Termination of action

At a central synapse, the termination of action of a peptide relies on these peptidases. Thus, if there is considerable release at any one time, the peptide may saturate the enzyme(s) and so metabolism will not keep pace with release. 

Five key features of neurotransmitter function provide potential targets for pharmacologic therapy synthesis, storage, release, and termination of action of the transmitter, and receptor effects. These processes are discussed here in detail. 

Physiological note. The termination of action of noradrenaline released at nerve endings is by ... 

Termination of NE actions is mainly due to removal from the neuroeffector junction back into the sympathetic nerve ending via a NE transporter system (uptake 1) (4). At some sympathetic nerve endings, the NE released may activate prejunctional alpha adrenoceptors (5) involved in feedback regulation, which results in decreased release of the neurotransmitter. Diffusion away from the neuroeffector junction may also contribute to termination of actions. NE accumulated into target cells (e.g., via uptake 2) is rapidly inactivated by catechol-O-rnethykransferase (COMT). 

In summary, unlike with cholinergic neurons, where termination of action is rapidly accomplished by a single efficient process, hydrolysis of the neurotransmitter by AChE, in the case of catecholamines, a multiple of processes occur simultaneously. A major intraneural reuptake process, a dilution effect by diffusion away from the synaptic cleft, which includes uptake (U2) into extraneural tissue, oxidative deamination by MAO and m-methylation of the catechol moiety by COMT. 

Destruction or dissipation of the transmitter and termination of action. To sustain high frequency transmission and regulation of function, the synaptic dwell-time of the primary neurotransmitter must be relatively short. At cholinergic synapses involved in rapid neurotransmission, high and locahzed concentrations of acetylcholinesterase (AChE) are localized to hydrolyze ACh. When AChE is inhibited, removal of the transmitter occurs principally by diffusion, and the effects of ACh are potentiated and prolonged (see Chapter 8). 

TERMINATION OF THE ACTIONS OF CATECHOLAMINES The actions of NE and Epi are terminated by (1) reuptake into nerve terminals by NET (2) dilution by diffusion out of the junctional cleft and uptake at end organs and extraneuronal sites by ENT, OCTl, and OCT2. Subsequent to uptake, the catecholamines are subject to metabolic transformation by MAO and catechol-0-methyltransferase (COMT). In addition, catecholamines are metabolized by sulfotransferases (see Chapter 3). Termination of action by a powerful degradative enzymatic pathway, such as that provided by AChE in cholinergic transmission, is absent from the adrenergic system. Inhibitors of neuronal reuptake of catecholamines (e.g., cocaine, imipramine) potentiate the effects of the... 

GI absorption of chlorpromazine is modified unpredictably by food and probably is decreased by antacids. Antipsychotic agents bind significantly to membranes and to plasma proteins. Elimination kinetics can be multiphasic and variable with dose, and termination of action may rely on clearance of both active metabolites and the parent compound. Approximate elimination half-lives of clinically employed antipsychotic agents are provided in Table 18-2 see also Appendix II, Pharmacokinetic Data in the 11th edition of the parent text. 

Figure 6-2. Characteristics of transmitter synthesis, storage, release, and termination of action at cholinergic and noradrenergic nerve terminals are shown from the top downward. Circles represent transporters ACh. acetylcholine AChE. acetylcholinesterase ChAT, choline acetate transferase DOPA, dihydroxyphenylalanine NE, norepinephrine TCA, tricyclic antidepressant TH, tyrosine hydroxylase.

The time span from the beginning of the onset of action up to the termination of action. 

In Fig. 1.4, please note the differences in the onset of action, termination of action and the duration of action as a consequence of the differences in the absorption characteristics of a dmg owing to formulation differences. One may observe similar differences in the absorption characteristics of a dmg when it is administered via different dosage forms or different extravascular routes. 

Nerve agents phosphonylate serine Ser203 at the este-ratic part of the active site of enzyme AChE (EC 3.1.1.7). AChE plays a key role in the termination of action of a neurotransmitter acetylcholine (ACh) in the peripheral nervous system and central nervous system, and persistent inhibition of AChE can lead to life-threatening consequences (Marrs, 1993). 

---