CHOLINESTERASE INHIBITORS AND ANTICHOINERGICS Flashcards
Cholinergic agonists moa
Bind to cholinergic receptors and mimic the actions of acetylcholine
also called parasympathomimetic drugs; copy parasympathetic nervous system
Anticholinesterase moa
Inhibit acetylcholinesterase enzyme (the enzyme that destroys acetylcholine). This increases acetylcholine levels at the receptor sites and prolonging its effects.
Examples of cholinergic agonists
Bethanechol
Carbachol
Cevimeline
Pilocarpine
cholinergic Pharmacokinetics administration forms and how are they excreted?
Action and metabolism vary widely
Administered topically, orally, and subcutaneously
No I/V or I/M because rapid break down and rapid actions leads to crisis
Metabolized at the muscarinic and nicotinic receptor sites in the plasma and liver
Excreted by the kidneys
Cholinergic drugs
Pharmacodynamics COMMIT to memory
Mimic (copy) the actions of acetylcholine
Combine with the receptors on the target organs’ cell membranes
Actions
Salivation, slow heart rate, dilation of blood vessels, constriction of bronchioles , increase gut activity, contraction of urinary bladder and constriction of pupil
Cholinergic drugs Pharmacotherapeutics:
Cholinergic agonists are used in the following conditions
Urinary retention due to weak or atonic bladder
Lack of bowl movements especially post op period
Glaucoma to reduce intraocular pressure
Salivary gland hypofunction
cholinergic drug
Drug interactions
Other cholinergic drugs leads to toxicity
Cholinergic blocking agents
Quinidine
Cholinergic drugs:
Adverse reactions (wet as ocean)
7 things
Decrease heart rate* and lower BP
Nausea/vomiting
Increased activity of gut cramping and diarrhea
Excessive sweating/salivation
Increase urination
Blurred vision due to pupillary constriction
Shortness of breath due to bronchoconstriction
ACH
Acetylcholine applies breaks on heart but accelerates gut and bladder smooth muscles
Anticholinesterase drugs MOA
Block action of enzyme acetylcholinesterase , preventing breakdown of acetylcholine
This increases levels of acetylcholine are receptor sites leads to more stimulation by acetylcholine
Anticholinesterase drugs can be divided into two groups
Reversible- short duration of action; examples- physostigmine
Irreversible- long-lasting effects; examples- insecticides, nerve gas for warfare
Cholinergic drugs: Anticholinesterase drugs
pharmacokinetics
Absorbed from GI tract, subcutaneously, and mucous membranes
Can cross blood-brain barrier
Metabolized by enzymes in plasma
Excreted by the kidneys
cholinergic drugs: anti cholinesterase pharmacodynamics
Produce a stimulant or depressant effect on cholinergic receptors based on site, dose, and duration of action
Anticholinesterase drugs
Pharmacotherapeutics/ Indications
Glaucoma to reduce eye pressure
To increase bladder motility
To increase tone and motility of GI tract in patient with post op low gut motility ( paralytic ileus)
To improve muscle strength in myasthenia gravis
Antidote for cholinergic blocking agents
To treat dementia in Alzheimer’s’ disease (Alzheimer’s disease is due to deficiency of acetylcholine in brain)
when do we put scopolamine on
dont touch it, wash your hands, put it on in PRE op. take it off after 3 days.
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Cholinergic drugs: Anticholinesterase drugs
Adverse effects
Cardiac arrhythmias Nausea/vomiting Diarrhea Shortness of breath, wheezing Headache, seizures
best drugs to dry up secretions
rybinol
Cholinergic blocking agents/Anticholinergic Drugs
how do they act?
what are some examples?
are they competitive or noncompetitive antagonist
Interrupt parasympathetic nerve impulses in the central and autonomic nervous systems
Examples– atropine, belladonna, scopolamine
Atropine competes with acetylcholine for receptor sites – competitive antagonist
hr 58
hr 30
58- glycol
30- atropine
Cholinergic blocking agents pharmacokinetics
Pharmacokinetics
Absorbed through GI tract, eyes, mucous membranes, skin
Crosses blood-brain barrier
Metabolized in liver; excreted by kidneys
cholinergic
Pharmacodynamics
Stimulating or depressing effects depending on target organ and disorder
Cholinergic BLOCKING agents Pharmacotherapeutics / Indications. what do they do to the smooth muscles of the GI and Urinary bladder?
All cholinergic blocking agents relax smooth muscles of GI and urinary bladder. Therefore these are used in
Hyperactive bladder (e.g. Detrol ®)
Hyperactive gut (colic/ irritable bowel syndrome)
Biliary colic
Before endoscopy or sigmoidoscopy to relax GI smooth muscles
reglan- in class discussion who do we not give it to?
bowel obstruction!
when is Atropine give
is given before surgery to dry up secretions
To speed up heart rate during bradycardia *
To dilate pupil for eye exam
As an antidote for pesticide poisoning; blocks DUMBELSS i.e. Diarrhea, Urination, Miosis, Bronchospasm, Bradycardia, Excitation of skeletal muscles, Lacrimation, Salivation (and abdominal cramps)
Cholinergic blocking agents drug interactions
Tricyclic and tetracyclic antidepressants
cholinergic blocking agents adverse reactions
Adverse reactions Dry mouth Decreased sweating Reduced bronchial secretions Blurred vision due to pupillary dilatation Confusion Tachycardia increase body temperature
Treatment: antidote
for cholinergic blocking agents
physostigmine
atropine greater than 10mg
hallucinations delirium and coma
atropine greater than 5mg
rapid heart rate, palpitations, marked dryness of mouth dilation fo pupil some blurring of near vision
atropine 0.5mg
slight cardiac slowing some dryness of the mouth inhibition of sweating
Muscarinic receptors are located in:
Heart
Salivary glands
GI smooth muscle
GU tract
anticholinergic drugs moa
Competitively antagonize the neurotransmitter (NT) acetylcholine (Ach) at cholinergic postganglionic sites.
Naturally occurring tertiary amine belladonna alkaloids are
Atropine and Scopolamine.
glycopyrrolate naturally occurring or not?
, semisynthetic, and usually quaternary ammonium derivatives.
These are usually more potent than their parent compound and NO CNS EFFECTS, secondary to poor penetration to the brain.
Atropine & scopolomine:
Naturally occurring drugs are formed into esters.
Resemble cocaine structurally.
Atropine has a weak analgesic effect.
Mixed of equal parts of dextrorotatory & levorotatory isomers.
Anticholinergic effects are due to levorotatory form.
Have a cationic portion that fits into muscarinic cholinergic receptor, like Ach
Anticholinergic drugs MOA
Combine reversibly w/ muscarinic cholinergic receptors, preventing access of Ach to these sites.
Anticholinergic drug w/ muscarinic receptors results in NO cell membrane change.
DO NOT prevent release of Ach or react with it.
They are competitive antagonists, the effects of anticholinergic drugs can be overcome by concentration of Ach in the area of the muscarinic receptors.
5 muscarinic cholinergic receptor subtypes:
M1…CNS & stomach
M2…Lungs, heart & eyes
M3…CNS, airway smooth muscle & glandular tissue
M4 & M5…CNS
which is not a CNS Subtype? Mu2
glycopyrrolate and metabolic 02 consumption
Glycopyrrolate increases metabolic O2 consumption, atropine has no effect, & scopolamine has a decreased effect.
scopolamine and antisialagogue effects
has greater antisialagogue (decrease production of saliva) & ocular effects than atropine.
atropine and anticholinergic effects on the heart?
has greater anticholinergic effects on the heart, bronchial smooth muscle & GI tract than scopolamine.
Atropine onset
~ 1 min. Duration of 30 – 60 min
Glycopyrrolate onset
2 – 3 min (IM injection ~ 16 min), with same duration
name the two anticholinergic drugs that can penetrate the BBB
atropine and scopolamine
name drug that can’t penetrate the bbb
glycopyrrolate
hydrolysis of atropine
Atropine is hydrolyzed to tropine and tropic acid, little hydrolysis in plasma. T1/2=2.3h
how much of scopolamine is broken down and excreted in the urine
Scopolamine is broken down almost entirely; ~1% excreted unchanged in the urine
how is glycopyrrolate eliminated?
Glycopyrrolate elimination is more rapid than atropine T1/2= 1.25h, and is significantly prolonged in uremia
Pts w/ glaucoma & pregnancy have special considerations:
Scopolamine > atropine > glycopyrrolate in causing mydriasis
Atropine and scopolamine can cross placenta, but fetal HR does not significantly change
Scopolamine is the selected choice potency?
amnesia?
100X more potent than atropine in decreasing the activity of RAS
Depresses the cerebral cortex, and also effects other areas of the brain causing amnesia
scopolamine what effects do you see with opioids and benzos
Greatly enhances the sedative effects of concomitantly administer drugs, especially opioids & benzo’s
Morphine + Scopolamine=
Morphine + Scopolamine = favored combo when a reliable sedative is needed in pre-op
elderly considerations for scopolamine
Can have symptoms from restlessness to somnolence (drowsiness), which are more likely to occur in the elderly (which could explain the delayed awakening or agitation seen in post anesthesia care unit (PACU)
atropine and memory deficit?
Atropine has been associated with an increased incidence of memory deficit after anesthesia (compared to glycopyrrolate)
arousal for atropine?
Arousal in 30 min after cessation of anesthesia is delayed after giving atropine-neostigmine (but not glycopyrrolate-neo mix) which is used to antagonize effects of NDNMB
Inhaled anesthetics and anticholinergic drugs
Inhaled anesthetics can potentiate the effects of anticholinergic drugs on the CNS, which could lead to an increased in postop restlessness or somnolence
Physiostigmine reversal??
is effective in the reversal of restlessness/somnolence secondary to CNS effects of tertiary amine anticholinergic drugs.
scopolamine tell me about potency and antisialagogue effect
Scopolamine is 3X more potent as an antisialagogue than atropine
Therefore, scopolamine is selected for the use when both antisialagogue and sedation are needed.
why would you select glycopyrrolate
Gylcopyrrolate is selected for absence of sedative effects, and as an antisialagogue it is 2X more potent than atropine and the duration is longer
Glyco is good for a juicy patient
intraoperative bradycardia
Anticholinergics are the drug of choice treating intraoperative bradycardia, particularly that resulting from increased parasympathetic nervous system
They work by increasing the HR by blocking effects of Ach on SA node (shortening the PR interval)
Which anticholinergic is best for bradycardia is glycopyrrolate good for bradycardia?
Atropine (15-70µg/kg) has greater effect than scopolamine or gylcopyrrolate, indicating the degree of control normally exerted on the vagas nerve on the SA node.
The same dosage of gylcopyrrolate given as atropine produces similar increases in HR, but with a slower onset
Vagal tone:
Young adults w/ great vagal tone, the influence of atropine is enhanced…
Versus infants/elderly, even large doses may fail to increase HR
During anesthesia, where a volatile drug is used, the dose of atropine needed may increase perhaps due to depression of vagal centers
Clinical uses: anticholinergics Combined with anticholinesterases
Given with anticholinesterase for antagonism of NDNMB to prevent parasympathetic effects that predictably go with IV administration of edrophonium, neo or pyridostigmine.
The use of atropine (rapid) or glyco (slower), depends on the speed on onset
Causes impairment of PSNS control of HR that persists early in the postop period, the use of glycopyrrolate has shorter duration of effect and may be preferred in patients at risk for CV complications, because impairment of PNS has been associated with increased incidence of dysrhythmias in response to myocardial ischemia and decreased survival after MI
anticholinergics and bronchodilator
As bronchodilators, administered as aerosols, reflect antagonism of Ach effects on airway smooth muscle via muscarinic receptors (present predominantly in large and medium sized airways) in response to vagal nerve stimulation.
As aerosols, the advantage is absence of adverse CV side effects.
Atropine 1-2mg diluted in 3-5mL NS via nebulizer.
This decreases airway resistance & increases dead space, especially in pts w/ asthma or chronic bronchitis
atropine nebulizer
Atropine 1-2mg diluted in 3-5mL NS via nebulizer.
This decreases airway resistance & increases dead space, especially in pts w/ asthma or chronic bronchitis
Glycopyrrolate as a bronchodilator,
Glycopyrrolate is equally effective as a bronchodilator, No CNS effects, HR effects are minimal
scopolamine and bronchodilator
Scopolamine decreases airway resistance and increases dead space ~ 1/3, but the effects depend largely on degree of preexisting bronchomotor tone
Ipratropium (Atrovent)
a N-isopropyl derivative of atropine, an anticholinergic aerosol selected for pts w/ COPD
Prevents & treats bronchospasm due to β-adrenergic antagonists or psychogenic stimuli
Has slower onset & less effective than β-agonists for bronchial asthma, because these drugs inhibit the release & the subsequent airway smooth muscle contraction caused by chemical mediators (histamine & leukotrienes)
Is more effective than β-agonist for bronchodilation for chronic bronchitis or emphysema (blocks M3 receptors)
Bronchoconstriction secondary to tracheal intubation treatment
Bronchoconstriction secondary to tracheal intubation (due to an irritant reflex response mediated by Ach from parasympathetic nerves acting on muscarinic receptors of airway smooth muscles) is responsive to inhaled ipratropium
Effects of aerosol ipratropium on HR & intraocular pressure
Effects of aerosol ipratropium on HR & intraocular pressure do not occur (because of the <1% systemic absorption)…
This also can relate to prolonged effect at the desired site of action.
There is no tolerance to the bronchodilator effect.
atropine & biliary tract & ureter effect.
Atropine decreases the tone of the smooth muscles of the biliary tract & ureter.
sphincter of Oddi
May not be able to reverse opioid-induced spasm of the sphincter of Oddi, but Atropine may prevent spasm of the ureter produced by morphine (atropine + morphine to treat renal colic)
anticholinergics- bladder effects
Diminishes the tone of fundus of bladder, & increases tone of sphincter, due to urinary retention (tx urinary incontinence)
IM scopolamine
is a more potent mydriatic than atropine or glycopyrrolate-caution in pts w/ glaucoma
atropine preop and iop
Atropine doses used for pre-op are unlikely to cause increased IOP, especially is an anticholinesterase or cholinergic topical is continued
how many days to recover from atropine?
Complete recovery from atropine takes 7-14 days.
resulting in mydriasis & cycloplegia
Topical anticholinergic block the action of Ach at both sites.
Circular muscle of the iris that constricts the pupil, & is innervated by cholinergic fibers from III cranial nerve, also causes contraction of ciliary muscle, which makes the lens more convex
In pts w/ glaucoma the mydriasis obstructs passage of intraocular fluid in the venous circulation, causing a hazardous increase IOP.
Clinical uses: antagonism of gastric hydrogen ion secretion
Original use of glycopyrrolate to control gastric acidity, for the control of peptic ulcer disease (PUD)
None of the anticholinergics are selective for this effect, the high doses required for PUD results in unacceptable secretory, ocular, & CV side effects
Therefore, H2 antagonists have replaced their use
Anticholinergic drugs have predictable effects on the tone and motility of the GI tract because the PSNS provides almost exclusive motor innervation
High doses of anticholinergic drugs do prevent excess peristalsis of the GI tract that would be associated with anticholinesterases for the antagonism of NDNMB*
Clinical uses: Prevention of motion-induced nausea
Transdermal absorption of scopolamine provides sustained therapeutic plasma concentrations that protect against motion-induced nausea without side effects such as sedation, cycloplegia, or drying or secretions
Patch delivers 5µg/h for 72 hours
Protection against nausea is best if applied 4 hours before noxious stimulus, but less effective after symptoms of nausea have presented
Motion sickness is caused by stimulation of vestibular apparatus and scopolamine blocks transmission to the medulla of impulses from overstimulation.
Clinical uses: management of parkinson disease
Benzotropine & trihexphendyl are used for tremor, rigidity and dysonia
Also used to treat extrapyramidal side effects of antidopaminergic effects of metoclopramide
Disadvantages of using anticholinergics in pts w/ Parkinson include memory impairment, hallucinations, visual blurring, and aggravation of glaucoma (especially in elderly)
Central anticholinergic syndrome
Scopolamine & atropine (some) enter the CNS and cause symptoms of central anticholinergic syndrome
Symptoms: restlessness and hallucinations, to somnolence and unconsciousness (often mistaken for delayed recovery from anesthesia)
These responses reflect blockade of muscarinic cholinergic receptors and competitive inhibition of Ach in the CNS.
Not likely w/ glycopyrrolate, since it doesn’t cross BBB
Physiosigmine, is the treatment for central anticholinergic syndrome
Overdose of anticholinergics
Rapid onset of symptoms characteristic of muscarinic cholinergic receptor blockade (dry mouth, swallowing & talking difficult, vision blurred, photophobia, prominent tachycardia, dry skin, flushed, rash in “blush area”)
Even therapeutic doses of anticholinergic drugs sometimes may selectively dilate cutaneous vessels in the blush area
Body temperature can be increased by anticholinergic drugs, especially when the room temperature is increased. This increase in body temperature reflects inhibition of sweating by anticholinergic drugs, reflecting innervation of sweat glands is by SNS that release Ach as the NT.
Overdose of anticholinergics
minute ventilation
fatal effects
Causes increase in minute ventilation due to CNS stimulation & impact of physiological dead space secondary to bronchodilation
Nicotinic blockade is reflected by skeletal muscle weakness, orthostatic hypotension
Fatal events result in seizures, coma & medullary ventilatory center paralysis
Treatment: Physiostigmine 15-60µg/kg IV, repeat doses may be necessary
Decreased barrier pressure
Barrier pressure is the difference between gastric pressure and LES pressure.
Administration of atropine or glycopyrrolate decrease LES pressure and barrier pressure and the resistance to acid reflux
