Lecture 3 Flashcards
which cholinesterase inhibitors are the carbamates
neostigmine and physostigmine
which are the carbamates can enter CNS
- Neostigmine: a quaternary amine, is not well absorbed orally and doesn’t cross the blood brain barrier.
- Physostigmine is a tertiary amine, so is absorbed orally and will get into the brain
effect time of carbamates
form a covalent bond with an effect lasting 30 mins- 6 hrs
route of admininistration and effect time of edrophonium
- Injected
- binds reversibly
- very short acting (5-10) minutes
use of organophosphates in today’s society
- Organophosphates are used as pesticides and as nerve gases.
- They are highly lipid soluble
MOA of Organophosphates
- They phosphorylate the cholinesterase enyzyme and form a very long-lasting bond.
- This bond then undergoes “aging”; breaking one of the phosphorus oxygen bonds increases the strength of the bond until it becomes irreversible.
after organophosphate poisoning, administration of what can prevent death
-
Pradlidoxime (2-PAM)
- if added before aging occurs, it can prevent aging and regenerate the cholinesterase enzyme.
- If aging is not prevented, organophosphate poisoning may be fatal.
- must be used within 3-4 hours
Though controversial, what is a method used in emergency departments to differentiate between organophosphate poisoning and carbamate poisoning
- administer 2-PAM
can pralidoxime (2-PAM) enter CNS
- strong nucleophile
- does not enter CNS
effects of cholinesterase inhibitors have an effect similar to what other receptor agonists you have learned about
- effects of cholinesterase inhibitors will be similar to stimulation of both muscarinic and nicotinic receptors, because the effect of ACh is enhanced.
- The effect in a particular tissue will reflect the predominant tone in that tissue.
effects of cholinesterase (AChE) inhibitors in the CNS
- alertness, improve memory
- convulsions and respiratory arrest with poisoning
The Eye, respiratory tract, GI, and genitourinary tract all have what prevailing tone? So cholinesterase inhibitors will behave like what receptor agonist in these tissues?
- parasympathetic tone is dominant in these tissues
- the effect is very similar to that of muscarinic agonists
effect of cholinesterase inhibitors in the eye
- miosis
- near vision
effect of cholinesterase inhibitors in GI, and bladder
- stimulation!
- diarrhea
- urination
effect of cholinesterase inhibitors in respiratory tract
- salivation
- secretion
- bronchoconstriction
effect of cholinesterase inhibitors on cardiovascular system
- in the heart, mainly parasympathetic responses are seen
- bradycardia
- decreased force of atrial contraction
- decreased cardiac output
- There is little effect on the vasculature (thus BP) since there is no direct cholinergic innervation.
effect of cholinesterase inhibitors on neuromuscular junction
- Low concentrations will increase the strength of contraction of skeletal muscle
- Higher or toxic concentrations, fibrillation of the muscle may occur, and neuromuscular blockade may result from desensitization of nicotinic receptors.
treatment for myasthenia gravis
- myasthenia gravis: antibodies against nicotinic receptors
- treatment: low dose of cholinesterase inhibitors
- Neostigmine
- Pyridostigmine
- ambenonium
action of Neostigmine lasts for how long
4 hours
Uses of Neostigmine
- increase bladder motility
- reverse neuromuscular blockage in surgery
- treat myasthenia gravis
which cholinesterase inhibitor is used for the diagnosis of myasthenia gravis? why?
- Edrophonium
- short acting (5-10), if myasthenic, muscle strength will improve for about 5 minutes
How is Edrophonium used to decide if a AChE inhibitor treatment dose is right?
- Edrophonium would decrease muscle strength if dose is too high
- would increase muscle strength if dose is too low
what is Echothiophate
- organophosphate with a very long duration of action
use of Echothiophate
- It is applied in the eye when long-term control of intraocular pressure is required, often in glaucoma emergency situations
- Not lipid soluble, so does not get absorbed systemically
What are Soman, Sarin, and Tabun
- organophosphates
- Nerve gases
What are Parathion and Malathion
- organophosphates
- used as pesticides
- lipid soluble
- inactivated fairly rapidly by birds and mammals.
Treatment of open-angle glaucoma
- Both physostigmine (cholinesterase inhibitors) and echothiophate (cholinesterase inhibitors) may be used to treat open-angle glaucoma, although pilocarpine (Direct-Acting Cholinergic Agonist) is used more often.
Acute closed-angle (aka narrow angle) glaucoma is treated with
- combination of pilocarpine and a cholinesterase inhibitor until the pressure is controlled and surgery can correct the problem.
What is used in the reversal of neuromuscular blockade in surgery
- The effects of the non-depolarizing neuromuscular blocking agents can be reversed by administration of cholinesterase inhibitors.
- Neostigmine
- edrophonium
what is Myasthenia Gravis
- autoimmune disease: antibodies to nicotinic ACh receptors
- not enough ACh can be released to produce the same number of open ion channels
- weakness and fatigue worsen with exercise
List the AChE inhibitor toxicity symptoms
SLUDGE
- Salivation
- Lacrimation
- Urination
- Defecation
- Gastric distress
- Emesis
+ neuromuscular stimulation followed by blockade, causing paralysis
Treatment of organophophate AChE inhibitor poisoning
- administer atropine until pupils dilate
- administer 2-PAM is less than 3-4 hours since exposure
- maintain respiration
- Diazepam for convulsions
What are Carbaryl, Propoxur, and Aldicarb
Carbamates (AChE inhibitors) insecticides
MOA of Antimuscarinic (Anticholinergic) drugs
- bind to muscarinic receptor
- do not activate receptor
- will displace acetylcholine or agonist from receptor
- Their effect will be to antagonize the actions of parasympathetic stimulation.
prototype Antimuscarinic (Anticholinergic) drug
Atropine
List the Muscarinic Antagonists
- Atropine
- Scopolamine
- Tropicamide
- Homatropine
- Ipratropium (Atrovent)
- Tiotropium (Spiriva)
- Dicyclomine (Bentyl)
- Tolterodine (Detrol)
- Oxybutynin
- Glycopyrrolate
route of administration of muscarinic antagonists.
- Atropine and Scopolamine are well absorbed orally
- Scopolamine can be absorbed through skin
Effect of Scopolamine on CNS function
- Euphoria
- Sedation
- Amnesia
Scopolamine can be given by transdermal patch to treat what?
motion sickness
which muscarinic antagonist can enter CNS
- Atropine enters CNS only at high doses
- Scopolamine enters CNS very easily
Why does Atropine effect certain tissues only at certain doses
- The effect of blocking muscarinic receptors will depend to a great deal on the amount of prevailing parasympathetic tone in different tissues
- Because of this, there is a dose-related sequence of effects of cholinergic blockade
Which tissues are affected by Atropine at low doses, medium doses, high doses?
- Low: salivary, sweat glands, bronchioles
- dry mouth, decreased sweating
- Medium: GI, urinary tract, Heart, eye
- urinary retention
- High: CNS
atropine effect on CNS
- little effect, except at toxic doses
- CNS stimulation followed by depression
- can cause confusion and coma
scopolamine effect on CNS
- drowsiness, memory loss
- relieves motion sickness
- toxic: hallucinations, agitation, coma
muscarinic antagonist effect in eye
- tone reduced
- pupil dilates: mydriasis
- photophobia
- lens flattens
- cycloplegia (loss of accommodation for near vision)
contraindication to the use of anticholinergics
- Narrow angle glaucoma
- Because anticholinergic drugs inhibit the ciliary muscle and close the trabecular system, they may obstruct the outflow of aqueous humor, and increase intraocular pressure, especially in narrow angle (closed-angle) glaucoma
- Benign prostatic hyperplasia (BPH)
Which cholinergic antagonists are short-acting drugs that are useful for producing mydriasis used for ophthalmology
- Tropicamide (6 hr)
- homatropine
Muscarinic Antagonists effect on cardiovascular system
- The atria and sinoatrial node are innervated by the parasympathetic nervous system (vagus nerve), and are thus sensitive to antimuscarinic drugs.
- Antimuscarinic drugs will block M2 receptors in the heart.
- With moderate doses of atropine, postsynaptic M2 receptors in the SA node will be blocked, and vagal tone will be decreased, resulting in tachycardia.
- Also, blockade of presynaptic M2 receptors will remove inhibition of norepinephrine release.
Muscarinic Antagonists will have the greatest effect on cardiovascular system of what patient population
- Tachycardia would be most noticeable in a healthy young adult with high vagal tone (increase of 25- 35 bpm).
- Babies and elderly people have far less vagal tone, so the cardiac effects of muscarinic blockade will be small.
does muscarinic antagonists have effect on the cardiac ventricles?
Cholinergic antagonists have little or no effect on the ventricles, which don’t receive parasympathetic innervation.
what effect do muscarinic antagonists have on blood vessels
- Because blood vessels do not receive parasympathetic inputs, antimuscarinic drugs have little effect on peripheral resistance or blood pressure.
- However, vasodilation may result from release of nitric oxide from endothelial cells in response to circulating muscarinic agonists.
- Atropine will completely block the decrease in blood pressure seen with muscarinic agonists.
- Atropine in toxic doses may cause vasodilation in the face, to get rid of excess heat.
what effect do muscarinic antagonists have on respiratory system
- The bronchioles receive parasympathetic inputs and the airway smooth muscles have M3 receptors
- Blockade of muscarinic receptors may produce bronchodilation
the effects of muscarinic antagonists are most helpful in what respiratory condition
- COPD
- acute asthma attacks
which muscarinic antagonists are used for bonchodilation due to their local effect in the lung
- Ipratropium (Atrovent)
- Tiotropium (Spiriva).
What effect do muscarinic antagonists have in GI system
- Muscarinic antagonists generally inhibit motility and secretions in the GI tract, and have been used as antispasmodics.
which muscarinic antagonist is used as an antispasmodic
Dicyclomine (Bentyl)
Atropine is combined with an opioid (Diphenoxylate) to treat diarrhea. Why are these two combined?
- The powerful effect of the opioid to decrease gastrointestinal motility is potentiated by addition of atropine.
- The unpleasant effect of atropine at high doses lowers the abuse potential of the opioid.
muscarinic antagonist effect on bladder
- Smooth muscle of the ureters and bladder wall are relaxed by anticholinergics, and voiding is reduced.
which muscarinic antagonists are used to treat overactive bladder and urinary frequency.
- Tolterodine (Detrol), a selective M3 receptor antagonist, no CNS side effects. Because of this, it is the preferred drug in the elderly.
which muscarinic antagonist is used to treat or prevent bladder spasms
Oxybutynin : prevents bladder spasm after prostate surgery
problem with given muscarinic antagonist to men with benign prostatic hyperplasia
can cause urinary retention
- thus, contraindicated
muscarinic antagonist effect on Sweat, lacrimal, and Salivary Glands
- inhibition of sweat glands
- body temp increases with toxic doses
- inhibition of lacrimal glands
- dry eyes
- decreased salivation
- dry mouth
