Histamine and Antihistamines Histamine and Antihistamines

A. Histamine Synthesis

TypeLocationFunction

H1 histamine receptor

Found on: • Smooth muscle• Endothelium• CNS tissue

Causes: vasodilationBronchoconstrictionbronchial smooth muscle contraction separation of endothelial cells (responsible for hives), and pain and itching due to insect stings;

the primary receptors involved in allergic rhinitis symptoms and motion sickness;

sleep regulation.

H2 histamine receptor

Located on parietal cells

Primarily stimulate gastric acid secretion

H3 histamine receptor

Found on central nervous system and to a lesser extent peripheral nervous system tissue

Decreased neurotransmitter release: histamine, acetylcholine, norepinephrine, serotonin

H4 histamine receptor

Found primarily in the basophils and in the bone marrow. It is also found on thymus, small intestine, spleen, and colon.

Plays a role in chemotaxis.

B. Release of histamine can occur by two processes:

1. Energy- and Ca2+-dependent degranulation reaction. The release of histamine from mast cells is induced by:

A. immunoglobulin E (IgE) fixation to mast cells (sensitization) and subsequent exposure to a specific antigen;

B. complement activation (mediated by immunoglobulin G or immunoglobulin M) may also induce degranulation.

2. Energy- and Ca2+-independent release (displacement).

• Displacement is induced by:

A. drugs such as morphine, tubocurarine, guanethidine, and amine antibiotics.

B. mast cell damage, which is caused by noxious agents such as venom or by mechanical trauma, can release histamine.

Mechanism of action

A. Histamine (H1)-receptors – H1-receptors are found in the brain, heart,

bronchi, gastrointestinal tract, vascular smooth muscles, and leukocytes.

– H1-receptors are membrane bound and coupled to G-proteins, specifically Gq/11, and their activation causes:

– increase in phospholipase A2 and D activity – increases in diacylglycerol and intracellular Ca2+– increased cyclic guanosine 5′-monophosphate (cGMP)

– Activation of H1-receptors in the brain increases wakefulness.

– Activation of H1-receptors in vessels causes vasodilation and an increase in permeability.

– Activation of H1-receptors typically stimulates nonvascular smooth muscle.

B. Histamine (H2)-receptors 1. H2-receptors are membrane bound; they are

found in the brain, heart, vascular smooth muscles, leukocytes, and parietal cells.

2. The response of H2-receptors is coupled via Gαs to increased cyclic AMP (cAMP) production.

3. Activation of H2-receptors: • increases gastric acid production• causes vasodilation • generally relaxes smooth muscles.

C. Histamine (H3)-receptors 1. H3-receptors are found in the central nervous

system (CNS) and peripheral nervous system (PNS) at presynaptic nerve terminals.

2. H3-receptors are membrane bound and coupled to Gi/o; their activation increases intracellular Ca2+ and decreases cAMP.

3. Stimulation of H3-receptors – on nerve cells causes a decrease in

histamine release – in the CNS, stimulation of H3 modulates the

release of dopamine, acetylcholine, serotonin, and norepinephrine.

– Activation of H3-receptors on the vagus nerve decreases acetylcholine (ACh) release.

D. Histamine (H4)-receptors

1. H4-receptors are found on hematopoietic cells and in the spleen, thymus, and colon.

2. Stimulation of H4 receptors increases chemotaxis of mast cells and leukocytes cells toward sites of inflammation.

3. H4 receptors are coupled to Gi/Go and thereby inhibit the production of cAMP and increase intracellular Ca2+

Histamine agonists

• Histamine, betazole, and impromidine.

– Betazole has approximately tenfold greater activity at H2-receptors than at H1-receptors.

– Impromidine is an investigational agent; its ratio of H2 to H1 activity is about 10,000.

– Methimepip is an H3-specific agonist.

• The uses of histamine agonists are primarily diagnostic.

• These agents are used: 1. in allergy testing to assess histamine sensitivity 2. in the test of gastric secretory function

• The adverse effects of these agents can be quite severe; they include:

• flushing • a burning sensation • hypotension • tachycardia• bronchoconstriction.

Clinical Uses of Antihistamines

• Allergic rhinitis (common cold)• Allergic conjunctivitis (pink eye)• Allergic dermatological conditions• Urticaria (hives)• Angioedema (swelling of the skin)• Puritus (atopic dermatitis, insect bites)• Anaphylactic reactions (severe allergies)• Nausea and vomiting (first generation H1-

antihistamines)• Sedation (first generation H1-antihistamines)

Histamine (H1)-receptor antagonistsHistamine (H1)-receptor antagonists

• Competitive inhibitors.

• Classification:

1. First-generation agents 2. Second-generation agents

First-generation agents

• Groups:1. Alkylamines2. Ethanolamines3. Ethylenediamines4. Piperazines5. Tricyclics

First-generation agents

1.Alkylamines – Alkylamines include – Chlorpheniramine – Brompheniramine

– These agents produce slight sedation.

2. Ethanolamines – Include – diphenhydramine – doxylamine – clemastine – dimenhydrinate (combination of diphenhydramine and 8-

chlorotheophylline)– Ethanolamines produce marked sedation; – doxylamine is marketed only as a sleeping

aid.– Ethanolamines also act as antiemetics.

3. Ethylenediamines

–Include: –pyrilamine and antazoline.

–Ethylenediamines produce moderate sedation and can cause gastrointestinal upset.

4. Piperazines – include meclizine and cyclizine.– Piperazines produce marked adverse

gastrointestinal effects and moderate sedation.

– These agents have A.antiemetic B.antivertigo activities.

5. Phenothiazines – include promethazine.– Phenothazines produce marked sedation.– These agents have antiemetic activity.– Phenothiazines are also weak α-

adrenoceptor antagonists.

6. Methylpiperidines – include cyproheptadine.– have antihistamine, anticholinergic, and

antiserotonin activities.

2.2. Second-generation agentsSecond-generation agents

2.2. PiperidinesPiperidines Loratadine [Claritin] Loratadine [Claritin] Desloratadine [Clarinex] Desloratadine [Clarinex] – Poor CNS penetration: reduced sedation – Little or no anticholinergic activity– Desloratadine:Desloratadine:

• is the active metabolite of loratadine• has about 15-fold greater affinity for the H1

receptor than the parent compound

FexophenadineFexophenadine – is structurally different than the other

piperidine antihistamines, – sedative activity is low but dose dependent.

2.2. ClemastineClemastine • is a second-generation ethanolamine• longer duration of action than

dimenhydramine • it has some antiemetic activity.

3.3. Alkylamines: Alkylamines: A.A. acrivastine.acrivastine.

• Acrivastine is not associated with cardiac effects.

B.B. Cetirizine [Zyrtec]Cetirizine [Zyrtec] – Cetirizine is not associated with cardiac

abnormalities.– Cetirizine has poor penetration into the

CNS.– Cetirizine is less sedating; – it is ineffective for motion sickness or

antiemesis.

Pharmacologic propertiesof Histamine (H1)-receptor antagonists

• well absorbed after oral administration.

1st generation

2nd generation

Onset30 min30 min

Duration3-8 hrs3-24 hours

• H1-receptor antagonists are lipid soluble; most first-generation agents cross the blood— brain barrier.

• H1-receptor antagonists are metabolized in the liver;

• many induce microsomal enzymes and alter their own metabolism and that of other drugs.

Pharmacologic Actions

• Many H1-receptor antagonists, especially the ethanolamines, phenothiazines, and ethylenediamines, have muscarinic—cholinergic antagonist activity.

• Most of these agents are effective local anesthetics, probably because of a blockade of sodium channels in excitable tissues.

• Dimenhydrinate and promethazine are potent local anesthetics.

• H1-receptor antagonists relax histamine-induced contraction of bronchial smooth muscle and have some use in allergic bronchospasm.

• These agents block the vasodilator action of histamine.

• H1-receptor antagonists inhibit histamine-induced increases in capillary permeability.

• These agents block mucus secretion and sensory nerve stimulation.

• H1-receptor antagonists, especially the first-generation agents, frequently cause CNS depression (marked by sedation, decreased alertness, and decreased appetite).

• In children and some adults, these agents stimulate the CNS.

Therapeutic Uses

1. Treatment of allergic rhinitis and conjunctivitis.

• Clemastine is approved for the treatment of rhinorrhea. • Many antihistamines are used to treat the common cold,

based on their anticholinergic properties, but they are only marginally effective for this use.

• Diphenhydramine also has an antitussive effect not mediated by H1-receptor antagonism.

2. Treatment of urticaria and atopic dermatitis, including hives

3. Sedatives. Several (doxylamine, diphenhydramine) are marketed as over-the-counter (OTC) sleep aids.

4. Prevention of motion sickness

5. Appetite suppressants

Adverse effects

• (significantly reduced with second-generation agents)• Sedation, dizziness, and loss of appetite.• These agents can cause gastrointestinal upset, nausea,

and constipation or diarrhea.• H1-receptor antagonists produce anticholinergic effects

(dry mouth, blurred vision, and urine retention).

• Two second-generation H1 antagonists, astemizole and terfenadine (a prodrug of fexofenadine) were discontinued or removed from the market because they were associated with Q-T prolongation and ventricular tachycardias.

Histamine (H2)-receptor antagonistsHistamine (H2)-receptor antagonists

• CimetidineCimetidine [Tagamet] • RanitidineRanitidine [Zantac] • FamotidineFamotidine [Pepcid AC]• NizatidineNizatidine [Axid]

Competitive antagonists at the H2-receptor, which predominates in the gastric parietal cell.

• Used in the treatment of: Used in the treatment of:

1. Gastrointestinal disorders, including heartburn and acid-induced indigestion.

2. These agents promote the healing of gastric and duodenal ulcers.

3. Used to treat hypersecretory states such as Zollinger-Ellison syndrome.

Pharmacokinetics Pharmacokinetics

• The bioavailability of H2-antagonists goes from 50% for ranitidine and famotidine to approximately 90% for nizatidine and advised dosages take this into account.

• They are taken especially in the evening to reduce night gastric acidity.

• Their elimination is primarily renal. • Cimetidine inhibits cytochrome P-450 and

increases the concentrations and the effects of many other drugs.

Adverse effects

• H2 antagonists are generally well-tolerated, except for cimetidine where all of the following adverse drug reactions (ADRs) are common.

• Infrequent ADRs include hypotension. • Rare ADRs include: headache, tiredness, dizziness,

confusion, diarrhea, constipation, and rash.

• Additionally, cimetidine may also cause gynecomastia in males, loss of libido, and impotence, which are reversible upon discontinuation.

The chromones:The chromones:

• CromolynCromolyn [Intal] • Nedocromil sodiumNedocromil sodium [Tilade]

• These are administered by inhalation.

• They inhibit the release of histamine and other autocoids from the mast cell.

• Each is used prophylactically in the treatment of asthma

• they do not reverse bronchospasm.

• Adverse effects: Adverse effects: – confined to the site of application– Include:

–sore throat –dry mouth.

• Nedocromil sodium Nedocromil sodium – more effective in reducing bronchospasm

caused by exercise or cold air.