are nonpolar and well absorbed from GI tract, cross BBB
Quarternary ammonium antagonists - methscopolamine, iprotrapium, tiotropium, glycopyrrolate, umaclidinium
these are poorly absorbed and barely cross BBB
Action of Ach antagonists
Block ACh binding to M receptors, nonselective- binds all of them.
-M receptors are constitutively active and most antimuscarinic drugs are inverse agonists that stabalize the receptor in the inactive state.
binds pre and post synaptic receptors at both parasympathetic and sympathetic muscinaric synapses, peripheral ganglia and CNS
Atroptine dose-related effects
Too Low dose - 0.5mg paradoxical bradycardia, slight cardiac slowing, some dryness of mouth and inhibition of sweating
1 mg — dry mouth, tachycardia, mild dilation of pupils
Higher doses:
2mg - rapid heart rate, blurred vision, dilated pupils
5mg - 10 mg: difficulty speaking and swallowing, difficulty with urination, GI ileus, progression into hot skin causing atropine flush, ataxia, restlessness, hallucinations and delerium, coma.
Effects of muscarinic antagonist
Decreased REM sleep and fatigue, tachycardia, bronchodilation, dry mouth, delayed gastric emptying and constipation, problems with microurition, blurred vision, dry eyes, hyperthermia
With too low doses - paradoxical bradycardia
What are the therapeutic uses of atropine?
Mydriasis and cycloplegia As a preanesthesia To counteract over-vagal stimulation of the heart - lowered HR; used in this manner primarily as a short-term intervention Cholinergic poisoning - too much Ach Treatment of peptic ulcer disease as an antispasmodic
used along with scopolamine, glycopyrrolate, preoperatively to reduce bronchotracheal secretions and spasm.
Therpuetic use of ipratropium and tiotropium
They are bronchdilators, inhalded
also, umeclidinium
Used for management of COPD
Ipratropium can be in a nasal spray as well, short acting
muscinarinic antagonists
Oxybutnin
Oral, treatment of overactive bladder, somewhat selective M3 receptor inhibitor, cyp3A4 metabolism, antimuscinaric side effects
atropine-like drugs in general induce urinary retention by blocking Ach binding to it’s receptor and causing detruser muscle contration.
other drugs - tolterodine, darifenacin, soliffenacin. fesoterodine, and trospium
not for use in men with prostatic hyperplasia
muscinarinic antagonists
Cyclopentolate and tropicamide
Used topically for mydriasis and cycloplegia for visualization of optic nerve, retina and lens
Shorter duration and preffered over atropinee and scopolamine
muscinarinic antagonists
Benztropine and trihexyphenidyl
Adjunctive Rx Parkinson’s disease - treatment of drug induced extrapyramidal symptoms
muscinarinic antagonists
What are the contraindications for atropine like agents?
Narrow-angle glaucome - obstruct aqueous humor outlow
Prostatic hyperplasia - exarcerbate urinary retention
Tachycardia - aggravates
GI obstruction, paralytic ileus, severe ulcerative colitis
Toxicity of anticholinergic drugs
Red as beet — flushed with hot skin, sweating is inhibited, capillary vasodialation as an attempt to give off excess heat
Dry as a bone — salviary and other secretion are inhibited, dry mouth, dry skin, reduced GI secretions
-constipation, dyspepsia
Blind as a bat — large, nonreactive pupils and blurred vision
Hot as hades — hyperthermia, tachycardia, and hypertension
Mad as a hatter — confusion, disorientation, hallucinations, seisuzes and coma
Reversal with physostigmine
what are the effects of ganglion blockers?
They supress homeostatic reflexes that typically moderate autonomic functions
nondepolarizing block of AChR’s of both ANS systems (para and sym) - inhibits ganglionic transmission
Can give knowlegde of effector organ responses to autonomic stimulation and help determine the predominant resting tone.
What organ systems have a primarily sympathetic tone at rest?
Arterioles - drug causes vasodilation and hypotension
veins - drug causes dilation, pooling of blood in periphery and decreased venous return
sweat glands - drug causes anhidrosis
Genital tract - drug causes sexual impairment
Which organ systems have a predominately parasympathetic tone at rest?
Heart - drug causes tachycardia
iris - drug causes mydriasis
ciliary muscle - causes cycloplegia (farsightedness)
GI tract - causes reduced tone and motility and decrease in gastric and pancreatic secretions.
urinary bladder - urinary retention
salivary glands - xerostemia
genital tract
previous therapeutic uses of ganglionic inhibitors
Was used classically for chronic hypertension, acute hypertensive crisis and controlled hypotension
Discontinued because of lack of selectivity leading to a broad range of undesirable effects
What are the contraindication and drug interactions of ganglionic inhibitors?
Contraindications - cononary insuffciency, pyloric stenosis, glaucoma, uremia, recent MI, unreliable or uncontrollable patients
Drug interactions - patients on ganglionic blocks are still responsive to autonomic drugs acting on mAChRs, alpha and beta receptors leading to exaggerated or reversed ANS responses
what are the types of neuromuscular nicotinic receptor antagonists?
Succinylchoine
Benzylisoquinolines
Aminosteroids
Quarternary ammonium compounds, depolarizing agenst and non—depolarizing agents
Does not cross BBB, IV with poor absorption.
Succinylcholine
A depolarizing agent - fexible structure
Metabolized by plasma cholinesterase
Works almost instantly and lasts for mere minutes… metabolized quickly (4 to 6 min)
first causes fasciculations (because of channel opening) followed by flaccid paralysis
People deficient in plasma cholinesterase will have the drug active longer causing prolonged apnea at therapuetic doses
can be used to facilitate endotracheal intubation, unlikely to cause hypoxia in a pre-oxygenated patient
Amino sterols
metabolized heptically and renally - active metabolites
Intermediate acting drugs - rocuronium and vecuronium
Long acting - pancuronium
Nondepolarizing
Benzylquinolines
Non-hepatic metabolism
Short acting - mivacurium (plasma cholinesterase)
Intermediate — atracurium (metabolite laudanosine crosses BBB) and Cisatrcurium (spontaneous metabolism)
Long acting - doxacurium and Tubocurarine (renal metabolism)
Non-depolarizing nicotinic antagonists
Rocuronium
Amino steroid, onset in 1-2 minutes and lasts for 36 to 73 minutes
least potent NM blocker
rapid-induction anesthesia and relaxing laryngeal and jaw muscles for tracheal intubation, can be used to relax muscles for patients on mechanical ventilation
causes hypersensitivity reactions more commonly than the other drug versions
Cisatracuruim
benzylquinoline, intermediate acting
onset in 2 - 8 minutes
duration for 45 to 90 minutes
does not cause histamine release and less is metabolized to laudanosine. clincally used in place of atracurium.
Does not accumulate and degrades in plasma without aid of enzymes
facilitation of endotracheal intubation, skeletal muscle relaxation during surgery or mechanical ventilation
Vecuronium
amino steroid
onset - 2 to 3 minutes
duration - 40 to 45 minutes
Intermediate-acting agent; facilitation of endotracheal intubation, skeletal muscle relaxation during surgery or mechanical ventilation
Pancuronium
long acting amino steroid
onset: 3 to 5 min
duration: 85 to 100 min
more potent than the short-acting versions. Difficult to achieve reversal post-op
facilitation of endotracheal intubation, skeletal muscle relaxation during surgery or mechanical ventilation
slightly increases HR
Atracurium
intermediate acting benzyquinoline
onset in 3 min
duration is 45 min
spontaneous decomposition with an active metabolite - laudanosine: crosses BBB and decreases seizure threshold.
Can accumulate in patients with biliary obstruction or prolonged use of atracurium. (excreted both in renal and biliary systems)
causes histamine release
General therapuetic uses of neuromuscular blocks
as an adjuvant to surgical anesthesia
facilitate intubation - endotracheal intubation, laryngoscopy, bronchoscopy and esophagoscopy
control of ventilation
used in orthopedic procedures
pain and consciousness is still intact with these NM blockers - to be used with anesthesia
What would you administer to reverse a competitve nondepolarizing neuromuscular blocking drug?
Neostigmine - inhibits degradtion of Ach, allowing the Ach to accumulate and outcompete the NM blocking agent
pyridostigmine, edrophonium - same mechanism
also, sugammadex
What is purpose of sugammadex?
Reversal of steriodal NM blocking agents - rocuronium and vecuronium
Forms a tight 1:1 complex that is excreted in the urine
Name the adverse affects on succinylcholine?
Prolonged apnea - especially in patients with low or absent plasma cholinesterase
Maligant hyperthermia - paitents with congenital myopathies
Bradycardia - in children, requires pretreament with atropine
Others - histamine release, hyperkalemia, myalgia, myoglobinuria and increase intra gastric and intraocular pressure
regurgitation and aspiration secondary to increase intragastric pressure - a complication is more likely to occur in patients with delayed gastric empying (diabetes, traumatic injury, esophageal dysfunction and obesity)
What are the contraindications of succinylcholine?
Myopathies or UMN disease -> malignant hyperthermia, or personal/family history of
-> other muscular dystrophies; paraplegia or quadroplegia
spinal cord injuries, multiple trauma
Burn patients - increased risk of hyperkalemia
Patients with spinal or ocular injury
Children
Older age because of a decrease in renal clearance
Scopolamine
Transdermally for motion sickness, preanesthesia, mydraisis and cyclopllegia — gets into CNS at low doses (which is why it is used for motion sickness)
spreads widely and quickly to CNS and rest of body, CNS effects are greater than other antimuscarinic’s
therpeutic use of methscopolamine
decreases GI secretions and peristalsis, used in peptic ulcer disease but for the most part have been replaced by proton pump inhibitors (omeprazole) and H2 receptor blockers (ranitidine)
antispasmotics - antimuscarinics
symptomatic treatment of IBS, spastic colitis hypermotility, biliary or renal colic (use with morphine or other opiods)
drugs - dicyclomine, hyoscyamine, belladonna alkaloids
ophthalmic therapeutic uses of antimuscarinics
induction mydriasis for fundascopic exam, eye surgery, iridocyclitis and keratitis therapy
alternate with a miotic to prevent or break adhesions between iris and lens
reversal of antimuscarinic toxicity
rx physostigmine - increases levels on Ach in synapsis which outcompetes the antimuscarinic drug (anti cholinesterase inhibitor)
other required measures - respiratory and cardiovascular support, detoxification and seizure treatment with denzodiazepine
what structure allow specificity for neuromuscular blockade?
2 ammonium groups separated by 10 Carbon atoms, (succinylcholine, pancorium etc)
ANS blocking agents (the no longer used ganglionic blockers) have 2 ammonium groups separated by 6 C’s
treatment for malignant hyperthermia
dantrolene - blocks the ryanodyne receptor in skeletal muscle (RyR1) which blocks the opening of the calcium channel on the sacroplasmic reticulum
does not effect cardiac and smooth muscle
Tubocurarine
long duration, non-deplorizing NM blocker, associated with the greatest amount of histamine release and hypotension
not used clinically.
drug interactions of NM blockers - which one is favorable?
volatile halogenated anesthetics - favorable, stabalizes the effect
aminoglycoside antibiotics - potentiates NM Blockade
other antibiotics - tetracycline, clindamycin, vancomycin, colistin and polymyxin B
