Dr. Carl B. Goodman Professor of Pharmacology Florida A&M University College of Pharmacy & Pharmaceutical Sciences 308E FSH-SRC

Drugs that stimulate the parasympathetic nervous system (PSNS) The PSNS is the opposing system to the SNS Cholinergic neurotransmitter Acetylcholine (ACh) Cholinergic receptors Muscarinic receptors Nicotinic receptors

Cholinergic neurotransmitter Acetylcholine (ACh) Cholinergic receptors Muscarinic receptors Nicotinic receptors

Effects of cholinergic stimulation on body organs

Useful in the treatment of : Myasthenia gravis Autoimmune disease where Abs are destroying the nicotinic receptors-severe muscle weakness Alzheimer’s disease Loss of cholinergic neurons-important cognitive function, memory storage and retrieval Atony of smooth muscle of the GI and Urinary systems

Arecholine Pilocarpine Urecholine(Betanechol) Carbachol Choline Metacholine Mushrooms (Boletus sp., Clitocybe sp., Inocybe sp.)

Function Reduce intraocular pressure Useful for glaucoma and intraocular surgery Examples: Acetylcholine, Carbachol, Pilocarpine Topical application due to poor oral absorption Bethanechol chloride (Urecholine) Increases tone and motility of bladder and GI tract Relaxes sphincters in bladder and GI tract, allowing them to empty Helpful for postsurgical atony of the bladder and GI tract Oral dose or SC injection Side effects/adverse reactions Hypotension, bradycardia, excessive salivation, increased secretion of gastric acid, bronchoconstriction, abdominal cramps

Nicotine agonists have no therapeutic applications except in producing skeletal muscle paralysis Indirect acting agents are used when an increased nicotinic activation is needed Nicotine used commonly in the form of “Chewing Gum” and Transdermal Patch by smokers Nicotine is used in some insecticides (CNS stimulation- convulsion)

Also called cholinesterase (ChE) inhibitors, and/or acetylcholinesterase (AChE) inhibitors Functions Cause skeletal muscle contractions Used for diagnosis and treatment of myasthenia gravis Used to reverse neuromuscular blocking drugs Atracurium (Tracrium), Cisatracurium (Nimbex), Doxacurium (Nuromax), Mivacurium (Mivacron), Pancuronium (Pavulon), Rocuronium (Zemuron), and Succinylcholine

Functions Used to reverse anticholinergic poisoning: ex. Jimson weed (belladonna alkaloids)- Atropine, Scopolamine, Hyoscyamine Antidote: Physostigmine (Glaucoma (crosses blood-brain barrier - CNS), Pyridostigmine Side effects: bradycardia, asthma, peptic ulcers Contraindications Intestinal and urinary obstruction

Salivation Lacrimation Urination Diarrhea GI distress Emesis

Bind to cholinesterase for a period of minutes to hours Produce pupil constriction in glaucoma Increase muscle strength with myasthenia gravis Edrophonium (Tensilon) Short acting Cholinesterase inhibitor Used to diagnosis MG Treat Neuromuscular Blockers

Neostigmine (Prostigmine) Prototype of anticholinesterase (Carbamate) Treatment of Myasthenia gravis Antidote for Tubocurarine and other Neuromuscular blocking agents Poorly absorbed orally so requires large doses when given parenterally Can develop resistance to its action over time

Pyridostigmine (Mestinon) Maintenance drug of choice for patients with Myasthenia gravis Slow release formulation

Physostigmine (Eserine) Only anticholinesterase capable of crossing the blood brain barrier Is more lipid soluble than the others Can be used to treat Glaucoma Used as an antidote for overdosage of Anticholinergics such as: Atropine, Antihistamine, TCA, Phenothiazine

Donepezil (Aricept) Delays the onset of the disease by up to 55 weeks Galantamine (Reminyl) One of the newest drug on the market Rivastigmine (Exelon) Long acting and given twice a day dosing Tacrine (Cognex) Hepatotoxic with elevated liver enzymes usually with 18 weeks, especially in women Poor oral bioavailability, the necessity for four-times daily dosing

Irreversible cholinesterase inhibitors Bind to cholinesterase and form a permanent covalent bond The body must make new cholinesterase to break these bonds Produce pupil constriction Antidote to reverse organophosphate Pralidoxime (Protopam)

Cholinergic or muscarinic antagonists Antimuscarinic agents Antispasmodic agents Action of anticholinergic drugs

Effects of anticholinergics Atropine- effects the muscarinic receptor Function To decrease salivary secretions Act as antispasmodic To increase heart rate Side effects/adverse reactions Tachycardia, dry mouth, abdominal distention, palpitations, nasal congestion, photophobia, blurred vision, flushing, urinary retention Glycopyrrolate (Robinul)- Nicotinic receptor blocker

Selected anticholinergic drugs for treating parkinsonism or pseudoparkinsonism Benztropine (Cogentin) Biperiden (Akineton) Procyclidine (Kemadrin) Trihexyphenidyl HCl (Artane)

Side effects similar to anticholinergics Anticholinergics used as antihistamine for treating motion sickness Scopolamine (Transderm Scōp) Dimenhydrinate (Dramamine) Antihistamines’ side effects Dry mouth, visual disturbances, constipation, urinary retention, tachycardia, hypotension