Histamine & Antihistamines

What is an allergy?
Allergy = An abnormally high sensitivity to certain substances, such as pollens, foods, or microorganisms.
Common indications of mild allergy may include sneezing, itching, and skin rashes.
A severe allergic reaction is known as an anaphylactic shock which can be life-threatening (airway
constriction & extreme hypotension. Immediate medical attention needs to be administered.
What causes an allergy?

People with allergies have immune systems that overreacts when exposed to substances.

These substances (ex. Pollen) cause the body to respond with release of Histamine which is
main proponent of allergic reactions in individuals.

Histamine

Discovered in 1911 by Sir Henry Dale, identified as a potent vasoactive substance in guinea pigs
and dogs through experiments.

Soon recognized to be major mediator of allergic reactions such as rhinitis, asthma, urticaria (hives),
pruritis (itching) and

Histamine stored in special granules, and to exert its action, must be released.
Mast Cells Tissue

Basophils Blood

Histamine Formation

Synthesized in mammalian tissues by decarboxylation of the amino acid l-histidine

Conditions That Release Histamine

Histamine released from: Tissue injury, allergic reactions, drugs (antibiotics, toxins)

Histamine once released interacts with specific receptors on the cell surface.

There 4 histamine receptors found on cells:

H1 Receptor: Endothelial and smooth muscle cells, adrenal medulla, brain; histamine increases Ca2+
intake leading to vasodilation, increased vascular permeability, and contraction of nonvascular smooth
muscle. H1 receptor is the target of Antihistamines
H2 Receptor: Gastric mucosa cells; histamine induces gastric acid released.
A form of antihistamine drugs bind to H2 receptors to treat for GERD (ex. Nexium, Prevacid)
H3 Receptor: CNS neurotransmitter properties as a neural pre-synaptic receptor; may somehow regulate
histamine release.
H4 Receptor: Found in immune active cells and involved in their chemotaxis.

Pharmacological Effects of Histamine

Pharmacological Effects
Exocrine Glands:
Gastric glands
Salivary glands
Sweat glands Secretion
Pancreas
Bronchial glands
Lacrimal glands

Secretion

Effects on the arterioles, capillaries & Venules:

Vasodilatation
Increased Permeability- edema
Systemic hypotension
Effects on the vascular smooth muscles:

Bronchial tree
Gastrointestinal tract
Uterus

Contraction

Antihistamine: Mechanism of Action

BLOCK action of histamine at the receptor sites

Compete
with
histamine
for
binding
at
unoccupied
If histamine is already bound, antihistamines cannot remove histamine.

The binding of H1 blockers to the histamine receptors prevents the adverse consequences of
histamine stimulation:

receptors.

Vasodilatation

Increased gastrointestinal and respiratory secretions

Increased capillary permeability

Absorbed well by GI tract (effective orally) with a maximum absorption 1-2 Hr

and a high safety margin.

The binding of H1 blockers to the histamine receptors prevents the adverse consequences of
histamine stimulation:

Vasodilatation

Increased gastrointestinal and respiratory secretions

Increased capillary permeability

Absorbed well by GI tract (effective orally) with a maximum absorption 1-2 Hr

and a high safety margin.

Histamine vs. Antihistamine

Cardiovascular (small blood vessels)

Histamine effects:

Dilation

Increased
(allowing substances to leak into tissues)

(Histamine Decreases Blood Pressure)

permeability

Antihistamine effects:

Prevent dilation of blood vessels

Prevent increased permeability

Immune System

Histamine effects:

Mast cells release histamine and other substances, resulting in allergic reaction.

Antihistamine effects:

Bind to histamine receptors, preventing histamine from causing the allergic response.

Smooth Muscle

Histamine effects:

Stimulate salivary, gastric and bronchial secretions.

Antihistamine effects:

Prevent salivary, gastric and bronchial secretions.

Antihistamines effects

Skin:

Block capillary permeability

itching
5

Anticholinergic:

Drying effect that reduces nasal, salivary, and lacrimal gland secretions (runny nose, tearing, and itching
eyes)

Sedative:

Some antihistamines cause drowsiness (1st generation antihistamines)

Medical uses for Antihistamines

Management of: Seasonal allergic rhinitis (Hay fever)

Nasal allergies

Allergic reactions to food, microbes, dust, etc.

Motion sickness

Sinus congestions

Sleep disorders

Therapeutic Uses of H1 Blockers

ACTIONS NOT CAUSED BY H1 RECEPTOR BOLCKADE

1. antinausea and antiemetic effects (antimuscarinic effects)

2. antiparkinsonism effects (antimuscarinic effects)

3. peripheral antimuscarinic effects

4. adrenoceptor-blocking actions (phenothiazines)

5. manifested as orthostatic hypotension

6. serotonin-blocking action (cyproheptadine)

7. local anesthesia, blockade of sodium channels

(diphenhydramine and promethazine)

Drug Interactions of H1 Blockers

1st Generation

Older drugs

Work both peripherally and centrally

Have anticholinergic effects, and in some cases more effective than nonsedating agents

Examples:

diphenhydramine (Benadryl),
chlorpheniramine (Chlor-Trimeton

1st Generation Side Effects

CNS depression and anti-cholinergic effects that lead to:

Drowsiness

Appetite loss.

nausea and vomiting.

constipation or diarrhea.

Insomnia

Tachycardia

dry mouth

blurred vision

Urinary retention

Secreted in breast milk and can cross the placenta.

2nd Generation

Non-sedating antihistamines

Developed to eliminate side effects, (sedation)

Bulky and not as lipophilic and thus does not readily cross BBB, fewer CNS side effects

Longer duration of action (increases compliance)

Better specificity for H1 and/or H2 receptor to block histamines effects

Examples:

fexofenadine(Allegra)
loratadine (Claritin)

H2 Antagonist Pharmacological Effects

1. Competitive antagonists at the H2 receptors

2. Inhibits secretory function of gastric mucosa.
3. Few other effects than those on gastric secretion.
4. reduces volume of gastric acid and concentration of pepsin

Most Common Adverse Effects

diarrhea, dizziness, somnolence, headache, and rash. Also constipation, vomiting, and arthralgia

OTC Available H2 Antagonists

1) cimetidine (Tagamet) associated with most side-effects

2) rantidine (Zantac)
3) famotidine (Pepcid)
4 nizatidine (Axid)

H2 Antagonist Therapeutic Uses

Due its effecacy in decrease HCL secretion:

1. Duodenal ulcer
2. Gastric Ulcer
3. Zollinger-Ellison syndrome (a pathological hyper-secretory state resulting in excessive gastric pepsin &
HCl)
4. Gastro-esophageal reflux disease
5. Used prior to surgery in patients with GI obstruction to elevate gastric pH
6. Reflux esophagitis
7. Antacid
Toxic reactions
(Usually associated with cimetidine or tagamet)

1. Most common (seen in only 1-2% of patients): diarrhea, dizziness, somnolence, headache, and
rash. Also constipation, vomiting and arthralgia.

2. CNS effects: slurred speech, delirium, confusion. Most commonly seen in older patients or
those with liver or kidney impairment

3. Endocrine function (minor and reversible): antiandrogen effects, e.g., loss of libido, impotence,
reduced sperm count

4. Blood dyscrasias.

5. Liver: reversible cholestasis.

H2 Antagonist Drug Interaction

Cimetidine: increased activity of drugs that are metabolized through cytochrome P450 pathway
and also reduces blood flow through the liver including. e.g., warfarin, phenytoin, propanolol,
metoprolol, quinidine, caffeine, lidocaine, theophylline, benzodiazepines, ethanol, tricyclic
antidepressants, and calcium channel blockers.

All H2 blockers except famotidine (Pepcid) increase thebioavailability of ethanol.

Agents that inhibit gastric secretion alter the bioavailability

and rate of absorption of many other drugs

Histamine Release Inhibitors:

Therapeutic Uses

mild to moderate bronchial asthma to prevent asthma attacks.

effective in children
reduces need of steroid or bronchodilators
ineffective for an acute attack
becomes effective over time (e.g. 2-3 weeks)
allergic rhinitis
atopic diseases of the eye
giant papillary conjunctivitis

Histamine Release Inhibitors:

Dosage forms

aerosol powder (Intal) and solution - asthma

nasal spray (Nasalcrom) - allergic rhinitis

optic solution 4% - (Opticrom) - allergic

conjunctivitis

Toxicity
well tolerated, few adverse reactions irritation due to powder inhalation
Stinging, Burning, Bad Taste
Coughing, sneezing, allergic reactions
10