Pharmacology Chapter 7

Front 1

MECHANISM
Direct-Acting Cholinomimetic Agonists
Nicotinic Mechanism

Back 1

The nicotinic acetylcholine ACh receptor is located on a channel protein that is selective for sodium and potassium. When the receptor is activated, the channel opens and depolarization of the cell occurs as a direct result of the influx of sodium, causing an excitatory postsynaptic potential (EPSP). If large enough, the EPSP evokes a propagated action potential in the surrounding membrane. The nicotinic receptors on sympathetic and parasympathetic ganglion cells (NN, also denoted NG) differ slightly from those on neuromuscular end plates (NM).

Front 2

MECHANISM
Direct-Acting Cholinomimetic Agonists
Muscarinic Mechanism

Back 2

• One involves Gq-protein coupling of M1 and M3 muscarinic receptors to phospholipase C, a membrane-bound enzyme, leading to the release of the second messengers, diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (IP 3). DAG modulates the action of protein kinase C, an enzyme important in secretion, whereas IP3 evokes the release of calcium from intracellular storage sites, which results in contraction in smooth muscle.
• A second mechanism couples M2 muscarinic receptors to adenylyl cyclase through the inhibitory Gi-coupling protein.
• A third mechanism couples the same M2 receptors via the subunit of the G protein to potassium channels in the heart and elsewhere; muscarinic agonists facilitate opening of these channels. M4 and M5 receptors may be important in the central nervous system (CNS) but have not been shown to play major roles in peripheral organs.

Front 3

MECHANISM
Indirect-Acting Agonists
Carbamates

Back 3

Both carbamate and organophosphate inhibitors bind to cholinesterase and undergo prompt hydrolysis. The alcohol portion of the molecule is then released. The acidic portion (carbamate ion or phosphate ion) is released much more slowly, and this retained portion prevents the binding and hydrolysis of endogenous acetylcholine, thus amplifying acetylcholine effects wherever the transmitter is released.
After hydrolysis, the carbamate residue is released by cholinesterase over a period of 2–8 h.

Front 4

MECHANISM
Indirect-Acting Agonists
Organophosphates

Back 4

Both carbamate and Organophosphate inhibitors bind to cholinesterase and undergo prompt hydrolysis. The alcohol portion of the molecule is then released. The acidic portion (carbamate ion or phosphate ion) is released much more slowly, and this retained portion prevents the binding and hydrolysis of endogenous acetylcholine, thus amplifying acetylcholine effects wherever the transmitter is released.
Organophosphates are long-acting drugs; they form an extremely stable phosphate complex with the enzyme. After initial hydrolysis, the phosphoric acid residue is released over periods of days to weeks. Recovery is due in part to synthesis of new enzyme.

Front 5

MECHANISM
Indirect-Acting Agonists
edrophonium

Back 5

A third class has only one clinically useful member— edrophonium is an alcohol (not an ester) with a very short duration of action.