Parasympathetic nervous system

Cholinergic Agonists

Drugs that mimic acetylcholine; a.k.a. "Parasympathomimetic" Agents

and "Cholinomimetic Agents"

Direct acting cholinergic agonists

directly binds to receptors

Indirect-Acting Cholinergic Agonists

increases acetylcholine level by inhibiting acetylcholinesterase

Choline Esters

Poorly absorbed & distributed in the CNS, charged with quaternary ammonium group renders them insoluble in lipid; Hydrolyzed in the GIT

CARBACHOL

BETANECHOL (Urecholine)

ACETYLCHOLINE

METACHOLINE

Choline Esters

ACETYLCHOLINE

Prototype, quaternary ammonium compound that cannot penetrate membranes.

rapidly hydrolyzed; large IV bolus injection has brief effects of 5-20 seconds compared to IM or SC which has a local effect.

Dumbbells

Adverse effect of acetylcholine

METACHOLINE

acetyl-B-methylcholine; more resistant to enzymatic hydrolysis than Ach.

No nicotinic action, not used clinically

Used for diagnosis of asthma

CARBACHOL

very potent choline ester having both muscarinic and nicotinic effects

Act predominabntly on GIT, UB; nicotinic actions>Muscarinic actions

Used for Glaucoma (used together with pilocarpine)

BETANECHOL (Urecholine)

carbamoyl-B-methylcholine; Not hydrolyzed by cholinesterases

Act predominabntly on GIT, UB; No nicotinic actions

USES OF BETANECHOL:

1. Treatment of gastric retention

2. Treatment of postoperative abdominal

distention

3. Treatment of nonobstructive urinary

retention

4. Prevention of paralytic ileus

Alkaloids

tertiary amine- well absorbed orally except:Muscarine

Natural (derived from natural sources)

Cholinomimeticsstimulate-stimulate receptor of Acetylcholine

PILOCARPINE

NICOTINE

LOBELINE

MUSCARINE

ARECOLINE

Alkaloids

PILOCARPINE

Pilocarpus jaborandi; Muscarinic action similar to Ach

Use: Glaucoma- *stimulates M3 in the pupilà miosis-- > drains aqueous humor and decrease ocular pressure

NICOTINE

Nicotiana tabacum; component of cigarette smoke

Dangerous Effects: CNS action-convulsion, coma & respiratory arrest

Use in smoking cessation Use in smoking cessation

40mg (1 drop of pure nicotine liquid)

Acute Toxicity; fatal dose of nicotine

diazepam and atropine

Used in management of nicotine dependence

Depolarization

Influx of positive ions

LOBELINE

plant derivative similar to nicotine (Lobelia inflata)

MUSCARINE

mushroom Amanita muscaria; A quaternary ammonium salt

Action: Muscarinic action similar to Ach; No nicotinic action

Causes: Mushroom Poisoning (mimic Ach)

ARECOLINE

From Areca nut (Areca catechu)

Indirect acting Agonists (Acetylcholinesterase inhibitors)

Increases acetylcholine in the synaptic cleft by inhibiting acetylcholinesterase

Produce their primary effects by inhibiting acetylcholinesterase which hydrolyzes acetylcholine.

MOA of Indirect acting Agonists

Ach binds to the enzyme's active site & hydrolyzed yielding free choline & acetylated enzyme.

All of the cholinesterase inhibitors increase the concentration of endogenous Ach at cholinoceptor by inhibiting acetylcholinesterase.

REVERSIBLE INHIBITORS (indirect action agonist)

Attach to the ACHE enzyme and are only slowly hydrolyzed.

IRREVERSIBLE INHIBITORS (indirect action agonist)

Reacts to form a stable, phosphorylated enzyme, which is essentially not hydrolyzed.

QUATERNARY ALCOHOLS

CARBAMATES

PHYSOSTIGMINE (aka eserine)

NEOSTIGMINE (Prostigmin)

CARBAMATES

DEMECARIUM (Humorsol)

Indirect acting Agonists- Reversible

QUATERNARY ALCOHOLS

- Don't form a covalent bond and bind reversibly at the active site. The action is therefore very short-lived.

- 15-30 mins duration of action

Edrophonium (Tensilon)

-example of quantary alcohol,Short-acting;for diagnosis of Myasthenia gravis

CARBAMATES

- intermediate- long acting

- 2-8 hrs duration of action

PHYSOSTIGMINE (aka eserine)

highly lipid soluble , crosses blood brain barrier, Pharmacological Action similar to Ach

Uses: Ophthalmic uses, Treatment of poisonings with anticholinergic agents

NEOSTIGMINE (Prostigmin)

not lipid soluble, does not cross BBB; Pharmacological Action similar to Ach

Uses:

- Post-operative ileus

- Urinary retention

- Reverse NMJ block from curare-like drugs

- Myasthenia Gravis

CARBAMATES

- used for the treatment of muscle weakness and fatigue in people with myasthenia gravis

ptosis (blepharoptosis) or lazy eye

drooping, common with myasthenia gravis

Mestinon

Pyridostigmine

Mytelase

Ambenonium

DEMECARIUM (Humorsol)

Ophthalmic Solution; A cholinesterase inhibitor used to treat glaucoma by lowering the pressure inside the eye.

Similar moa to pilocarpine

Inc. Ach-- > stimulates M3 in the pupilà miosis-- > drains aqueous humor and decrease ocular pressure

- Tacrine (Cognex®)

- Donepezil (Aricept®)

- Galantamine

- Rivastigmine

Reversible inhibitors used in Alzheimer's Disease to incrase ach levels

Alzheimer's

a progressive disease, where dementia symptoms gradually worsen over a number of

years.

Acetylcholine (ACh) is essential for processing memory and learning= decreased in both concentration and function in patients

with Alzheimer's disease.

In its early stages, memory loss is mild, but with late-stage Alzheimer's, individuals lose the ability to carry on a conversation and respond to their

environment.

ORGANOPHOSPHATES

- Highly toxic compounds, widespread use as insecticides. (Warfare never gases

- Reacts to form a stable, phosphorylated enzyme, which is essentially not hydrolyzed.

- The pharmacological effects of cholinesterase inhibition persist until new enzyme is synthesized; Very long acting, Duration of action: several days

Type of antagonism:

Less than 24-48 hrs of exposure=potentially reversible

Greater than 24-48 hrs= definitely irreversible

Echothiophate, Isofluorophate, Parathion, Malathion, Sarin, Soman, Tabun

EXAMPLES OF ORGANOPHOSPHATES

Isofluorophate

both are used for glaucoma

Parathion

converted into Paraoxon

Malathion

converted into Malaoxon Both are used as insecticide (potent form of parathion)

Sarin, Soman, Tabun

nerve gases, used in biological warfare.

Atropine, Pralidoxime

ANTIDOTE FOR ORGANOPHOSPHATES TOXICITY

PRALIDOXIME

Also known as 2-PAM; It is used to combat poisoning by organophosphates or acetylcholinesterase inhibitors (nerve gas), in conjunction with atropine.

Cholinesterase activator

MOA OF PRALIDOXIME

It reactivates the cholinesterase by removing the phosphoryl group that is bound to the ester group.

In this reaction both the organophosphate and the pralidoxime are mutually inactivated.

Nerve Gases

G- stands for Germany. Developed and stockpiled for use in Germany during World War II.

Nerve agents have been used both in battle and in terrorist attacks, such as the 1995 release of sarin on commuter trains in Japan that killed 12 people and Iran-Iraq war.

Ethyl dimethylphosphoramidocyanidate

Tabun (GA)-1936

Isopropyl methylphosphonofluoridate

Sarin (GB)-1938

3-3-dimethylbutane-2-yl-methylphosphonofluoridate

Soman (GD)-1944

Cyclohexyl methylphosphofluoridate

Cyclosarin (GF)- 1949

Edrophonium (Dx) Neostigmine, Pyridostigmine, Ambenonium (Tx)

Dx and Tx of Myasthenia Gravis

Neostigmine

Mgt. of Atropine toxicity

Neostigmine, Edrophonium

Mgt. of neuromuscular blocker toxicity

Pilocarpine, Ecothiopate, Carbachol

Useful for glaucoma

Physostigmine

Use in non-obstructive ileus

Nicotine & Varenicline

Used in smoking cessation

Betanechol

Mgt. of Urinary retention

Myasthenia Gravis

An autoimmune disease (Antibodies disrupt Nm receptors) "Anti-ACR antibodies"

Early manifestations:

- Late afternoon muscle weakness

- Late afternoon ptosis

Final manifestation:

- Diaphragmatic muscle weakness

- Associated with thymic hyperplasia/tumor (increase activity of thymus gland)

Dx:

Pharmacologic-Edrophonium (Tensilon Test). Rapidly

relieved ptosis- (+) myasthenia gravis (right)

Immunologic- detects anti-ACR antibodies

Treatment:

1. Neostigmine, Pyridostigmine, Ambenonium

2. Thymectomy- removal of thymus gland

Cholinergic Antagonists

Drugs that block the action of acetylcholine to the cholinergic receptors.

a.k.a "Parasympatholytic Agents", Cholinergic

blockers, Anticholinergics

ANTIMUSCARINICS

-muscarinic antagonist

- Aka: Anticholinergics

ANTI-NICOTINICS

-nicotinic antagonist

-consist of ganglion-blockers & neuromuscular

junction blockers.

ATROPINE

SCOPOLAMINE

IPRATROPIUM, TIOTROPIUM, OXYTROPIUM

BENZTROPINE, BIPERIDEN, TRIHEXYPHENIDYL

HOMATROPINE, CYCLOPENTOLATE, TROPICAMIDE, GLYCOPYRROLATE

OXYBUTININ

TOLTERODINE

IMIPRAMINE

Example of Antimuscarinics

ATROPINE

- Atropa belladona or deadlynight shade or in Datura stramonium or jimsonweed (Jamestown weed) or thorn apple.

- l(-) hyoscyamine -naturally occuring atropine.

- more potent than d(+) isomers.

MOA of ATROPINE

- Atropine causes reversible blockade of cholinomimetic actions at muscarinic receptors.

- When atropine binds to the muscarinic receptor, it prevents the actions of muscarinic agonists such as the release of IP3 & the inhibition of adenylyl cyclase.

SCOPOLAMINE

-occurs in Hyoscyamus niger or henbane, as the l(-) stereoisomer.

- Also known as Hyoscine

- Used for motion sickness and abdominal cramps Morphine + Scopolamine = twilight sleep

twilight sleep

an amnesic condition characterized by insensitivity to pain without loss of consciousness

IPRATROPIUM, TIOTROPIUM, OXYTROPIUM

Used in the management of BA and COPD; reduce the accumulation of secretions in the trachea & laryngospasm

bronchial asthma

BA

chronic obstructive pulmonary disease

COPD

Atrovent

Ipratropium

Berodual

Ipratropium + Fenoterol

Combivent

Ipratropium + Salbuterol

IPRATROPIUM, TIOTROPIUM, OXYTROPIUM OF MOA

Relax bronchial smooth muscle by antagonizing m3 receptor

BENZTROPINE, BIPERIDEN, TRIHEXYPHENIDYL

Management of Parkinsonism; Also used to manage extra pyramidal symptoms (EPS)

Akineton

Biperiden

Cogentin

Benztropine

Artane

Trihexyphenidyl

MOA OF BENZTROPINE, BIPERIDEN, TRIHEXYPHENIDYL

Competitive antagonism of acetylcholine at cholinergic receptors in the corpus striatum, which then restores the balance.

HOMATROPINE, CYCLOPENTOLATE, TROPICAMIDE, GLYCOPYRROLATE

Mydriatic and Cycloplegic; Opthalmic examination

Glycopyrrolate-for peptic disease, hypermotility

-Homatropine (Isopto homatropine)

-Cyclopentolate (Cyclogyl)

-Tropicamide (Mydriacyl)

OXYBUTININ

bladder spasm after urologic surgery.

TOLTERODINE

an M3-selective antimuscarinic used for urinary incontinence in adults.

IMIPRAMINE

TCA drug, used to reduce incontinence.

PIRENZIPINE & TELENZIPINE

Used for the management of Peptic Ulcer Disease (PUD) lGastric acid, Pepsin & mucin are all reduced

Parietal cells

also known as oxyntic cells; are epithelial cells in the stomach that secrete hydrochloric acid (HCl) and intrinsic factor.

Ganglionic Blockers

Acts on the nicotinic receptors (Nn), Blocks the action of acetylcholine of both parasympathetic and sympathetic autonomic ganglia

Most of these drugs are no longer used clinically and are of historical importance only, because drugs that target the ganglia usually have a broad range of effects and therefore many side effects

MOA of Ganglionic Blockers

- Acts on the nicotinic receptors (Nn), probably by blocking the ion channels of the autonomic ganglia.

- Blocks the action of acetylcholine and at the nicotinic receptors of both parasympathetic and sympathetic autonomic ganglia.

TETRAETHYLAMMONIUM

HEXAMETHONIUM

DECAMETHONIUM

MECAMYLAMINE

TRIMETHAPHAN

NICOTINE

LOBELINE

Ganglionic Blockers

TETRAETHYLAMMONIUM

first recognized ganglionic blocker

HEXAMETHONIUM

first effective drug for management of hypertension. It is now rarely used for HTN due to lack of selectivity compared to newer agents.

DECAMETHONIUM

An analog of hexamethonium effective as neuromuscular depolarizing blocking agent.

MECAMYLAMINE

secondary amine studied for possible use in reducing nicotine craving in patients attempting to quit smoking.

TRIMETHAPHAN

short-acting ganglion blocker, occasionally used in the treatment of hypertensive emergencies & dissecting aortic aneurysm.

Neuromuscular Blockers

Blocks the cholinergic transmission between motor nerve endings and the nicotinic receptors on the neuromuscular end-plate of skeletal

muscle.

NON-DEPOLARIZING

-Reversible

-True NM Antagonist

-Curare derivatives

MOA of non-depolarizing neuromuscular blockers

Combines with nicotinic receptor & prevent the binding of acetylcholine thus prevent depolarization of the muscle cell membrane and inhibit muscle contraction

d-Tubocurarine (d-TC), Metocurine,Doxacurium, pancuronium, pipecuronium,gallamine

Long Acting

Atracurium, Cisatracurium, Vecuronium, Rocuronium

Intermediate acting

Mivacurine, Rapacuronium,

Short Acting