Cholinergic Pharmacology

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Result of muscarinic stimulants on non-innervated muscarinic receptors on the smooth muscle of blood vessels

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lower blood pressure even though parasympathetic nerve stimulation cannot lower blood pressure

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Drugs can increase cholinergic function by

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1) directly stimulating cholinergic receptors

2) indirectly increase the effectiveness of endogenous ACh

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Synthesis of ACh occurs...

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in the cytoplasm of cholinergic nerves where choline and acetyl CoA react

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Enzyme that catalyzes the synthesis of ACh from choline and acetyl CoA

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choline acetylase (choline acetyltransferase)

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rate-limiting step of ACh synthesis

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pumping choline back into the nerve

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Hemicholinum (HC-3)

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blocks transport of choline and consequently will eventually cause an inhibition of cholinergic function

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Any substance the lowers extracullular Ca++ or that interferes with Ca permeability through the membrane will

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inhibit the release of ACh into the synaptic cleft

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Botulinum toxin

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prevents the release of ACh from the nerve terminal

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Black widow venom (latrotoxin)

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causes excessive fusing of the granules with the nerve membrane that leads to excessive release and eventual depletion of the transmitter

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"True" Acetylcholinesterase

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found in the region of all cholinergic synapses and hydrolyzes the ester linkage yielding choline and acetic acid causing ACh to have a short half-life

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Pseudocholinesterases

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non-spectific enzyme found in the plasma and liver that degrade ACh that escapes from transmission sites and IV ACh

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Muscarinic receptors found in the heart

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M2

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Muscarinic receptors located in the peripheral autonomic organs

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M3

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Muscarinic receptors found in GI tract and autonomic ganglia

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M1

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Muscarinic receptors found in the CNS

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M1 to M5

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ACh acts on non-innervated muscarinic receptors in the endothelial cells of blood vessels which releases...

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derived relating factor (EDRF) to cause relaxation of the vessel smooth muscle

EDRF is Nitric Oxide (NO)

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Nicotinic Receptors are located at:

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1) NMJ
2) Autonomic ganglia
3) Adrenal medulla
4) CNS

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have profound actions on cholinergic receptors

limited usefulness --> so many organ systems affected

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Choline esters

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Acetylcholine

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-injected
-short half life
-low doses only activate muscarinic receptors
-high doses stimulate both muscarinic and nicotinic

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Methacholine

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=ACh + additional methyl group is added to the 2nd Carbon
-longer half life (partial refractory to AChase)

muscarinic >>>>>> nictotinic

Clinically: not used, so many generalized muscarinic effects

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Carbachol

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NH2 group on the terminal end of ACh--> refractory to AChase

nicotinic>>>>>>>>>>muscarinic

Releases ACh from cholinergic nerve endings

Clincally: topically on eye to produce miosis in the treatment of glaucoma

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Bethanechol

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both methyl and NH2 subs.

refractory to AChase

Muscarinic effects

Clinically: esophogeal reflux due to its stimulatory action on the lower esophageal sphincter

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Naturally occuring cholinergic stimulants (alkaloids):

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nicotine, muscarine, pilocarpine

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Nicotine

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tobacco leaves/widely abused

odorless, colorless liquid

stimulates all nicotinic receptors

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Results of giving nicotine repeatedly or in large doses

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blockade of nicotinic receptors due to sustained depolarization

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Muscarine

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from mushroom

Will stimulate all muscarinic receptors whether innervated or non-innervated

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Pilocarpine

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from South American shrub

selectively activates muscarinic receptors

not highly charged-->crosses membranes

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Mechanism of pilocarpine in treating glaucoma

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Outflow of aqueous humor is enhanced due to constriction of the iris sphincter muscle and the ciliary body behind the iris. These events mechanically widen the angle between the cornea and iris where aqueous outflow takes place

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The cholinomimetic effect of anticholinesterase agents is observed at which receptors?

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only at those cholinergic receptors that receive tonic neural input

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reversible AChase inhibitors

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duration of hours--> enzyme eventually freed of drug

Clincally: treats myasthenia gravis and glaucoma

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Irreversible AChase inhibitors

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bind so tightly so new enzyme must be synthesized to regain function

Insecticides, Chemical warfare agents

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from the Calabar bean

Not highly charged so it can enter CNS

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Physostigmine (Reversible AChase Inhibitor)

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Treatment of glaucoma (miosis and contraction of ciliary muscle)

Most rational agent for atropine poisoning (b/c CNS accessibility)

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Physostigmine (Reversible AChase inhibitor)

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Does not readily enter CNS

Dual action to directly stimulate nicotinic sites on skeletal muscle endplates

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Neostigmine (Reversible AChase inhibitor)

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Used to treat myasthenia gravis

Used w/ atropine to reverse actions of competitive neuromuscular blocking drugs (curare-like drugs)

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Neostigmine (Reversible AChase inhibitor)

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additional drugs to treat myasthenia gravis

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Ambenonium and Pyridostigmine (Reversible AChase inhibitors)

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short duration ---> diagnosis of M.G.

beneficial in titration of effective dose levels

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Edrophonium (Reveresible AChase Inhibitor)

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Side affects of AChase inhibitors

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Excessive muscarinic activation (sweating, salivation, increased GI and bladder motility)

Skeletal muscle weakness due to too much AChase inhibition (cholinergic crisis) or insufficient inhibition (myastenic crisis)

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used to treat cognitive dysfunction seen in patients with Alzheimer's disease

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Donepezil and Tacrine (Reversible AChase Inhibitors)

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Mechanism of Irreversible AChase inhibitors

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phosphorylate the esteric site on the AChase enzyme, binds tightly to enzyme

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Irreversible AChase inhibitor used to treat glaucoma in pts refractory to other less potent miotics

Long term use restricted to aphakic eyes b/c it causes cataracts

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Echothiophate

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Irreversible AChase Inhibitors that are common insecticides

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Parathion and Malathion

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Compound converted in the liver to an irreversible anti-AChase agent (paraoxon)

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Parathion

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Irreversible AChase inhibitor quickly inactivated to non-toxic metabolites in mammals and birds

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Malathion

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Irreversible Anti-cholinesterase war gases that are not reversed by "said" reactivators

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Sarin and Soman

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cholinesterase reactivator used to treat intoxication with some organophosphorous compounds

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pralidoxime (2-PAM)

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Muscarinic blocking drug taken orally derived from plants such as the deadly nightshade

Causes CNS excitation

Low doses=bradycardia
High doses=tachycardia (expected)

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Atropine

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red as a beet, hot as a pistol, dry as a bone, mad as a hatter

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Atropine poisoning effects

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Muscarinic blocking drug that causes CNS depression

Used in medicine to prevent motion sickness

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Scopolamine

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Muscarinic blocking drug that is less potent and shorter acting

Used for opthalmolgical exams

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Tropicamide

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Synthetic muscarinic blocking drugs that have fewer systemic (especially CNS) side effects

Applied topically to the airway by metered inhaler

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Ipratropium and Tiotropium

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Used instead of atropine for COPD b/c they produce bronchodialation w/o reduction in volume or increase in viscoity of bronchial secretions

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Ipratropium and Tiotropium

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Second line muscarinic blocking agent for the treatment of bronchial asthma but appears beneficial when combined w/ other bronchodialators

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Ipratropium

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Muscarinic blocking agent that has a longer duration of action so it can be administered as once/day

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Tiotropium

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Muscarinic blocking agent that is a CNS acting drug used to treat symptoms of Parkinson's disease

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Benztropine

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Muscarinic blocking agent used to treat spasms of the bladder

admin. orally or topically (via catheter) to improve continence

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Oxybutynin

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Receptors affected by blockade of autonomic ganglia

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all innervated receptors

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Nicotine

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Ganglionic stimulant that would act on all nicotinic receptors on the post ganglionic neurons and adrenal chromaffin cells

at high doses/given repeatedly becomes ganglionic blockade

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Was used therapeutically to treat severe hypertensive disease but is no longer used

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ganglionic blockades

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prototype ganglionic blockade agent used experimentally that does not compete with ACh at the nicotinic receptors found on the endplate of skeletal muscle

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Hexamethonium (C6)

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Types of receptors found in blood vessels in the skin

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alpha innervated

few B-2/M non-innervated

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Types of receptors found in blood vessels in the kidney

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Alpha-innervated

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Effect of parasympathetic system on bronchial constriction

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slight

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MAO inhibitor

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selegiline

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COMT inhibitor

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tolcapone, Tasmar

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blocks serotonin uptake

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Fluoxetine (Prozac)

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binds to GABA receptors and increases the frequency of the GABA-stimulated chloride channel opening

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Benzodiazpines (diazepam, Valium)

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Ester local anesthetic with low potency, slow onset, and short duration of action

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Procaine (novacain)

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Ester local anesthetic with fast onset and is short action.

Commonly used for labor and C-sections

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Chloroprocaine

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Ester LA that is more potent and has longer duration than procaine

Use for spinal anesthesia

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Tetracaine

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Ester LA used only as a topical anesthetic

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Benzocaine

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the most widely used local anesthetic

produces fast, intermediate lasting

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lidocaine

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Widely used amide LA with long duration

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Bupivacaine

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Intermediate action LA w/ properties similar to Lidocaine but w/ higher therapeutic index and longer duration of action

Toxic in neonate, not effective topical anesthetic

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Mepivacaine

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Local amide anesthetic with long duration and less cardiotoxic effects the bupivicaine

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Ropivacaine