HISTAMINE

Histamine is formed from the amino acid histidine and is stored in high concentrations in mast cells.

Localisation lungs, skin, GIT

Excess production of histamine in the body it is released from mast cells in response to: IgE-mediated (immediate) allergic reactions, this autacoid plays an important pathophysiologic role in seasonal rhinitis (hay fever), urticaria, and angioneurotic edema. Drugs (tubocurarine, morfine etc.)

Histamine and serotonin receptor subtypes.1

ReceptorSubtype

Distribution PostreceptorMechanism

PrototypeAntagonist

H1 Smooth muscle IP3, DAG DiphenhydramineH2 Stomach, heart,

mast cells

cAMP Cimetidine

H3 Nerve endings,CNS

G protein-coupled Impromidine

5-HTfd Brain cAMP -5-HT2 Smooth muscle,

platelets

IP3, DAG Ketanserin

5-HT3 Area postrema(CNS), sensory

and enteric nerves

Gated cautionchannel

Ondansetron

1 Many other serotonin receptors are recognized in the CNS. They arediscussed in Chapter 20.

H1 receptor:

This receptor is important in smooth muscle effects, especially those caused by IgE-mediated responses. IP3 and DAG are released.

Bronchoconstriction and vasodilation, the latter by release of endothelium-derived relaxing factor (EDRF), are typical retracts, opening gaps in the permeability barrier and resulting in the formation of local edema.

These effect are manifest in allergic reactions and in mastocytosis, a rare neoplasm of mast cells.

H2 receptor:

This receptor mediates gastric acid secretion by parietal cells in the stomach. It also has a cardiac stimulant effect. A third action is to reduce histamine release from mast cells - a negative feedback effect.

These actions are mediated by activation of adenylyl cyclase, which increases intracellular cAMP.

H3 receptor:

This receptor appears to be involved mainly in presynaptic modulation of histaminergic neurotransmission in the central nervous system. In the periphery, it appears to be a presynaptic heteroreceptor with modulatory effects on the release of other transmitters.

Antihistaminika - H1

• sedative

difenhydramin

embramin

prometazin

cyproheptadin

bisulepin

dimetinden

azatadin

klemastin

• nonsedative

terfenadine

astemizol

cetirizin

loratidin

HISTAMINE H1 ANTAGONISTS

Diphenhydramine and chlorpheniramine may be considered prototypes.

H1 blockers are all active by the oral route. Most are metabolized extensively in the liver. Half-lives of the older H1 blockers vary from 4 to 12 hours.

Several newer agents (eg, terfenadine, astemizole) have half-lives of 12 to 24 hours and decreased CNS penetration.

Mechanism & Effects

H1 blockers are competitive antagonists at the H1 receptor.

Because their structure closely resembles that of muscarinic blockers and alpha adrenoceptor blockers, many of these agents are pharmacologic antagonists at these autonomic receptors. A few also block serotonin receptors. However, they have negligible effects at H2 receptors.

Many H1 blockers are potent local anesthetics.

Clinical Use:

In the periphery, they competitively inhibit the effects of histamine (especially if given before histamine release occurs). major applications in allergies of the immediate type (ie, those caused by antigens acting of IgE antibody-sensitized mast cells). These conditions include hay fever and urticardia.

The drugs have a broad spectrum of adverse effects that limit their usefulness but can sometimes be used to good effect (eg, the sedative effect is used in over-the-counter-sleep aids).

H1-blocking drugs have sedative and antimotion sickness effects in the CNS.

Toxicity: Sedation is common, especially with diphenhydramine and promethazine. It is much less common with newer agents that do not enter the CNS readily. Antimuscarinic effects (dry mouth, blurred vision etc.) -blocking actions may cause orthostatic hypotension.

Interaction Drugs with sedative effects, eg, benzodiazpeines and alcohol. Drug that inhibit hepatic metabolism (ketaconazole) may result in dangerously high levels of nonsedating antihistaminic drugs (e.g. terfenadine) the plasma concentration of either antihistamine may increase and precipitate lethal arrhythmias.

HISTAMINE H2 ANTAGONISTS

cimetidine is the prototype. (ranitidine, famotidine)

These drugs do not resemble H1 blockers structurally. They are orally active, with half-lives of 1-3 hours.

Because they are relatively nontoxic, they can be given in large doses, so that the duration of action of a single dose may be 13-24 hours.

Mechanism & Effects:

selective and have no significant blocking action at H1 or autonomic receptors.

The only therapeutic effect of clinical importance is the reduction of gastric acid secretion

Blockade of cardiovascular H2 receptor-mediated effects can be demonstrated, but has no clinical significance.

Clinical Use:

Acid-peptic disease, especially duodenal ulcer: Acute ulcer is usually treated with two more doses per day, recurrence of the ulcer can often be prevented with a single bedtime dose. H2 blockers are also effective in accelerating healing and prevneting recurrences of gastric peptic ulcers.

Zollinger-Ellison syndrom

Gastroesophageal reflux disease (GERD)

Toxicity

Cimetidine is a potent inhibitor of hepatic drug-metabolizing enzymes and may reduce hepatic blood flow. has significant antiandrogen effects in many patients.

Ranitidine has a weaker inhibitory effect on hepatic drug metabolism, neither it nor the newer H2 blockers appear to have endocrine effects.

SEROTONIN (5-HYDROXYTRYPTAMINE, 5-HT) & RELATED AGONISTS

Serotonin is produced from tryptophan and stored in the enterochromaffin cells of the gut and in the CNS.

Excess production in the body can be detected by measuring its major metabolite, 5-hydroxy-indoleacetic acid, in the urine.

Histamine and serotonin receptor subtypes.1

ReceptorSubtype

Distribution PostreceptorMechanism

PrototypeAntagonist

H1 Smooth muscle IP3, DAG DiphenhydramineH2 Stomach, heart,

mast cells

cAMP Cimetidine

H3 Nerve endings,CNS

G protein-coupled Impromidine

5-HTfd Brain cAMP -5-HT2 Smooth muscle,

platelets

IP3, DAG Ketanserin

5-HT3 Area postrema(CNS), sensory

and enteric nerves

Gated cautionchannel

Ondansetron

1 Many other serotonin receptors are recognized in the CNS. They arediscussed in Chapter 20.

Serotonin appeas to play a physiologic role as a neurotransmitter in both the CNS and the enteric nervous system, and possibly as a local hormone that modulates gastrointestinal activity. Serotonin is also stored (but synthesized to only a minimal extent) in platelets.

Only one drug is in use for its serotonin agonist effects; several are in use or under investigation as serotonin antagonist

5-HT1 receptors

5-HT1 receptors are most important in the brain and mediate synaptic inhibition via increased potassium conductance (Table 16-2).

Peripheral 5-HT1 receptors mediate both excitatory and inhibitory effects in various smooth muscle tissues.

5-HT2 receptors

5-HT2 receptors are important in both brain and peripheral tissues. These receptors mediate synaptic excitation in the CNS and smooth muscle contration (gut, bronchi, uterus, vessels) or dilation (vessels). The mechanism involves (in different tissues) decreased potassium conductance, decreased cAMP, and increased IP3.

In carcinoid tumor, this receptor probably mediates some of the vasodilation, diarrhea, and bronchoconstriction characteristic of the disease.

5-HT3 receptors

5-HT3 receptors are found in the CNS, especially in the chemoreceptive area and vomiting center, and in peripheral sensory and enteric nerves.

These receptors mediate excitation via a 5-HT-gated cation channel (ie, the mechanism of serotonin at the 5-HT3 receptor resembles that of Ach at nicotinic cholinergic cation channels).

Antagonists acting at this receptor have proved to be useful antiemetic drugs.

Clinical Use

Serotonin has no clinical applications. Other agonists:

Sumatriptan 5-HTld agonist. It is effective in the treatment of acute migraine and cluster headache attacks, an observation that strengthens the association of serotonin abnormalities with these headache syndromes.

At present it is available only for parenteral injection, unlike the ergot antimigraine medications, which are available for oral and rectal (suppository) use.

A number of important antidepressant drugs act at serotonergic synapses by inhibiting the reuptake carrier for 5-HT.

Serotonin antagonists

Ketanserin is 5-HT2 and alpha adrenoceptor blocker.

Phenoxybenzamine (an alpha adrenoceptor blocker) and cyproheptadine (an H1 blocker and antimuscarinic compound) are also good 5-HT2 blockers.

Ondansetron, dolasetron are a 5-HT3 blockers.

The ergot alkaloids are partial agonists at 5-HT (and other) receptors.

Clinical Uses

Ketanserin is under investigation as an AHT drug.

Ketanserin, cyproheptadine, and phenoxybenzamine may be of value (separately or in combination) in the treatment of carcinoid tumor, a neoplasm that secretes large amounts of serotonin (and peptides) and causes diarrhea, bronchoconstriction, and flushing.

Ondasetron is used to control postoperative vomiting and vomiting associated with cancer chemotherapy.

Toxicity

Adverse effects of ketanserin are those of alpha blockade and H1 blockade.

The toxicities of ondasetron include diarrhea and headache.