6. Histamine and Antihistaminic Agents

What is another word for local hormones?

Autacoids

Describe autacoids or local hormones and give some examples.

• Released locally

• Act at the site/near the site of their release

• Histamine, 5-HT/serotonin, bradykinin, eicosanoids

What is the function of histamine?

Important mediator of immediate allergic and inflammatory reactions

Where is histamine distributed and where is it stored?

• Distributed: in skin, GIT, mucosa, lungs, brain, CSF

• Stored:

  • Mast cells: skin, gastric and intestinal mucosa, lungs

  • Non-mast cell: brain, epidermis, gastric mucosa

How is histamine synthesized?

Locally from the amino acid histidine

How is histamine degraded?

Rapidly by oxidation and methylation

List the responses of histamine.

1. Allergic and inflammatory reactions

2. Gastric acid secretion

3. Neurotransmission in parts of brain

Histamine has no clinical applications, but agents that _______ the action of histamine (______________/histamine ________ _________) have important therapeutic applications.

inhibit

antihistamines

histamine receptor blockers

List the types of histamine receptors and what category of receptors they belong to.

• H₁, H₂, and H₃

• G-protein coupled receptors

H₁

What are the pharmacological effects of histamine on H₁ receptors in smooth muscle?

• Bronchial smooth muscles:

  • Contraction

  • Constriction of bronchioles

  • Results in symptoms of asthma

  • Decreased lung capacity

• Intestinal smooth muscles:

  • Contraction

  • Constriction results in intestinal cramps

• Uterus:

  • Contraction

H₁

What are the pharmacological effects of histamine on H₁ receptors on blood vessels?

Vasodilation

H₁

What are the pharmacological effects of histamine on H₁ receptors on the brain?

Neurotransmitter (involved in arousal and alertness)

H₁

What are the pharmacological effects of histamine on H₁ receptors on sensory nerve endings?

• Stimulation

• Causes itching and pain

H₁

What are the pharmacological effects of histamine on H₁ receptors on exocrine secretions?

Increased production of nasal and bronchial mucus, resulting in respiratory symptoms

H₂

What are the pharmacological effects of histamine on H₂ receptors on gastric glands/stomach?

Stimulation of gastric HCl secretion

H₂

What are the pharmacological effects of histamine on H₂ receptors on blood vessels?

Vasodilation

H₂

What are the pharmacological effects of histamine on H₂ receptors on the heart?

• Positive inotropy

• Positive chronotropy

H₃

What are the pharmacological effects of histamine on H₃ receptors on brain?

Pre-synaptically

H₁ and H₂

What are the pharmacological effects of histamine on H₁ and H₂ receptors on CVS?

• Vasodilation

• Positive chronotropism (H₂R)

• Positive inotropism (H₁ and H₂R)

H₁ and H₂

What are the pharmacological effects of histamine on H₁ and H₂ receptors on skin?

• Dilation

• Increased permeability of capillaries, that results in leakage of proteins and fluids into the tissues

Describe the histamine-triple response (HALO).

Histamine elicits triple response, consisting of:

1. Red spot: due to intense capillary dilatation

2. Wheal: due to exudation of fluid from capillaries

3. Flare: i.e. redness in the surrounding area due to arteriolar dilatation

What type of antihistamine drugs are used? Describe their mechanism.

• Histamine (H₁) antagonists/blockers

• Competitively antagonizes the actions of histamine at the H₁ receptors

Describe the antagonism of histamine of the histamine antagonists/blockers.

• Effectively block histamine induced bronchoconstriction, contraction of intestinal and other smooth muscles, and triple response (esp. wheal. flare, and itch)

• Fall in BP produced by low doses of histamine is blocked (additional H₂ antagonists required for complete blockage caused by higher doses)

List the classifications of antihistamine drugs.

1. First generation

2. Second generation

3. Third generation

List the classifications of first generation antihistamines.

1. Highly sedative

2. Moderately sedative

3. Mild sedative

List the highly sedative drugs in the first generation of antihistamines.

1. Diphenhydramine

2. Promethazine

List the moderately sedative drugs in the first generation of antihistamines.

1. Cinnarizine

2. Pheniramine

3. Cyproheptadine

List the mildly sedative drugs in the first generation of antihistamines.

1. Chlorpheniramine

2. Cyclizine

List the drugs in the second generation of antihistamines.

1. Cetrizine

2. Levocetrizine

3. Desloratidine

4. Terfinadine

5. Loratidine

6. Azelastine

List the drugs in the third generation of antihistamines.

1. Metabolite of terfenadine

2. Astemizole

3. Loratadine (development stage)

4. Norastemizole and descarboethoxy loratadine (metabolites of astemizole and loratadine)

5. Fexofenadine (the active metabolite of terfenadine)

Which generation of drugs show sedative effects?

In general, studies of the new generation of drugs show a weaker sedative effect when compared with the first-generation drugs. However, the second-generation drugs, often called non-sedating antihistamines, can also induce sedation (dose dependent)

List the antihistaminic actions on allergies/anti-allergy.

• Manifestations of immediate hypersensitivity (Type I reaction) are suppressed

• Urticaria, itching, and angioedema are well controlled

List the antihistaminic actions on the CNS.

Older antihistamines produce variable degrees of CNS depression, depending on drug’s

• ability to cross BBB

• affinity for central (compared to peripheral) H₁ receptors

List the antihistaminic actions on the anticholinergic action.

Antagonize muscarinic actions of ACh

List the antihistaminic actions on local anesthetics.

Membrane stabilizing property, but causes irritation

List the antihistaminic actions on the blood pressure.

Fall in BP on IV; not evident on oral administration

What are the clinical uses of antihistamines on allergic rhinitis?

Relieves rhinorrhea, sneezing, and itching of eyes and nasal mucosa

What are the clinical uses of antihistamines on common cold?

• Palliative (relieves symptoms)

• Dries out nasal mucosa

• Often combined w/nasal decongestant & analgesics

What are the clinical uses of promethazine and why?

• Pre-anesthetic sedation

• Prevention of nausea and vomiting

• Used for its anticholinergic and sedative properties

What are the clinical uses of promethazine and diphenhydramine and why?

• Motion sickness (mild)

• Morning sickness (Promethazine)

• Drug-induced vomiting (Promethazine)

• Post-operative vomiting (Promethazine)

• Radiation sickness (Promethazine)

• Prevent or diminish nausea and vomiting by both the chemoreceptor (CTZ) and vestibular pathways; effect due to blockage of central H₁ and M₁ muscarinic receptors

What are the clinical uses of cinnarizine and meclizine and why?

• Vertigo

• Cinnarizine has additional anticholinergic, anti-5-HT, sedative, and vasodilator properties

• Meclizine is useful for treatment of vertigo associated with vestibular disorders

Which antihistamines are used for cough and why?

1. Chlorpheniramine

2. Promethazine

3. Diphenhydramine

Provides relief by sedative and anticholinergic properties

Which antihistamine can give mild symptomatic relief in early cases of Parkinson’s disease?

Promethazine

_____________ or sedatives induce sedation/sleep, especially in children.

Somnifacients

List the advantages of first generation antihistamines.

1. Effective

2. Inexpensive

3. Widely used

List the disadvantages/adverse effects of first generation anti-histamines.

Tend to interact with other receptors = variety of unwanted adverse effects

(First 5 - frequent but mild)

1. Sedation

2. Diminished alertness and concentration

3. Motor-incoordination

4. Fatigue

5. Tendency to fall asleep (cautioned to not operate motor vehicles or machinery)

6. Dryness of mouth

7. Alternation in bowel movement

8. Urinary retention

9. Blurring of vision (due to anticholinergic effects)

List the advantages of the second generation of antihistamines.

1. Long acting

2. Do not cause sedation as they do not cross BBB as readily as 1st gen

3. Absence of CNS depressant property

4. Higher H₁ selectivity, do not block M₁ receptors, so no anticholinergic adverse effects

5. Additional anti-allergy mechanisms - some also inhibit late phase allergic reactions by acting on leukotrienes

6. Do not potentiate alcohol or benzodiazepine CNS depressant effects

List and describe the drug interactions of second generation antihistamines.

• Lethal ventricular arrythmias in many patients taking either early 2nd gen agents (terfenadine/astemazole) + antibiotics like ketaconazole or erythromycin (CYP3A4 inhibitors)

  • The antibiotics inhibit metabolism (CYP3A4) and increase conc. of antihistamines

  • Withdrawn from market due to ventricular tachycardia (Torsades de pointes) occurring w/higher doses or when co-administered with CYP3A4 inhibitors

• Grapefruit juice also increases terfenadine’s blood level by inhibiting CYP3A4

List the means of management of anaphylaxis and when they are used.

1. Adrenaline (I.M): primary treatment; may be repeated every 5-15 mins

2. Adjuncts: antihistamines; inhibit histamine that would produce bronchoconstriction, etc

3. Corticosteroids (prednisone): severe allergic case as is anti-inflammatory and immunosuppressant

4. Nebulized salbutamol and leukotriene inhibitors (montelukast)

Describe adrenaline, its actions, and why it is the drug of choice for anaphylaxis.

• Physiological antagonist of histamine

• Actions on smooth muscle - opposite of histamine

• Acts via β2 receptors on smooth muscle, causing cAMP-mediated relaxation

• Therefore, is drug of choice in systemic anaphylaxis + other conditions w/massive release of histamine

Adrenaline followed by a short course of _____________ is indicated for ____________ attending drug hypersensitivity.

glucocorticoids

bronchospasm

Which drug type are the only effective drugs in type II, III, and IV reactions?

Glucocorticoids