exam 1 lecture 2 cholingergic agonists and antagonists

How is ACh synthesized?

Synthesized from choline and acetyl CoA via the enzyme choline acetyltransferase

How is choline recycled?

It can be transported back into the neuron via a sodium coupled uptake system

What are the cholinergic receptors?

Muscarinic and nicotinic receptors

What are muscarinic receptors and how are they activated

GPCR

Located on the ganglia, neurons, and autonomic effector organs

M1: gastric parietal cells, M2: cardiac cells and smooth muscle M3: bladder, exocrine glands, smooth muscle

M1/M3: increases intracellular Ca2+

M2: inhibits adenylyl Cyclase, increasing K+

How does nicotine binding affect nicotinic receptors?

Low concentration: receptor stimulation

High concentration: receptor blockage

What are the locations of the nicotinic receptors?

Nn: CNS, adrenal medulla, autonomic ganglia

Nm: NMJ in skeletal muscles

What is the function of direct acting cholinergic agonists?

Mimic the effects of ACH by directly binding to cholinergic receptors

Pharmacological preparations have longer action and little specificity

Acetylcholine (class/action)

Direct acting cholinergic agonist

Decreases HR and CO (decreases firing of SA node)

Vasodilation by producing nitric oxide

Increases salivary, intestinal, and bronchioles secretions

Bronchoconstriction

Increased intestinal motility

Urination

Miosis

Acetylcholine uses

Intraocular injection used to produce miosis during eye surgery

Methacholine (class and uses)

Direct acting cholinergic agonist Decreases HR

Used to assist in diagnosis of asthma due to bronchoconstriction effects (methacholine challenge test)

-test is positive if 20% or greater decrease in breathing ability vs baseline occurs

Bethanechol (class/action)

Direct acting cholinergic agonist

Directly stimulates muscarinic receptors Pharmacological preparations

Acts on smooth muscle of bladder and GI tract

-increases in testing motility and relaxes bladder muscles to stimulate urination

-not hydrolysis by AChE

Uses of bethanechol

Stimulates atonic bladder to treat urinary retention post partum and post op

Neurogenic atony

Megacolon

Carbachol (class/uses)

Direct acting cholinergic agonist

Muscarinic and nicotinic activity

-nicotinic activity causes release of epi from adrenal medulla

Not a substrate of AChE

Acts on heart and GI tract

Uses of carbachol

Induce miosis during ophthalmic surgery

Pupillary constriction and a decrease in intraocular pressure in pts with glaucoma

Pilocarpine (class/action)

Direct acting cholinergic agonist

Uncharged alkaloid with Muscarinic activity that can cross the CNS

stimulates secretions

-rapid miosis and contraction of ciliary muscle

Uses and adverse effects of pilocarpine

Glaucoma: emergently lowers intraoccular pressure in pts

Xerostomia

Sjogren syndrome: helps dry mouth and lack of tears

Mydriasis: reverses mydriasis due to atropine

Side effects: blurred vision, night blindness

What are indirect acting cholinergic agonists

Anticholinesterase agents

Indirectly lead to a cholinergic action by preventing the degradation of ACh

Affect both Muscarinic and nicotinic receptors of ANS, as well as NMJ and brain

Physostigmine (class and action)

Indirect acting reversible anticholinesterase agent (cholinergic agonist)

Can penetrate CNS

30min-2hr onset of action

Physostigmine uses and adverse effects

Reverse overdose of anti cholinergic drugs (atropine)

Reverse neuromuscular blockers

Side effects:

-convulsions in high doses

-bradycardia

-decreased cardiac output

-paralysis of skeletal muscle at high doses

Neostigmine (class/action)

Indirect acting reversible anticholinesterase agent (cholinergic agonist)

Onset of action 30min-2 hrs

Poorly absorbed in GI tract and can’t cross BBB

Neostigmine uses and side effects

Stimulate bladder and GI tract (especially post op)

Antidote for competitive neuromuscular blockers

Manage symptoms of myasthenia gravis

Adverse effects:

-generalized cholinergic stimulation

Pyridostigmine (class, uses, adverse effects)

Indirect acting reversible anticholinesterase agent

3-6 hr duration of action

Uses:

-PO: chronic management of myasthenia gravis

-IV: reversal of nondepolarizing neuromuscular blocking agents

Side effects: bradycardia, GI upset

Describe alzheimers disease and common medications

Deficiency of cholinergic neurons in the CNS —> lower levels of AChE Acts on in CNS

Anticholinesterase agents used for mild to moderate AD dementia

-donepzil, rivastigmine, galantamine

What are indirect acting irreversible anticholinesterase agents

Organophosphate that covalently bind to AChE

Permanent inactivation of enzymes until new AChE enzymes are synthesized

What are the common actions of organophosphates

Generalized cholinergic stimulation

Motor function paralysis

Convulsions

Echothiphate (class and action)

Indirect acting Irreversible anticholinesterase agent

Organophosphate that covalently binds to AChE, permanently inactivating it

Effects last 1-4 weeks

Echothiphate (therapeutic uses and adverse effects)

Topical ophthalmic solution to treat open angle glaucoma

Side effects: Risk of cataracts

Treatment of organophosphate toxicity

Pralidoxime

-antidote to reactívate inhibited AChE

-can’t treat CNS effects

-can’t overcome toxicity of reversible AChE inhibitors

Atropine

-anti cholinergic agent

-reverses bronchorrhea and bronchoconstriction

Diazepam

-treats seizures

What are cholinergic antagonists?

Agents that bind to cholinergic receptors (Muscarinic or nicotinic) and prevent effects of ACh and/or cholinergic agonists

What are the types of cholinergic antagonists

Antimuscarinic agents (parasympatholytics)

-only antagonize Muscarinic receptors

Ganglionic blockers

-antagonize nicotinic receptors of sympathetic and parasympathetic ganglia

Neuromuscular blocking agents

-mostly Nicotinic antagonists

-interfere with transmission of efferent impulses to skeletal muscles

Describe antimuscarinic agents

Block Muscarinic receptors to inhibit Muscarinic functions

Have little or no action at NMJs or autonomic ganglia because they do not block nicotinic receptors

Atropine (class/action)

Antimuscarinic, anti cholinergic, parasympatholytic

Prevents ACh from binding to Muscarinic receptors via competitive antagonism

Duration of action: 4 hours

Low dose: slight decrease in hr by blocking M1 receptors

High dose: increase HR by blocking M2 receptors on SA node

Uses of atropine

Bradycardia (sinus Brady and during NMB reversal)

Suppresses respiratory secretions prior to surgery

Treats spastic disorders of GI tract by decreasing GI motility

Topical ophthalmic agents with mydriatic and cycloplegic effects

Antidote for cholinergic agonists

Side effects of atropine

Dry mouth, blurry vision, tachycardia, urinary retention, constipation

CNS effects: restless, confusion, hallucinations, delirium, depression, collapse of circulatory and respiratory systems

Scopolamine (class and actions)

Antimuscarinic, anti cholinergic, parasympatholytic

Acts on CNS

Long duration of action

Can block short term memory

Produces sedation but paradoxical excitement at higher levels

Therapeutic uses of scopolamine

Prevents motion sickness and postoperative N/V

Tropicamide and cyclopentolate (classs/action)

Antimuscarinic, anti cholinergic, parasympatholytic

Topical ophthalmic solutions used to cause mydriasis and cycloplegia

Shorter acting than atropine for eye uses

Benztropine and trihexyphenidyl (class/actions)

Antimuscarinic, anti cholinergic, parasympatholytic

Block M1 receptors in the CNS

Uses:

-manages tremors in Parkinson’s

-extrapyramidal symptoms of antipsychotics

MOA of overactive bladder/urinary incontinence drugs

Antimuscarinic, anti cholinergic, parasympatholytic

Completely block Muscarinic M3 receptors in bladder, decreasing bladder capacity and reducing frequency of bladder contractions

Side effects: dry mouth, constipation, blurred vision

Drugs for tx of overactive bladder and urinary incontinence

Darifenacin

Fesoterodine

Oxybutynin

Solifenacin

Tolterodine

Trospium chloride

How do ganglionic blockers work?

Act on nicotinic receptors of parasympathetic and sympathetic autonomic ganglia

Nondepolarize, competitive antagonists (besides nicotine)

Block CNS output of ANS

rarely used therapeutically

Nicotine (class, effects, use)

Ganglionic blocker, cholinergic antagonists

Depolarizes autonomic ganglia resulting first in stimulation of ganglia the paralysis in large doses

Increased NT release from sympathetic and parasympathetic ganglia.

Used in smoking cessation

Neuromuscular blocking agents (class, MOA)

Cholinergic antagonists

Block cholinergic transmission between motor nerve endings and nicotinic receptors on skeletal muscle

Therapeutic uses of neuromuscular blockers

RSI

surgery to facilitate intubation and adjunct to anesthesia for complete muscle relaxation

Nondepolarizing neuromuscular blockers (MOA)

Low doses- competitively blocks ACH at nicotinic receptors in bladder

High doses - blocks ion channels of the motor end plate

Doesn’t cross the BBB

metabolism and elimination varies between agents

Nondepolarizing neuromuscular blockers

Pancuronium, vecuronium, rocuronium, atracurium, cisatracurium

Effect of halogenated hydrocarbon anesthetics on nondepolarizing blockers

Sensitizes the NMJ to effects of NMBs, enhanced effect

Ex: desflurane

Effect of aminoglycoside antibiotics on nondepolarizing NMBs

Inhibit ACh release by competing with Ca2+ ions —> enhanced NMB effect

Ex: gentamicin, tobramycin

Effect of ca2+ channel blockers on nondepolarizing NMBs

Increased neuromuscular blockade of competitive blockers —> enhanced effect

Ex: amplodine

Succinylcholine (class/action)

Depolarizing NMB, anti cholinergic

Depolarizes plasma membrane, then blocks it from being able to transmit further impulses

succinylcholine (uses and side effects)

RSI

electroconvulsive shock treatment

Adverse effects: malignant hyperthermia, apnea, hyperkalemia

Cause caution in pts with electrolyte imbalances, on digoxin, use diuretics, hx of burns, hx of renal failure

Which of the following changes could happen in a person when the parasympathetic system is inhibited using a pharmacological agent?

Dry mouth

Which is correct regarding somatic motor neurons

They do not have ganglia

a dentist would like to reduce salivation in a pt in preparation for an oral procedure. Which of the following would be strategies useful in reducing salivation?

Block Muscarinic receptors in salivary glands

Sarin is a volatile nerve agent that inhibits cholinesterase enzymes. Which of the following symptoms would you expect to see in a pt exposed to sarin?

Constriction of pupils (miosis)

Head and neck irradiation in cancer pts can decrease salivary secretion and cause dry mouth, all of the following drugs or classes are theoretically useful in improving increased salivary secretion and except:

Muscarinic antagonists

Which of the following drug classes will be useful in treating symptoms of myasthenia gravis?

Anticholinesterase agents

Atropine is one of the ingredients in the antidiarrheal combination diphenoxylate/atropine. Which of the following effects is produced by atropine that contributes to its antidiarrheal effect?

Reduction in GI motility

Which of the following is correct regarding NMBs?

Cholinesterase inhibitors reduce the effects of nondepolarizing NMBs