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74 Cards in this Set
- Front
- Back
scopalamine origin
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henbane
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atropine/belladonna found in
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Datura plant (jimson)
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anticholinergic effect?
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Lowers the “rest and digest” of the parasympathetic by antagonizing acetylcholine receptor
acetylcholinesterase inhibitors. |
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anticholinergic uses?
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Treatment for reflex-mediated bradycardia
Prophylaxis against anticholinesterase toxicity,(treatment for cholinergic crisis, cholinergic adjunct for curariform block) Antisialagogue preanesthetic medication (not atropine) Prophylaxis against arrhythmias induced by succinylcholine for intubation Anesthesia adjunct (preanethesia) with an opioid reduce excitement, produce amnesia protect against opioid-induced respiratory depression. Prophylaxis against aspiration Postoperative nausea and vomiting Sedation |
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local anesthetics block the?
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Na channel
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Parenteral ___________ is also indicated in conjunction with analgesics in cardiopulmonary bypass patients who cannot be deeply anesthetized because of the risk of severe hypotension or circulatory collapse
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scopolamine
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Other anticholinergic uses...
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Antidote
Anticholiesterase (cholinergic crisis), muscarine, organophosphate overdose Resuscitation Opthalmic (mydriasis/cycloplegia) Urinary Incontinence treatment - Darifenacin, M2 antagonist Peptic Ulcer Treatment Adjunct Irritable bowel syndrome Motion Sickness Asthma - ipratropium and tiotropium Antidiarrheal (constituent of Lomotil) Antivertigo Allergies (better options) Constituent of nonprescription cold remedies Management of Parkinson's Disease – Benzotropine Treat antidopaminergic effects of metoclopramide Hiccups |
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what causes mydriasis/cycloplegia?
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anticholinergics
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anticholinergic for asthma?
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ipratropium and tiotropium
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anticholinergic for Management of Parkinson's Disease –
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Benzotropine
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what can treat the antidopaminergic effects of metoclopramide?
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anticholinergics
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Metoclopramide is a dopamine _____?
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antagonist
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anticholinergics effect on lactation
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inhibition
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Parasympathetic Effects of anticholinergics on eye, salivary gland, heart, lungs, pancreas, intestine and bladder
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Eye: Contraction to give miosis and near vision
Salivary Glands: Secretion Heart: Decreased HR, conduction velocity, contraction Lungs: Bronchoconstriction Pancreas: Increased insulin secretion Intestine: Increased Motility and tone Bladder: Sphincter relaxation and Detrosor contraction |
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Anti-cholinergic vs. Antimuscarinic?
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The anticholinergics are anti-muscarinics more specifically
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anticholinergic for COPD
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Ipratropium – isopropyl atropine analog
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The _____ is the natural occurring and the active compound but given as racemic mixture
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levorotary
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anticholinergic SAR facts
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These have the ester again – recognized by the acetylcholine receptor. Not recognized by acetylcholinesterase or any other esterase.
These structures have a chiral carbon. |
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tropic acid is in?
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atropine (hyoscyamine) pka 9.9
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mandelic acid is in?
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glycopyrolate (robinul)
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scopolamine pka
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7.5-7.8
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2 naturally occurring anticholinergics
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scopolaine and atropine
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2 synthetic anticholinergics
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glycoryrrolate and ipratropium
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are anticholinergis acids?
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NO, even though they have an acidic portion
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As bases, _________ are often formulated as water soluble conjugate acids at slightly acidic pHs.
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anticholinergics
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Parasympathetic Muscarinic Postganglionic (effector) receptor sites: [4]
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autonomic effector cells (smooth muscle)
cardiac muscle Sinoatrial/atrioventricular nodes exocrine glands. |
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anticholinergics....
non-comp or comp? |
Competitive antagonists
Block acetylcholine from binding. G- protein will not be released and will not activiate second messenger |
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anticholinergic effect on pre synaptic neruon...
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Have no effect on the pre-synaptic neuron. Acetylcholine will continue to be released
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M1 receptor....
location 2nd messenger effect clinical effect clinically selective drug? |
CNS,Stomach
Phospholipase C Stimulation H+ secretion Yes |
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M2 receptor....
location 2nd messenger effect clinical effect clinically selective drug? |
Heart,CNS,Airway Smooth Muscle
Adenylate Cyclase Inhibition Bradycardia No* |
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M3 receptor....
location 2nd messenger effect clinical effect clinically selective drug? |
CNS
Salivary Glands Airway Smooth Muscle Vascular Endothelial Cells Phospholipase C Stimulation,Salivation Bronchodilation Vasodilation No |
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M4 receptor....
location 2nd messenger effect clinical effect clinically selective drug? |
CNS, Heart
Adenylate Cyclase Inhibition ? No |
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M5 receptor....
location 2nd messenger effect clinical effect clinically selective drug? |
CNS
Phospholipase C Stimulation ? No |
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the anticholinergic/antimuscarinics that we use affect what M recoptors?
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all M types
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Dose variability
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Lower dose
Bronchial/salivary secretions (M3) heart and eye effects (M2) control GI and genitourinary tract inhibition of H+ secretions (M1) Higher dose So If giving higher doses to control H+ then will have side effects of the other lower concentrations. If giving low dose to minimize salivary secretions, might not see other effects |
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Atropine dose variablity examples.....from low to high dosage
same trend with all 3 compounds |
Atropine
0.5 mg slight cardiac slowing/some dryness of mouth/inhibition of sweating 1.0 mg dryness of mouth/thirst/acceleration of heart/mild dilation of pupils 2.0 mg rapid heart rate/palpitation/marked dryness of mouth/dilated pupils/blurring of near vision 5.0 mg all above worse/difficulty is speaking and swallowing/restlessness and fatigue/headache/dry and hot skin/ reduced intestinal peristalsis 10+ mg all above worse/ pulse rapid and weak/iris obliterated/vision very blurred/skin flushed, hot and dry and scarlet/ataxia/restlessness and excitement/hallucinations/delirium COMA |
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What would govern between atropine, glycopyrolate or scopolamine?
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unwanted side effect or speed of onset
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most sedative
least |
most scopalamine
no sedative effects with glycopyrolate |
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most antisialogogue?
least? |
most scopolamine
least atropine |
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most HR effect?
least? |
most-atropine
least scoplomine |
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most smooth muscle relaxation?
least? |
most atropine/glycopyrolate
least glycopyrolate |
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most mydriasis/cycloplegia?
least? |
most-scopolamine
least-non with glycopyrolate |
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motion sickness tx most?
least? |
most-scopolamine
least-none with glycopyrolate |
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gastric acid reduction-most?
least? |
all equal
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agent with fetal HR effect
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maybe scopolamine- only
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agent for glaucoma patient?
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must be careful with scopolamine dosage so atropine maybe better choice
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agent for pregnant pt?
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Although atropine and scopolamine can both cross placenta, no change for atropine (scopolamine has not been tested) also no change for glycopyrrolate – expected since not very lipophylic.
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why does scopolamine have more sedative effects?
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higher PKA
Although scop and atropine are tertiary amines, at physiological pH, more of atropine is ionized so less concentration to CNS. |
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agent for bradycardia tx?
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atropine because faster onset.
This increased heart rate is an anticholinergic effects but remember for later chapters, this is also an adrenergic agonist effect (same effect observed for epinephrine) |
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what causes scopolamine/MS sedative effects?
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Depress RAS to give sedation
Depress other areas of brain to give amnesia |
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Antisialagogue effects
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Scopalamine w/ sedation Glycopyrrolate w/o
Added to nonprescription cold remedies to stop upper airway secretions |
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Increased Heart Rate, Tachycardia (Atropine-fast onset))
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Treatment for reflex-mediated bradycardia
Effect primarily at sinoatrial node Less change at extremes of age Lower dose with volatile anesthetic Glycopyrrolate may be best choice for patients at risk for cardiovascular complications (faster offset) |
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most potent?
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scopolamine, then glyco
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how does atropine the HR?
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Block Ach binding at sinoatrial node. Higher doses for those with lower vagal tone. Young adults with high vagal tone show most effect. Volatile anestheics depress vagal center so need less drug
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Relax Smooth Muscle (Glycopyrrolate)
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Bronchodilation
Decrease airway resistance/increase dead space Biliary and ureteral Smooth Muscle Relaxation Modest antispasmodic wont overcome opioid effects on sphincter of Oddi but will on ureteral contraction. Reduces tone of funcus of bladder giving urinary retention Gastrointestinal Tract Descrease peristalsis increases transit time High drug concentration required |
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Mydriasis /Cycloplegia
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Block constriction of pupil and contraction of ciliary muscles.
7-14 day recovery time Care must be taken with Glaucoma patients (acute angle effects) End result is dilated pupils – reputed to be why Cleopatra and Renaissance women used belladonna on their eyes to look more alluring. I was give Ipratropim bromide and instructed to thoroughly wash my hands after using inhaler because if I touched by eyes, I would be unable to see clearly for a week. |
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choice for NO CNS effects?
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glycopyrolate
no cardiac effects if arelolized |
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Alternative is Ipratropium bromine (N-isopropyl derivative) which is often used for COPD. Ipratropium could also be used against brochoconstriction due to tracheal intubation since this seems to be an acetylcholine mediated response. Ipratropium and a b-agonuist such as albuterol is good treatment for COPD
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xxxxx
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Gastric H+ Secretion notes
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Requires high doses and will see other effects
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Prevention of Motion Sickness
best choice? |
Transdermal scopalamine is best choice
Transdermal – low dose minimizes other effects that might see like sedation. Must apply at least 4 hours ahead of time. Blocks trasmission of signals to the medulla that come from overstimulation of the vestibular apparatus. Some say because lowers salivation. Need again be careful of any transfer to eye after handeling of the patch |
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Presynaptic inhibitory M1 receptor (feedback blocker) (antagonistic effect)
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vagal nerve endings
Sympathetic effects (allows more ach to be released) Adrenergic neurons Sympathomimetic effects (we can cause the release of nor-epi, which is the natural ligand for adrenergic neurons) Inhibition of this presynaptic receptor prevents the feedback inhibition of acetylcholine release. More acetylcholine is released and my in fact see paradoxical slowing of the heart rate. Also can cause release of norepiniphrine so can get sympathetic effects (fight and flight) This response can happen with low doses (parasympathetci) paradoxical lowering |
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Absorption/Distribution
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Tertiary amines rapidly absorbed/distributed
shown to cross placenta (tachycardia in fetus) Can cross BBB (CNS effects) Quaternary amines poor absorption/distribution Tertiary amines oral absorption in GI (not stomach why?) can be absorbed through mucosa Quat amines (glycopyrrolate) – if given orally, only about 10 – 25% absorbed Quaternary amines do not cross BBB but tertiary can. This means the teriary amines can have some CNS activity. At different doses see sedation and excitation. |
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Protein Binding
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Atropine - Moderate (
Scopalamine – Low (BEST DISTRIBUTED) Glycopryrolate - (worst distributed/absorbed) |
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% ionization of Glycopyrolate?
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100% ionized at ANY ph
Scop is more unionized at phys PH, therfore more will cross the BBB. Glyco 15-20% bioavail with PO |
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Metabolism
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99% Scopalamine/80% Atropine/20% Glycopyrolate
Hepatic Metabolism Atropine hydrolyzed to Tropine and Tropic Acid (ester bond-hydrolysis in liver) Although atropine is hydrolyzed, this cannot be done with plasma esterases in humans though animals have the correct esterase. Scopolamine is the least ionized The purpose of metabolism is to make things more water soluble |
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The dose of glycopyrolate is about ______ that of atropine and scopolamine
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half
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Atropine facts
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dose 0.01 – 0.02
onset comparable to Glycopyrollate duration Oral: 4–6 hrParenteral: Brief elimination 2.5 hr Renal (~20% unchanged) |
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scopolamine facts
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dose 0.01 – 0.02
onset Oral: 30–60 Parenteral: 30 duration Oral: 4–6 hrParenteral: 4 hr 8 hr elimination Renal (1% unchanged) |
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glycopyrolate facts
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dose 0.005-0.001
*about _ onset IM/SC: 14-30 IV: 1 Duration Antisialagogue: Up to 7 hrVagal blocking: 2–3 hr elimnation 1.7 hr *Renal (80% unchanged) |
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Side Effects
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CNS – Central Anticholinergic Syndrome
Low doses atropine mild stimulating Higher doses are depressant Gastroesophageal Reflux Decreasing tone of lower esophageal sphincter decreases barrier. Sopalamine>atropine have seen glycopyrrolate with IV before induction of anesthesia Restlessness, confusion, hallucinations, combative (children), somnolence, unconsciousness especially in elderly but also those under age 13 |
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Overdose (Central and Peripheral Anticholinergic Syndrome)
mostly seen in extremes of age |
Blurred vision, continuing, or changes in near vision clumsiness or unsteadiness confusion difficulty in breathing dizziness drowsiness, severe dryness of mouth, nose, or throat, severe fast heartbeat fever “atropine fever” (sweat inhibition) hallucinations muscle weakness, severe Seizures slurred speechtiredness, severe unusual excitement, nervousness, restlessness, or irritability unusual warmth, dryness, and flushing of skin
Respiratory paralysis with quaternary compounds due to curare-like effects |
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atropine fever from?
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inhibition of sweating
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Overdose Treatment
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Physostigmine (Antilirium)
sometimes Neostigmine Barbiturate/Benzodiazepine Norepinephrine Physostigmine/neostigmine – these acetylcholinesterase inhibitors will allow for the increase of acetylcholine at the receptor sites. This will increase concentration at the muscaric receptor and cause a reversal. Physostigmine best for CNS effects because physo can cross BBB. Neostigmine cannot as well. Low dose IV and repeated doses since pysostigmine is metabolized fairly rapidly Barb or benzo for the delirium Norepinephrine for increasiing blood pressure |
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Other Drugs/same receptor
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Edrophonium – M2/M3 competitive antagonist
Antihistamines * Remember, the depolarizing and non-depolarizing muscle relaxants do block acetylcholine receptors but the nicotinic receptors Edrophonium was acetylcholinesterase inhibitor but also seems to have some mild anti-muscarinic effects as well. Antihistimines have anticholinergic and that is why helpful in cold remedies. |