2011 06 Pharmacology Anti Allergy Drugs

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HISTAMINE

y Primary mediator of allergic reactions

Drugs that are commonly used for allergic

reactions (antihistamines) are intended to

block the effects of histamine

y Formed by decarboxylation of histidine by L-

histidine decarboxylase

y It is in the mast cell if it is stored in the tissues,

but it is stored in the basophils if it is in the

blood y Other non-mast cell sites include the

epidermis, gastric mucosa, neurons within the

CNS and regenerating or rapidly growing

tissues; these areas also contain some mast

cells

y Before histamine is released from the mast cell

to have manifested an allergic reaction, it has

to have a sensitizing exposure.

Once exposed to the allergen, the body

will produce antibodies against that

allergen for the next exposure Reaction occurs on second exposure:

when allergen is re-introduce to the body,

the antigen-antibody complex is now

formed which attaches itself to the mast

cell, then a series of processes occurs,

leading to degranulation of that mast cell

to release mediators.

y Produces an effect by interacting with

histaminergic receptors.

Histaminergic Receptors G-protein coupled

receptors

y H1 coupled to GS; the phosphoinositol

pathway is involved; peripheral nerve ending,

bronchial and intestinal smooth muscles, small

blood vessels

y H2 linked to the cyclic AMP system that will

release cyclic AMP as second messenger;

primarily in gastric parietal cells

y H3 presynaptic autoreceptors in neurons that

mediate feedback inhibition of the release and

synthesis of histamine

y H4 similar to H3, expressed in cells of the hematopoietic lineage

Type Major Tissue

Locations

Major Biologic

Effects

H1

Bronchial &

intestinal smooth

muscles,

Acute allergic

responses

endothelial cells,

CNS, peripheral

nerve endings

H2 Gastric parietal

cells, heart, CNS

Secretion of gastric

acid

H3 CNS: presynaptic

neuron

Modulates

neurotransmission --

mediates feedback mechanism

H4 Hematopoietic

cells

Regulates immune

responses

HistamineEffects:

1. CVS

a. Dilatation of resistance vessels (arterioles) o H1 and H2 receptors distributed

throughout the resistance vessels in

most vascular beds

o H1 (rapid in onset and short-lived), H2 (slow but more sustained)

b. Decrease systemic blood pressure

c. Increase capillary permeability

o Effect on postcapillaryvenules o Outward passage of plasma protein

and fluid edema formation

o Mediated by H1 receptors on

endothelial cells

Subject: PharmacologyTopic: Anti-allergy DrugsLecturer: Dr. Ma. Luisa DelacruzDate of Lecture:06/29/2011Transcriptionist: ChooOoosSs 01Pages: 5

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d. Triple Response Lewis

1. Localized red spot

y Capillary dilatation (same as

"petichiae: red spots)

2. Brighter red flush or flare around the

area of the red spot

y Axon reflex

3. Wheal

y Formed because of increase capillary permeability, the fluid

and protein go out into

interstitial area (edema

formation)

*Fig. Produced by scratching the skin -> elicit the triple

response lewis

*Wheal- elevated area

*Flare- reddened area surrounding th wheal

2. Hearto H2: (+) inotropic effect, (+) chronotropic

effect

y Increase force of contraction of atrial

& ventricular muscles promoting

influx of Ca++(H2)

y Increase heart rate by hastening

diastolic depolarization in the

sinoatrial node (H2) o H1: increase automaticity arrhythmias

o Histamine shock

y In large doses (systemic anaphylaxis) causes a profound and progressive

fall in blood pressure

y Resembles surgical or traumatic

shock

Results in diminish effective

blood volume, reduce venous

return and marked decrease in

cardiac output

Circulatory collapse = decrease

in venous return decreased

cardiac output

3. Extravascular smooth muscle

a. Contraction due to H1 activation

y Histamine induces

bronchoconstriction

b. Relaxation due to H2 activation

c. Intense bronchoconstriction in patients

with asthma and other pulmonary

diseases

y Asthmatic attack due to allergic

reactions

d. Histamine-induced bronchospasm may

involve an additional reflex component

that arises from irritation of efferent vagal

nerve endings

e. Contraction of intestinal smooth muscles

4. CNSa. Nociception pain perception

b. Arousal

c. Satiation

d. Cognitive function

e. Control of pituitary hormone release

f. Nausea & vomiting

*Vestibular center and Chemoreceptor Trigger Zone has H

1receptor which when activated can produce nausea and

vomiting, because they are linked to vomiting center.

5. Dizziness, vertigo

6. Peripheral nerve endings

i. Perception of itchiness & pain is due to the

activation of H1 receptors in the nerve

endings

a. Stimulation of various nerve endings

and sensory effects

b. If released in the epidermis (superficial

stimulation) itch c. If released in the dermis (deep

stimulation) pain sometimes

accompanied by itching

y Narrow margin for itch and pain

perception



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ANAPHYLAXIS

y Severe form of allergic reaction y Potentially fatal

y Manifestations:

Angioderma, pruritus

Dyspnea

Tachycardia

Hypotension

Loss of consciousness

Classification of Anti-allergy Drugs (H1 receptor

antagonists, epinephrine, histamine release

inhibitors, corticosteroids)

I. H1 Receptor Antagonists (Classical

Antihistamines)

a. 1st generation

o Chlorpheniramine

o Cyclizine

o Dimenhydrinate

o Hydroxyzine

o Meclizine

o Promethazine

o Diphenhydramine HCl: prototype of 1st

generation drugs

y Pharmacokinetics Rapidly absorbed after oral

administration

y Usually given orally but also

has parenteral

administration

Peak plasma concentration in 1-2

hours

y Elimination half life is 4-8 hours

y Widely distributed throughout the

body including the CNS

y Metabolized in the liver by CYP

enzymes isoenzymes not yet

identified

y Excreted in small amounts in

breast milk

y Small amount excreted unchanged

in the urine y Therapeutic Uses:

1. Type 1 hypersensitivity reaction

- Acute allergic reaction

Secondary to food, drugs, insect

bites, etc.

Seasonal rhinitis & conjunctivitis

- Limited efficacy in asthma since in

asthma, other mediators are involved

(not just histamine)

2. Adjunct role to epinephrine in the

treatment of severe allergic

reactions/anaphylaxis

y Epinephrine - reverses the effect

of histamine but needs anti-

histamine to prevent further

inflammatory reactions

3. Antipruritic

4. Motion sickness, vertigo

- Meclizine (aka Bonamine) is an

antihistamine widely used for motion

sickness

5. Prophylaxis & treatment

6. Anti-emetic - Prevention of vomiting

7. Parkinson's disease

- Diphenhydramine (Benadryl®) has

been used to decrease muscle

stiffness and tremors, which are

associated with the disease.

(Wellness.com)

8. Drug-induced extrapyramidal adverse

effects

Adverse Effects

1.

CNSy Drowsiness (often transient)

o May be a good thing, when

trying to avoid scratching and

the feeling of itchiness

y Sedation, dizziness, faintness,

disturbed coordination

2. GIT

y Loss of appetite, epigastric

distress, constipation or diarrhea

3. Hematologic

y Hemolytic anemia, leukopenia,

thrombocytopenia,

agranulocytosis

4. Metabolic - not very common

y Increased appetite, weight gain

y Some drug preparations (H1

receptor blocker; Pizotifen) for

children contain appetite

stimulants



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5. Respiratory

y Thickening of bronchial

secretions; chest tightness;

wheezing

y Not useful for asthma

because it can make the

mucus more viscid, making it

more difficult to expel

6. Others y Hypersensitivity reactions,

photosensitivity, in asthma

(anti-histamine) - dry

secretions

7. Cardiovascular

y Fatal ventricular arrhythmia

(torsade des pointes) with

Terfenadine and Astemizole

both are 2nd

generation

antihistamines and are now

withdrawn from the market

y Enhanced with simultaneous

administration of

Ketoconazole and Macrolide

antibiotics

y Precautions:

1. Avoid driving a motor vehicle or

operating machinery since taking

this drug makes you drowsy

2. Avoid taking Alcohol and other

CNS depressants

b. 2nd generation drugsy Characteristics (2nd gen. - useful as

anaprophylaxis) o Improved H1 selectivity and selectivity

is not absolute

o Decreasedlipophilicity

o Interfere with mediator release from

mast cells and can prevent histamine

release

Acrivastine

Cetirizine

Fexofenadine

Loratadine*

y Characteristics:

o Non-sedating

o Does not impair psychomotor

performance - not impair

cognition

o Does not produce excessive

mucosal drying

o No anti-cholinergic effect

y Prototype for 2nd generation

antihistamines

y Pharmacokineticso Rapidly absorbed after oral

administration

Given only once a day (longer

half -life) o Peak plasma levels is attained in 1

hour

o Does not cross the blood brain

barrier appreciably

Less lipid-soluble

o Metabolized in the liver by hepatic

CYP3A4 to an active metabolite:

Desloratadine

o Mean half -life of Loratadine 8.4

hrs;Desloratadine 24 hrs

o 98% protein bound

o Excreted in the urine and feces,

mainly as metabolite y Therapeutic Uses:

Acute allergic reactions

o Allergic rhinitis

o Allergic rhinitis

o Drug/food allergy

Chronic urticaria

Atopic dermatitis

y Adverse effects, though not

verycommon:

1. Fatigue, headache

2. Epigastric distress

3. Dry mouth

c. 3rd generation drugs

y Desloratadine

y Characteristics

1. Anti-inflammatory and

immunomodulatory activities

2. Direct effects on inflammatory

mediators:

y Inhibition of intracellular

adhesion molecules-1 (ICAM-

1) expression by nasal epithelial cells

y Metabolite of loratadine

y H1 receptor blocker

y Reversible, competitive

inhibitor of the interaction of

histamine with the H1

receptors

y Do not prevent histamine

release

y Do not reverse effects of

histamine y Prevents further histamine

effects

y Pharmacologic Effects

a. Smooth muscles

o Prevents contraction of bronchial

smooth muscles partially because

other mediators such as

leukotrienes and PAF are also

involved

y You have dilatation because it

will prevent constriction. But

the effect on bronchial smooth

muscles is partial which means

it cannot totally relax the

smooth muscles because other

mediators are involved

o Inhibition of the more rapid

vasodilator effects that are

mediated by activation of H1

receptors on endothelial cells



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b. Capillary permeability

o Blocks the reaction of increased

capillary permeability and prevent

further edema formation

produced by histamine

c. Central Nervous System (CNS) o Produce stimulation and

depression

o At therapeutic doses depressant diminished alertness, decrease

reaction time, sedation,

drowsiness, lethargy

More with 1st generation

agents

o High doses produce stimulation -

children are more sensitive to this

effect (example of doc:

Kapagmalikotyungmgabata,

parents sometimes give them anti-

histamines to make them fall

asleep.); restlessness,

nervousness, insomnia

o Striking feature of overdose:

Marked stimulation

Agitation, convulsions, and

coma in infants

d. Anticholinergic

o Atropine-like effects on muscarinic

receptors

Atropine - muscarinic blocker o Promethazine has the strongest

anticholinergic activity Exhibits profound sedative

effect

Used as pre-anesthetic

medication to induce

sedation in patients that

would undergo surgery

o Second generation H1 receptor

blockers have no effect on

muscarinic receptors

e. Local Anesthetic effects

o Diphenhydramine and Promethazine

o Blocks Na+ channels in excitable

membrane

o Alleviates pain and itchiness

Epinephrine

y Not an H1 receptor blocker; sympathomimetic

o Mimics the effects of the sympathetic

nervous system

o Acts on the adrenergic receptors

y Physiologic antagonist to histamine

o Physiologic antagonist: substance that can

reverse the action of another by acting on

its own receptors

o Histamine, by acting on the blood vessels,

causes vasodilation

o Epinephrine can rapidly reverse the action

of histamine by acting on 1 adrenergic

receptors (found in peripheral blood

vessels), resulting to vasoconstriction

o 2 bronchial smooth muscles, reverse

bronchoconstriction

y Drug of choice for severe allergic reaction

(anaphylaxis) o Desired effect is on 1

o A feature of anaphylaxis is laryngeal

edema, which is usually the cause of

fatality

o Acting on the 1 receptors induces vasoconstriction, resolving the edema

Histamine Release Inhibitors: used for prophylaxis

to prevent chronic allergic conditions, especially

asthma

a. Nedocromil

b. Cromolyn sodium

o Inhibits histamine release from mast cells

o Used to prevent hypersensitivity reactions

o Indicated for asthma prevention

Examples: o Spincapsule for asthma

o Ophthalmic drops for allergic

conjunctivitis

Corticosteroids

a. Methylprednisolone

b. Prednisone

c. Hydrocortisone

o Anti-inflammatory

o Inhibits phospholipase A2

y The enzyme is the rate-limiting step

for almost all the chemical inflammatory mediators

y Lack of phospholipase A2 inhibits

production of prostaglandins,

leukotrienes, platelet activating

factor, TNF, interleukins

y Reduces expression of

cyclooxygenase 2

o Immunosuppression

y Decrease circulating lymphocytes,

eosinophils, monocytes, basophils

y Increase circulating neutrophils

y Inhibit function of macrophages and

other antigen-presenting cells

END OF TRANSCRIPTION

2011 06 Pharmacology Anti Allergy Drugs

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