CEE 2. Pcol (Parasympathetic continuation)

q

M1 & M3 mechanism

i

M2 mechanism

Nerve endings (CNS)

LOCATION: M1

Heart, some nerve endings

LOCATION: M2

Effector cells: smooth muscle, glands, endothelium (others: sphincter muscle of the eye, heart, GIT, GUT)

LOCATION: M3

Mediates higher cognitive functions, stimulates enteric nervous system (**CNS**)

FUNCTION: M1

↓ heart rate and contractility of atria (Heart)

FUNCTION: M2

↑ exocrine gland secretions, gut peristalsis, bladder contraction, bronchoconstriction, gut peristalsis, pupillary sphincter muscle contraction, ciliary muscle contraction, insulin release, endothelium-mediated vasodilation

FUNCTION: M3

ANS ganglia

LOCATION: Nn

Neuromuscular end plate

LOCATION: Nm

1. acetyl cholinesterase
2. butyl cholinesterase

OFF PAPER: form choline acetate

stimulatory

Botulinum toxin is (stimulatory/inhibitory)

botox for wrinking

Botulinum toxin (cosmetic use)

Botulinum toxin

This agent inhibits the release of Ach from presynaptic terminals

anaerobic

Tetanus is a ___ bacteria (in terms of oxygen)

*Clostridium tetani*

Tetanus causative agent

gram (+)

*Clostridium tetani* is a ____ bacteria

GABA, Glycine

Tetanus inhibits ___ and ___

irreversibly inhibit

Organophosphates ___ cholinesterase enzymes

muscarinic

Organophosphate poisoning (DUMBBELS) show ____ responses

atropine

DOC for Organophosphate poisoning

Alice in Wonderland

ATROPINE poisoning mnemonics

Physostigmine

DOC for ATROPINE poisoning

carbamate

Physostigmine is a ___

DUMBBELSS

Organophosphate Poisoning mnemonic

reverse of DUMBBELSS

ANTI-CHOLINERGIC symptoms

* Diarrhea
* Urination
* Miosis
* Bradycardia
* Bronchoconstriction
* Emesis
* Lacrimation
* Salivation
* Sweating

what does DUMBBELSS stand for?

* Stimulated saliva flow


* Miosis
* ↓ heart rate (bradycardia)
* Bronchoconstriction
* ↑ peristalsis and secretion
* ↑ bile release
* Bladder contraction (urination)

Parasympathetic effects

* secretions from salivary and sweat glands
* secretions and contractions of the gut

EFFECTS OF ACETYLCHOLINE: Stimulates ___ & Stimulates ___

airways of the respiratory tract

EFFECTS OF ACETYLCHOLINE: Constriction of ___

contraction of the heart and relaxes smooth muscle of blood vessels

EFFECTS OF ACETYLCHOLINE: Inhibits ___

1. Ammonium Group
2. Choline Moiety
3. Acetyl/Ester Group

STRUCTURE-ACTIVITY RELATIONSHIP categories

ester bridge

Choline Moiety aka “___”

Ammonium

\
___ Group is the least absorbable

Intrinsic Activity, Affinity

The Ammonium group is essential for ___ and contributes to the ___ of the molecule for the receptors, partially through the binding energy and partially because of its action as a detecting and directing group.

water solubility

ACETYLCHOLINE Quaternary ammonium group imparts ___

poorly

ACETYLCHOLINE Quaternary ammonium group \~ ___ absorbed across lipid membranes

Less active and not used clinically

MODIFICATION OF THE QUATERNARY AMMONIUM GROUP

* Replacement with As, P, S or Se

Results to a cholinergic antagonist

MODIFICATION OF THE QUATERNARY AMMONIUM GROUP

* Replacement by three ethyl groups (large)

Affords an active compound but much less so than acetylcholine

MODIFICATION OF THE QUATERNARY AMMONIUM GROUP

* Replacement by three ethyl groups (small)

Leads to successively diminishing muscarinic activity

MODIFICATION OF THE QUATERNARY AMMONIUM GROUP

* NH, NH2, or NH3

muscarinic activity

Shortening or lengthening the chain of atoms that separates the ester group from the onium moiety reduces ___

Alpha substitution

A/n ___ on the choline moiety decreases both nicotinic and muscarinic activity, but muscarinic activity is decreased to a greater extent.

Beta substitution

A/n ___ on the choline moiety decreases both nicotinic activity to a greater degree

nicotinic

MODIFICATION OF THE ETHYLENE BRIDGE

* beta (nicotinic/muscarinic)

muscarinic

MODIFICATION OF THE ETHYLENE BRIDGE

* alpha (nicotinic/muscarinic)

decreases activity

MODIFICATION OF THE ETHYLENE BRIDGE

* Increasing chain length ___

Acetyl-β-methylcholine (or methacholine)

MODIFICATION OF THE ETHYLENE BRIDGE

* Much greater muscarinic potency
* Methyl group on Carbon β affords ___

less active compounds

MODIFICATION OF THE ETHYLENE BRIDGE

* Replacement of hydrogen with alkyl groups larger than methyl leads to ___

Acetyl-α- methylcholine

MODIFICATION OF THE ETHYLENE BRIDGE

* Much greater nicotinic than muscarinic potency
* Methyl group on Carbon ALPHA affords ___

muscarinic receptor

The Ester group in ACh contributes to the binding of the compound to the ___

less potent

MODIFICATION OF THE ACETYL GROUP

* When acetyl group is replaced by higher homologs, resulting esters are ___ than acetylcholine

cholinergic antagonist activity

MODIFICATION OF THE ACETYL GROUP

* Choline esters of aromatic or higher molecular weight acids possess ___

Nitrogen atom

STRUCTURE ACTIVITY RELATIONSHIP FOR MUSCARINIC AGONIST ACTIVITY

* Molecule must possess a ___ capable of bearing a positive charge, preferably a quaternary ammonium salt

quaternary ammonium salt

STRUCTURE ACTIVITY RELATIONSHIP FOR MUSCARINIC AGONIST ACTIVITY

* Molecule must possess a Nitrogen atom capable of bearing a positive charge, preferably a ___

alkyl groups

STRUCTURE ACTIVITY RELATIONSHIP FOR MUSCARINIC AGONIST ACTIVITY

* For maximum potency, the size of the ___ substituted on the Nitrogen should not exceed the size of a methyl group

Nitrogen

STRUCTURE ACTIVITY RELATIONSHIP FOR MUSCARINIC AGONIST ACTIVITY

* For maximum potency, the size of the alkyl groups substituted on the ___ should not exceed the size of a methyl group

methyl group

STRUCTURE ACTIVITY RELATIONSHIP FOR MUSCARINIC AGONIST ACTIVITY

* For maximum potency, the size of the alkyl groups substituted on the Nitrogen should not exceed the size of a ___

oxygen

STRUCTURE ACTIVITY RELATIONSHIP FOR MUSCARINIC AGONIST ACTIVITY

* The molecule should have an ___ atom capable of participating in a hydrogen bond

ester-like oxygen

STRUCTURE ACTIVITY RELATIONSHIP FOR MUSCARINIC AGONIST ACTIVITY

* The molecule should have an oxygen atom, preferably an ___, capable of participating in a hydrogen bond

hydrogen bond

STRUCTURE ACTIVITY RELATIONSHIP FOR MUSCARINIC AGONIST ACTIVITY

* The molecule should have an oxygen atom, preferably an ester-like oxygen, capable of participating in a ___

2-carbon unit

STRUCTURE ACTIVITY RELATIONSHIP FOR MUSCARINIC AGONIST ACTIVITY

* There should be a ___ between the O2 and N2 atom

O2, N2

STRUCTURE ACTIVITY RELATIONSHIP FOR MUSCARINIC AGONIST ACTIVITY

* There should be a 2-carbon unit between the ___ and ___ atom

1. Direct-Acting
2. Indirect-Acting

CHOLINOMIMETICS types

immediately binds

MOA: Direct-Acting CHOLINOMIMETICS

* induces Ach release
* inhibits degradation of Ach

MOA: Indirect-Acting CHOLINOMIMETICS

Edrophonium

CHOLINOMIMETICS: Short-acting aka “___“

Carbamates

CHOLINOMIMETICS: Intermediate-acting aka “___“

Organophosphate

CHOLINOMIMETICS: Long-acting aka “___“

Bethanicol

DRUG: bowel/bladder for post-surgery

Edrophonium

DRUG: diagnose MG

Savin

DRUG: agent orange

Myasthenia Gravis

DISEASE: body produces antibody against nicotinic Ach receptors, hence destroying said receptors

nicotinic Ach receptors

Myasthenia Gravis --- body produces antibody against ___

small muscles (especially in the face)

In MG, ___ are first to be affected

drooping of eyelids

first symptoms for MG

none

TREATMENT for MG

carbamates

MG is managed by ___

Neostigmine, Pyridostigmine

Drugs for management of MG

Physostigmine

In hospital practice, ___ is reserved for atropine poisoning

1. Antimuscarinic
2. Antinicotinic

ANTICHOLINERGIC type/s

Non-selective

Antimuscarinic types

1. Ganglion Blockers
2. Neuromuscular Blockers

Antinicotinic types

Alice in Wonderland

ANTICHOLINERGIC mnemonic

* HOT as a hate
* DRY as a bone
* BLIND as a bat
* RED as a beat
* MAD as a hatter

What does Alice in Wonderland stand for?

Histidine

Histamine comes from the amino acid ___

histidine decarboxylase

The enzyme responsible for catalyzing histamine is ___

cofactor

The biosynthesis of Histamine uses ___

pyridoxal phosphate

The biosynthesis of Histamine uses the cofactor: ___

vitamin B6.

pyridoxal phosphate is the active form of ___

mast cells, basophils

Once produced, histamine is primarily stored in specialized cells called ___ and ___

Imidadozole ring

Histidine contains ___ (precursor)

H1, H2

HISTAMINE RECEPTORS

Allergic & Anaphylactic responses

PRINCIPLE: H1 receptor

Increased secretion of Acid & pepsin

PRINCIPLE: H2 receptor

Gq

GPCR: H1 receptor

Gs

GPCR: H2 receptor

Phospholipase

What enzyme is activated by Gq?