PHARMA - ANS 2: Cholinergic Antagonist

Cholinergic Antagonist

Ganglion blockers and neuromuscular junction (NMJ) blockers make up the anti-nicotinic drugs.

Parasympatholytics

By being an antagonist in these receptor sites, these drugs are expected to REMOVE the predominant parasympathetic tone in tissues involved. Hence, also known as?

Muscarinic Receptor Antagonist

Prevent the effects of acetylcholine by blocking its binding to muscarinic receptors on the effector cells at parasympathetic cholinergic neuroeffector junctions in peripheral ganglia and the CNS

Belladona Alkaloids

Naturally occurring alkaloids. Example: Atropine (prototypical drug), Scopolamine

Atropine

Prototypical tertiary amine belladonna alkaloid. High affinity for muscarinic receptors. Binds competitively and prevents acetylcholine from binding to those sites. Acts both centrally and peripherally

Atropine

Its general actions last about 4 hours, except when placed topically in the eye, where the action may last for days. Neuroeffector organs have varying sensitivity to atropine, the greatest inhibitory effects are on the bronchial tissue and the secretion of sweat and saliva

Atropine

Blocks muscarinic activity, resulting in mydriasis or dilation of the pupil, unresponsiveness to light, and Cycloplegia. In patients with angle-closure glaucoma, intraocular pressure may rise dangerously

Topical atropine

For patients about to undergo ophthalmic surgeries for cataract extraction. Instilled ahead of time to induce mydriasis

Atropine

A very good antisialogogue or anti-secretion. Blocks muscarinic receptors in the salivary glands, producing dryness of the mouth or xerostomia

Atropine

Can be used as an antispasmodic to reduce the activity of the GI Tract. Although gastric motility is reduced, HCL (Hydrochloric Acid) production is not significantly affected. Not effective for the treatment of peptic ulcers

Atropine and scopolamine

Probably the most potent antispasmodic drugs available

Pirenzepine and M1 muscarinic antagonists

Reduce the gastric acid secretion at doses that do not antagonize

Atropine

Produces divergent effects depending on the dose. Treat bradycardia of whatever cause. Low doses: The desired effect may not be reached. The predominant effect is a slight decrease in heart rate, or further bradycardia. Results from blockade of the M1 receptors on the inhibitory pre-junctional neurons. Permitting an increase in acetylcholine release. Higher doses: Causes a progressive increase in heart rate by blocking the M2 receptors on the SA node

Atropine

Also an effective anti-secretory agent to block secretions in upper and lower respiratory tracts prior to surgery and used to prevent hypersalivation during intubation

Atropine

Used as an antidote for Organophosphate poisoning coming from insecticides, for overdose and clinically used anticholinesterases such as physostigmine, and in some types of mushroom poisoning.

Atropine

Rapidly absorbed. Partially metabolized by the liver. Eliminated Atropine is primarily in urine. Half life of about 4 hours

Atropine

Can cause dry mouth, blurred vision or sandy eyes, tachycardia, urinary retention, and constipation (depending on the dose). Effects on the CNS are restlessness, confusion, hallucination and delirium which may progress to depression, collapse of the circulatory and respiratory systems and death

Physostigmine

Low doses of cholinesterase inhibitors (____________) may be used to overcome atropine toxicity

Atropine

May also include or induce troublesome urinary retention. May be dangerous in children because they are sensitive in its effects particularly to rapid increases in body temperature that it may elicit

Scopolamine

Another muscarinic antagonist. Tertiary amide, plant alkaloid. Produces peripheral effects similar to atropine. has greater action on the CNS and a longer duration of action, as compared to atropine. One of the most effective anti-motion sickness drugs available. It has an unusual effect of blocking short-term memory

Scopolamine

Limited to prevention of motion sickness and post-operative nausea and vomiting. For motion sickness, it is available as a topical patch and provides effects for up to 3 days. Effective as prophylactic

Ipratropium and Tiotropium

Quaternary derivatives of atropine. Approved as bronchodilators for maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD). Delivered via inhalation. Has positive charges: Do not enter the systemic circulation or the CNS, Isolate their effects to the pulmonary system

Ipatropium

Used for bronchospasm management in asthma Requires dosing up to 4x daily

Tiotropium

Quaternary derivatives of atropine. Administered 1x daily

Tropicamide and Cyclopentolate

Used as ophthalmic solution to induce mydriasis and cycloplegia. Shorter duration of action compared to atropine

Tropicamide

Produces mydriasis for 6 hours

Cyclopentolate

Produces mydriasis for 24 hours

Benztropine and Trihexyphenidyl

Useful adjuncts with anti-Parkinsonian agents to treat Parkinson’s Disease and other types of Parkinsonian syndrome including antipsychotic-induced extrapyramidal symptoms (EPS).

Oxybutynin

Atropine-like drug Used to treat overactive bladder or urinary frequency. By blocking muscarinic receptors in the bladder: Intravesical pressure is lowered, Bladder capacity is increased, Frequency of bladder contraction is reduced. Side effects: dry mouth, constipation, and blurred vision which limits tolerability for this agents if used continually. Available as transdermal system or topical patch

Ganglionic Blockers

Specifically act on the nicotinic receptors of both parasympathetic and sympathetic autonomic ganglia nonselectively. Blocking the entire output of the autonomic nervous system at the nicotinic receptor. Rarely used therapeutically. Often serves as a tool for experimental pharmacology

Nicotine

Component of cigarette smoke. Poison with many undesirable actions. Without therapeutic benefit and deleterious to health. Depending on the dose, it depolarizes autonomic ganglia: Resulting in stimulation then paralysis of all ganglia, Stimulatory effects are complex, Result from increased release of neurotransmitters due to effects of both parasympathetic and sympathetic ganglia

Dopamine

What neurochemical is released as an effect of nicotine: pleasure, appetite suppression?

Norepinephrine

What neurochemical is released as an effect of nicotine: arousal, appetite suppression?

Acetylcholine

What neurochemical is released as an effect of nicotine: arousal, cognitive enhancement?

Glutamate

What neurochemical is released as an effect of nicotine: learning?

Serotonin

What neurochemical is released as an effect of nicotine: mood, appetite suppression?

B-endorphin

What neurochemical is released as an effect of nicotine: ↓ anxiety?

GABA

What neurochemical is released as an effect of nicotine: less anxiety?

Neuromuscular Blocking Agents

AKA “Paralytic agents” or “Muscle relaxants”. Depolarizing and Non-Depolarizing neuromuscular blocking agents. Block cholinergic transmission between motor nerve endings and the nicotinic receptors on the skeletal muscles. Causes paralysis. Clinically useful to facilitate to tracheal intubation and provide complete muscle relaxation during surgical manipulation

Depolarizing Muscle Relaxants

Unaffected by acetylcholinesterase but not by plasma cholinesterases. It mimics the effects of acetylcholine at the nicotinic receptor sites. Induces persistent depolarization followed by gradual repolarization that renders the receptor incapable of transmitting further impulses leading to paralysis

Non-Depolarizing Muscle Relaxants

Competitively block acetylcholine at the nicotinic receptors. They compete with acetylcholine at the receptor without stimulating it. Prevent depolarization of the muscle cell membrane. Inhibit muscular contraction, hence relaxation and paralysis

Succinylcholine

The single depolarizing agent available in clinical use. Unlike acetylcholine, it is not destroyed by acetylcholinesterases which leads it to accumulate at high concentrations in the synaptic cleft, remaining attached to the receptor for a relatively longer time and providing persistent depolarization of the receptors followed by gradual repolarization, rendering the muscle fiber paralyzed

Depolarization block

Occurs when doses are given regularly. When after an initial opening, perijunctional sodium channels close and will not reopen until the end plate is repolarized. Neural release of acetylcholine results in the binding of acetylcholine on an already depolarized end plate. This instance is potentiated by anticholinesterase agents such as neostigmine

Desensitization block

Occurs when doses are given continuously or at high dosage. Resembles non-depolarizing block. After administration of 7-10 mg/kg or 30-60 minutes after exposure, train-of-four and tetanic fade becomes apparent. Phase 2 block is reversed by neostigmine or edrophonium

Muscle Fasciculations

Due to the persistent depolarization at the nicotinic receptor _________________ are observed. Reported as painful by most patients after the procedure. But, pain can be prevented by giving a non-depolarizing blocker after succinylcholine

Potassium Release

Increases _________________ from intracellular stores into the plasma. Causes dangerous hyperkalemia in susceptible patients

Non-depolarizing neuromuscular blockers

Competitively block acetylcholine at the nicotinic receptors at the motor. Prevent binding of acetylcholine and depolarization of muscle cell membrane → inhibits muscle contraction

Atracurium and Cisatracurium

Independent of the liver and the kidneys for elimination. Undergo Hoffman Elimination and Ester Hydrolysis

Hoffman Elimination

Non-enzymatic degradation that Atracurium and Cisatracurium undergoes

Ester Hydrolysis

Distinct from plasma cholinesterase or acetylcholinesterase degradation

Laudanosine

Degradation product of ester hydrolysis

Pancuronium

Only neuromuscular blocker with: Direct vagolytic/sympathomimetic properties as a muscarinic antagonist activity, Increased BP, Increased HR, Increased CO. High incidence of residual block in the post anesthesia care unit (PACU) due to its known long duration of action

Rocuronium

Among the intermediate acting neuromuscular blocker, it exhibits the fastest onset of action (1.5-3 minutes). Ideal substitute to succinylcholine for immediate intubation. For rapid-sequence induction, it can be used at a higher dose if contraindicated with succinylcholine. Increased BP, Increased HR, Increased CO

B. Atropine

A 78-year-old man with bradycardia (HR 40 bpm) is brought to the ED. ECG shows sinus bradycardia without AV block. Which drug is most appropriate to rapidly increase his heart rate?

A. Propranolol

B. Atropine

C. Epinephrine

D. Dopamine

C. Precipitation of acute angle-closure glaucoma

A 62-year-old woman is being evaluated for worsening vision. Her ophthalmologist notes she recently started an antimuscarinic for overactive bladder. Which adverse effect is most concerning in this context?

A. Dry mouth

B. Constipation

C. Precipitation of acute angle-closure glaucoma

D. Tachycardia

B. Glycopyrrolate

A 50-year-old man undergoes abdominal surgery with atracurium for muscle relaxation. BP was 130/90mmg, HR 111 bpm. At the end of the procedure, the anesthesiologist plans to give neostigmine to reverse neuromuscular blockade. Which antimuscarinic should be co-administered to prevent muscarinic side effects?

A. Atropine

B. Glycopyrrolate

C. Scopolamine

D. Ipratropium

B. Atropine

A farmer presents with miosis, salivation, bradycardia, and muscle fasciculations after pesticide exposure. Which antimuscarinic is indicated in this scenario?

A. Physostigmine

B. Atropine

C. Scopolamine

D. Benztropine

B. Tertiary amine structure

A 65-year-old woman on oxybutynin for overactive bladder reports confusion and hallucinations. Which pharmacologic property explains these CNS effects?

A. Poor lipid solubility

B. Tertiary amine structure

C. Quaternary ammonium structure

D. Irreversible receptor binding