Serotonin or 5-hydroxytryptamine (5-HT)

It is a neurotransmitter, widely distributed in the CNS, beginning in the midbrain and projecting into thalamus, hypothalamus, cerebral cortex, and spinal cord. CNS serotonin is usually an inhibitory neurotransmitter and is associated with mood, the sleep-wake cycle.

Serotonin is thought to produce sleep by inhibiting CNS activity. 

In the blood, 5-HT is present in high concentration in platelets (regulator of platelets function) and also high concentration in intestine

Pharmacological effects:

Smooth muscles. 5-HT stimulates the G.I smooth muscle; it increases the peristaltic movement of intestine.
Serotonin contracts the smooth muscle of bronchi; 

Blood vessels. If serotonin is injected i.v, the blood pressure usually first rises, because of the contraction of large vessels and then falls because of arteriolar dilatation. Serotonin causes aggregation of platelets. 

Specific agonists

- Sumatriptan a selective 5-HT1D used in treatment of acute migraine.
- Buspirone a selective 5-HT1A used in anxiety.
- Ergotamine is a partial agonist used in migraine. It acts on 5-HT1A receptor.

Nonspecific 5-HT receptor agonist

o Dexfenfluramine used as appetite suppressant.

Specific antagonists

o Spiperone (acts on 1A receptor) and
o Methiothepin (acts on 1A, 1B, 1D receptors)

Agonist, Antagonist, and Partial Agonists

Agonists:  molecules that activate receptors.  A drug that mimics the body's own regulatory processes.
Antagonists:  produce their effects by preventing receptors activation by endogenous regulatory molecules and drugs.  Block activation of receptors by agonists.
Noncompetive Antagonist:  Bind irreversibly to receptors, and reduce the maximal response that an agonist can elicit.
Competitive Antagonist:  Bind reversibly to receptors, competing with agonists for binding sites.
Partial Agonists:  Have moderate intrinsic activity, the maximal effect that a partial agonist can produce is lower than that of a full agonist.  Act as antagonists as well as agonists.
 

Drug-Receptor Interactions

Drug Receptor:  any functional macromolecule in a cell to which a drug binds to produce its effects.  at receptors, drugs mimic or block the action of the body's own regulatory molecules.  

Receptors and Selectivity of Drug Action : If a drug interacts with only one kind of receptor, and if that receptor regulates just a few processes, then the effects of the drug will be limited.

Even though a drug is selective for one type of receptor, it can still produce a variety of effects.

Selectivity does not guarantee safety.

Theories of Drug-Receptor Interaction

- Simple Occupancy Theory:  Two factors - The intensity of the response to a drug is proportional to the number of receptors occupied by that drug, and the maximal response will occur when all available receptors have been occupied.

- Modified Occupancy Theory:  Assumes that all drugs acting at a particular receptor are identical with respect to the ability to bind to the receptor and the ability to influence receptor function once binding has taken place.

•    Affinity:  The strength of the attraction between a drug and its receptor.  Affinity is reflected in potency.  (Drugs with high affinity are very potent).

•    Intrinsic Activity:  The ability of a drug to activate a receptor following binding.  Reflected in the maximal efficacy (drugs with high intrinsic activity have high maximal efficacy).

CENTRAL NERVOUS SYSTEM PHARMACOLOGY

Antipsychotic Drugs

1. Phenothiazines

a. Aliphatic derivatives
(1) Chlorpromaxine
b. Piperidine derivatives
(1) Thioridazine
(2) Mesoridazine
c. Piperazine derivatives
(1) Fluphenazine
(2) Perphenazine
(3) Prochlorperazine
(4) Trifluoperazine

2. Haloperidol resembles the piperazine phenothiazines.

3. Thiothixene resembles the piperazine phenothiazines.

4. Others (e.g., loxapine, pimozide).

5. Newer and more atypical antipsychotic drugs:
a. Clozapine
b. Olanzapine
c. Quetiapine
d. Risperidone
e. Ziprasidone
f. Aripiprazole

Antidepressant Drugs

Drug treatment of depression is based on increasing serotonin (5-HT) or NE (or both) at synapses in selective tracts in the brain. This can be accomplished by different mechanisms.

Treatment takes several weeks to reach full clinical efficacy.

1. Tricyclic antidepressants (TCAs)
a. Amitriptyline
b. Desipramine
c. Doxepin
d. Imipramine
e. Protriptyline

2. Selective serotonin reuptake inhibitors (SSRIs)
a. Fluoxetine
b. Paroxetine
c. Sertraline
d. Fluvoxamine
e. Citalopram

3. Monoamine oxidase inhibitors (MAOIs)
a. Tranylcypromine
b. Phenelzine

4. Miscellaneous antidepressants

a. Bupropion
b. Maprotiline
c. Mirtazapine
d. Trazodone
e. St. John’s Wort

Antimania Drugs

These drugs are used to treat manic-depressive illness.

A. Drugs
1. Lithium
2. Carbamazepine
3. Valproic acid

Sedative Hypnotics

1. Benzodiazepines
2. Barbiturates
3. Zolpidem and zaleplon
4. Chloral hydrate
5. Buspirone
6. Other sedatives (e.g., mephenesin, meprobamate, methocarbamol, carisoprodol, cyclobenzaprine)
7. Baclofen
8. Antihistamines (e.g., diphenhydramine)
9. Ethyl alcohol

Antiepileptic Drugs

Phenytoin
Carbamazepine
Phenobarbital
Primidone
Gabapentin
Valproic acid
Ethosuximide

Anti-Parkinson Drugs

a. L-dopa plus carbidopa (Sinemet).
b. Bromocriptine, pergolide, pramipexole, ropinirole.
c. Benztropine, trihexyphenidyl, biperiden, procyclidine.
d. Diphenhydramine.
e. Amantadine.
f. Tolcapone and entacapone.
g. Selegiline.
 

Pramlintide -Amylin mimetics

Mechanism
synthetic analogue of human amylin that acts in conjunction with insulin
↓ release of glucagon
delays gastric emptying

Clinical use

type I and II DM

Propofol -Intravenous Anesthetics

- A nonbarbiturate anesthetic
- It is very lipid-soluble, acts rapidly and has a short recovery time.
- It is associated with less nausea and vomiting than some of the other IV anesthetics.
- Propofol is very similar to thiopental in its effects on the cardiorespiratory system.
- It does not have any analgesic properties but lowers the dose of opioid needed when the two agents are used in combination.

- The most significant adverse cardiovascular effect associated with propofol administration is hypotension. It should be used with caution in patients with cardiac disease.