Acetylcholinesterase inhibitors

- they aren't parasympathomimetics

- can mimic the effects of parasympathetic stimulation and other kinds of stimulation too- they produce skeletal muscle contractility as a potential effect, as well as CNS effects

Parasympathomimetics

- group of agents which, for the most part, are either muscarinic agonists or indirect-acting parasympathomimetics

- agent that mimics the effects of parasympathetic stimulation

Cholinomimetics

- mimic the effects of acetylcholine (Ach)

- Ach acts at a bunch of places; it has nicotinic or muscarinic effects

- we use parasympathomimetic instead of cholinomimetic

Muscarinic Agonists

- parasympathomimetic, but they can ALSO mimic the effects of sympathetic stimulation,

**ex. a muscarinic agonist will produce an increase in sweating, and that's mediated by a sympathetic cholinergic nerve

Indirect-acting Parasympathomimetics

 - carbachol; at its lowest doses it produces indirect parasympathomimetic-like effects

Acetylcholinesterase (AchE) Inhibitors

 - can increase Ach levels;

(Ach acts as a neurotransmitter at the

neuroeffector junction between cholinergic

nerves and muscarinic receptors)

- they can also produce nicotinic effects, because Ach acts at different places

Cholinergics

-parasympathomimetics 

- AchE inhibitors

- depolarizing neuromuscular blockers

Succinylcholine

depolarizing neuromuscular blocker 

In Vivo Diagnostics

(parasympathomimetics)

- methacholine can produce contraction of bronchial smooth muscle

- one can diagnose for pulmonary hyper-reactivity  by administering increasing doses (concentrations) of agents, including methacholine

- people who have hyper-reactivity of the respiratory tract will develop a contractile response at very low doses in the inspired air; this can be alleviated by giving a beta-2 agonist

Natural Cholinomimetics

Nicotine 

   Pilocarpine

   Muscarine 

    Arecholine 

Nicotine

- it is the prototype nicotinic receptor agonist

- it also produces an inactivation of the nicotinic receptor on continual stimulation

 - it is a natural cholinomimetic

Pilocarpine

- muscarinic agonist; acts on muscarinic receptors; has affinity and intrinsic activity,

- it is still used

Muscarine

- found in mushrooms

- it's able to stimulate muscarinic receptors

Arecholine

- naturally occurring cholinomimetic

- found in beetle nut 

- it mimics the effects of cholinergic stimulation

and has muscarinic agonist activity;

- not used at present 

Indirect-acting parasympathomimetics

Carbachol 

Metoclopramide 

Metoclopramide

- also known as Reglan

- acts as an indirect-acting parasympathomimetic;

- it promotes the release of Ach from cholinergic post-ganglionic nerve terminal endings

Muscarinic Agonists 

Methacholine- synthetic choline ester

Bethanecol- synthetic choline ester

Cevimeline- synthetic muscarinic agonist

Pilocarpine- naturally-occurring muscarinic agonist

Acetylcholine

- not first choice of drug, because:

            1. lacks selectivity, it acts at all

cholinergic receptors

            2. it's broken down very quickly by AchE

Naturally occurring, non-selective action

Uses for Parasympathomimetics

- narrow-angle glaucoma

- urinary Retention

- GERD

- Sjogren's Syndrome

- In Vivo Diagnostics

Synthetic Choline Esters

- Methacholine

- Carbachol

- Bethanechol 

Cholinesterase Susceptibility

- Ach is MOST susceptible to AchE (3+)

- methacholine is susceptible to

AchE to a degree (1+)

- carbachol and bethanecol are not broken

down by AchE, but the effect of carbachol can be influenced by cholinesterase

Carbachol

- the effects of carbachol can be influenced by cholinesterase; it depends on release of Ach at low doses, so even though carbachol itself is not broken down by AchE, an AchE inhibitor could potentiate the effects of low-dose carbachol because it acts to promote the release of Ach, which itself is susceptible to AchE

Methacholine

- has very prominent cardiovascular effects!!!

- it's rarely used systemically due to

cardiovascular receptor affinity

- Ach is 2+ for cardiovascular, but methacholine is much more potent because methacholine is not broken down as readily as Ach

Bethanechol

- has GI effects!!! 

Atropine 

- competitive muscarinic receptor antagonist;

- it antagonizes the effects of Ach on

muscarinic receptors, as well as

methacholine on muscarinic receptors

- carbachol has nicotinic effects as well as muscarinic effects, so it is not very 

well-antagonized by atropine

- bethanechol and cevimeline are

antagonized by atropine;

Metoclopramide and bethanechol

 - used in GERD to increase the lower esophageal sphincter tone; they also promote emptying of stomach 

Glaucoma

 - increase in intraocular fluid pressure

- can be genetic, NOT reversible!

- glucocorticoids increase your risk for glaucoma

- the continued elevation of IO fluid results in damage to the optic nerve; vision loss

- occurs very gradually

Glaucoma & how drugs work here

- the IO fluid goes through Canal of Schlemm

- some of the drugs used in glaucoma act by producing contraction of the pupillary sphincter, and as a consequence relieve the blockage of the Canal of Schlemm (narrow-angle glaucoma)

- some agents act by causing a decrease in the production of aqueous humor, decrese IOP

- parasympathomimetics, sympathomimetics

and prostaglandin derivatives are used

ANS Drug Mechanisms in Glaucoma

1. increase aqueous humor drainage

2. decrease aqueous humor formation

Increase aqueous humor drainage

-pilocarpine and carbachol

- can use parasympathomimetics, as they cause contraction of the sphincter muscle, or AchE inhibitors, as they increase the levels of Ach (also causing contraction of the sphincter muscle); these are called miotics, because they produce miosis

Decrease aqueous humor formation 

- carbonic anhydrase inhibitors, and

prostaglandin derivatives

       alpha-1 agonists- act on cilliary vessels 

            alpha-2 agonists- act on the cilliary body 

            beta-1 antagonists- act on the cilliary body to reduce aqueous humor formation

Pilocarpine and carbachol

Increase aqueous humor drainage

or "improve uveoscleral outflow"

- used topically because they can produce effects at other muscarinic receptors if used systemically

- they increase parasympathetic stimulation

Bethanechol and carbachol

- used in urinary retention as they increase

 activity of the detrusor muscle 

- they can produce effects wherever there are muscarinic receptors (or for carbachol, a cholinergic nerve); not preferred agents

- bethanechol is preferred over carbachol

Miotic for Surgery

 - Ach is used as a miotic for surgery

- it's administered into the eye, where it produces miosis for surgical procedures of the eye

- can't be used systemically as it has

non-selective effects

Methacholine

B-2 agonist for bronchoconstriction reversal 

Pilocarpine and cevimeline

- used to combat xerostomia

- Pilocarpine is used as topical drops in the

mouth to promote salivation

- Cevimeline is an agent which is used specifically in Sjogren's; it increases the exocrine grandular secretions

Precautions and Warnings

- these agents are used orally and/or topically;

NOT IV or SC because they will work at

all muscarinic receptors;

- bethanechol has a very high GI propensity, but it will produce bradycardia if it gets systemically

Precautions and Warnings

- miotics (AchE inhibitors) may cause bronchoconstriction, so don't use in asthma!

- parasympathomimetics can worsen

the symptoms of angina, as they cause bradycardia

-  do NOT be use in peptic ulcers 

Ophthalmic use

- a muscarinic agonist or AchE inhibitor will cause an increase in contractility of the pupil, so you get miosis AND accomodation for near vision; 

- muscarinic agonists can cause visual blurring

and impaired depth perception

- you won't be able to dilate your pupils, so it's difficult to drive at night; 

Precautions and Warnings

- parasympathetic stimulation causes

bradycardia, (a/v block);

- people who take beta-blockers have unopposed parasympathetic stimulation of the heart, and so giving a muscarinic agonist or a  parasympathomimetic will increase the slowing of the heart because you have beta-blockade and less sympathetic stimulation, (which is producing the opposite effect of parasympathetic stimulation)

- people taking beta-blockers will have a

greater likelihood of developing cardiac

conduction disturbances***

Cevimeline

 - is broken down by CYP2D6, so people who have

deficiencies in this enzyme will be very sensitive

to the effects of cevimeline 

Muscarinic Receptor Antagonists

- block the effects of Ach

- block the effects of muscarinic agonists

- can produce CNS effects if they can get there

Atropine

- prototype muscarinic receptor antagonists 

- able to get into CNS, as well as periphery

- "belladonna alkaloids", naturally occurring muscarinic receptor antagonists

Scopolamine

- has atropine-like effects

- can get into CNS, and unlike atropine, 

it can produce sedation; used in

preparation for surgery as

(1) enhances the effects of the general anesthetic

(2) combats some side-effects of GA

(excessive salivation, broncho-secretions)

- it blocks muscarinic receptors,

- can also combat motion sickness

but causes dry mouth

Homatropine

- belladonna alkaloid like atropine

- effects are comparable to atropine

- does not produce sedation like scopolamine

Tolteridine (Detrol)

- not a belladonna alkaloid

- it is a synthetic muscarinic receptor antagonist

Anticholinergics

- drugs that can block the effects of Ach; 2 kinds:

            1. drugs that can get into CNS and block Ach receptors in CNS= anticholinergics

            2. drugs which have antagonistic activity toward muscarinic AND nicotinic receptors; these are antagonists at cholinergic receptors

CNS-acting anticholinergics

- used in combatting diseases like Parkinsons;

- will still have peripheral muscarinic side-effects and precautions associated with peripherally-acting muscarinic antagonists 

Quaternary Ammonium

Muscarinic Antagonist

Ipratropium 

Tiotropium

Methscopolamine

Ipratropium

- used in respiratory difficulty; it blocks muscarinic receptors (Quaternary Ammonium Muscarinic Antagonist)

- can't produce relaxation of bronchial smooth muscle because the muscarinic receptors on the pulmonary tissue are non-innervated

- it's included in some respiratory preparations with beta-2 agonists, which will produce

relaxation in bronchial smooth muscle.

Methscopolamine= scopolamine methylbromide

- quaternary ammonium muscarinic receptor antagonists

- don't have any CNS effects

- produce only peripheral effects