Histamines and Antihistamines

Question 1

name the H₂ blockers

Answer 1

cimetidine

ranitidine

famotidine

nizatidine

Question 1

What is the name of the enzyme responsible for converting histidine to histamine?

Answer 1

L-histidine decarboxylase

Question 2

Describe the structure of histamine and its important components.

Answer 2

ethylamine chain is important for drug behavior at H₁ receptors

imidazole ring is important for action at H₂ receptors

Question 3

Discuss the metabolism of histamine.

Answer 3

oxidative deamination by N-methyltransferase and MAO (and other dehydrogenases)

finally turned into an acetic acid derivative

histaminase (diamine oxidase) is another pathway

Question 4

diamine oxidase

Answer 4

found in high concentrations in the digestive tract

important for metabolizing ingested histamine

Question 5

general sites of action of histamine

Answer 5

non-vascular smooth muscle

vascular smooth muscle (and sensory nerve endings in man)

gastric acid secretion

isolated heart peparations

possible neurotransmitter roles

Question 6

effect of histamine on non-vascular sooth muscle

Answer 6

all are H₁ effects

bronchoconstriction - smooth muscle very sensitive

intestinal smooth muscle contracts - high doses can cause diarrhea

Question 7

effect of histamine on vascular smooth muscle

Answer 7

effects all mediated by H₁

triple response of lewis due to skin trauma

Question 8

triple response of Lewis

Answer 8

redness - direct dilatation

flare - indirect dilatation

wheal - edema

Question 9

triple response of Lewis - redness

Answer 9

direct dilatation of blood vessels

reflected as a local red spot appearing within seconds after injection or injury

immediate effect mediated by H₁ receptors

at higher doses, a sustained H₂ component participates in redness

Question 10

triple response of Lewis - flare

Answer 10

indirect dilatation reflected as an irregular reddish area that develops slowly and extends beyond the original redness by about 1 cm

occurs indirectly via an axon reflex whereby histamine or injury excites sensory nerve terminals from the skin

impulses then travel up sensory nerve into spinal cord and also diverge via an axon collateral, which releases substance P

substance P binds to mast cells and release histamine, causing the flare

Question 11

triple response of Lewis - wheal

Answer 11

edema at injection site and the area of initial redness becomes raised due to increased permeability of small blood vessels, causing edema

Question 12

effect of histamine on gastric acid secretion

Answer 12

in very low doses, histamine causes secretion of gastric juice from parietal and chief cells of the mucosa respectively (H₂ mediated)

Question 13

enterochromaffin-like (ECL) cells

Answer 13

paracrine cells that release histamine to induce parietal cells to release HCl

gastrin and ACh are other stimulants that cause these cells to release histamine

Question 14

effect of histamine on isolated heart preparations

Answer 14

increases the rate and force of cardiac contraction (via H₂ receptors) and slows conduction int he AV node (via H₁ receptors, this is a minor effect)

may be important in producing arrhythmias during allergic reactions

Question 15

the effect of histamine on neurons

Answer 15

most important clinical effects of the H₁ antihistamines int he CNS are due to blockade of muscarinic receptors

Question 16

What cells contain histamine?

Answer 16

mast cell and the basophilic leukocyte

Question 17

What makes up the secretory granules of mas cells?

Answer 17

histamine

proteases

heparin

cytokines

Question 18

alpha-tryptase

Answer 18

a neutral protease found in the mast cell granule

Question 19

What cytokines are found in mast cell granules?

Answer 19

ECF-A - eosinophil chemotactic factor of anaphylaxis

TNFs - tumor necrosis factors

Question 20

anaphylaxis

Answer 20

the physiological stimulus to secretion of mast cells

leads to type I immediate hypersensitivity

Question 21

Describe the signaling pathway that causes mast cells to release their granules and their contents.

Answer 21

1. IgE antibodies become fixed to mast cells
2. exposure to antigen triggers binding to antibodies
3. phophorylation of interaction leads to activation of phospholipase C
4. causes IP3 synthesis and calcium liberation from storage sites in the ER
5. CRAC channels open in response to increased calium
6. increased cytoplasmic calcium concentrations promote exocitosis and dissociation of the component parts of the granules

Question 22

urticaria pigmentosa

Answer 22

a disease characterized by huge numbers of mast cells in the skin

when touched, may set of an exaggerated triple response

calcium dependent process, also activating phospholipase A₂

detection of alpha-tryptase and histamine metabolites as well as prostaglandin metabolites in the urine

anaphylactoid - not IgE mediated

Question 23

mechanism of insect stings and bites

Answer 23

poison has a phospholipase A₂ component as well as mast-cell degranulating peptides

G-protein induced histamine release

Question 24

histamine release inhibitors

Answer 24

increases in cAMP inhibit release from human basophils and animal mast cells (epinephrine and theophylline through beta-receptors)

Question 25

evokers of histamine release

Answer 25

atropine, curare, substance P, morphine, certain antibiotics, ACh, peptides, and other agents in high concentrations

Question 26

signaling mechanism for H₂ receptors

Answer 26

G-protein coupled receptor increases cAMP and thus PKA phosphorylation

Question 27

mechanism of H₁ receptor antagonists

Answer 27

competitive inhibitors of histamine at the H₁ receptor potently inhibit the effects of histamine if histamine is present at these receptor sites all are substituted ethylamine derivatives

Question 28

first generation H₁ receptor antagonists (What are some side-effects?)

Answer 28

classical phenothiazines piperazines \*\*CNS effects and thus sedating \*\*peripheral anti-muscarinic effects

Question 29

chlorpheniramine

Answer 29

**first generation, classical** contained in all OTC anti-allergy preparations (brompheniramine also popular) useful to treat mild allergic reactions also contained in cold tablets - relief due to anti-cholinergic effect of drying up secretions

Question 30

diphenhydramine

Answer 30

\*Benadril **first generation, calssical** effective for sleep due to anticholinergic effects antimuscarinic action like scopolamine this continues to be an agent of choice for insect bites, poison ivy, and other mild allergic reactions if sedation would not pose a problem

Question 31

dimenhydrinate

Answer 31

**first generation, classical** very powerful anti-ACh action, sleep inducing and also used to combat motion sickness

Question 32

doxylamine

Answer 32

**first generation, classical** another ethanolamine of similar structure used OTC by itself or witho ther agents as a sedative

Question 33

hydroxyzine

Answer 33

**first generation, classical** used to relieve itching caused by allergies control the nausea and omiting cause by various condition, including motion sickness sedative effect can be used to treat anxiety enhances the euphoric effect of opioids

Question 34

promethazine

Answer 34

**first generation, phenothiazine** strongest anti-ACh action of all antihistamines used to combat motion sickness and in anti-tussive preparations with codeine not sold OTC

Question 35

meclizine

Answer 35

**first generation, piperazine** OTC to treat motion sickness

Question 36

cyclizine

Answer 36

**first generation, piperazine** OTC to treat motion sickness

Question 37

second generation H₁ antagonists

Answer 37

agents are used because they have minimal sedative effects as they do not cross the blood-brain barrier also largeley devoid of muscarinic effects

Question 38

loratidien

Answer 38

\*Claritin **second generation** rapid in onset with no reports of arrhythmias racemic mixture, made available TOC useful for hives, itching, and allergic rhinitis non-sedating and has no anti-muscarinic effects

Question 39

desloratadine

Answer 39

**second generation** a single isomer (active metabolite) of loratadine no evidence that it is superior

Question 40

fexofenadine

Answer 40

\*Allegra **second generation** a derivative of terfenadine no cardiac effects non-sedating and devoid of anti-muscarinic effects excreted unchanged in the urine

Question 41

cetirizine

Answer 41

**second generation** substantial sedative effects a metabolite of hydroxyzine excreted unchanged in the urine approved for use in children as young as 6 months for the treatment of allergic rhinitis, itching, and hives effectiveness is enhanced by its ability to inhibit mast cell degranulation - synergy

Question 42

levocetirizine

Answer 42

**second generation** same uses as cetirizine with generally comparable effectiveness

Question 43

azelastine

Answer 43

**second generation** intranasal anti-histamine recommended as first line therapy for rhinitis additional anti-inflammatory effect, inhibiting the release of some mast cell mediators - synergy

Question 44

Doxepin

Answer 44

used clinically as a combined H1 and H2 blocker

Question 45

appropriate therapeutic uses of H₁ blockers

Answer 45

certain mild allergies, insect bites, poison ivy titrating a suntan or preventing a sunburn - H₁ blocker for first hour and cyclooxygenase inhibitor for the next 24 hours

Question 46

side effects and contrainidications of H₁ blockers

Answer 46

dry mouth constipation urinary retention narrow-angle glaucoma

Question 47

toxicity of H₁ blockers at high doses

Answer 47

**Dry** as a bone **Hot** as a stove **Red** as a beet **Blind** as a bat **Mad** as a hatter

Question 48

treatment of an acute asthmatic attack or anaphylactic shock

Answer 48

for anaphylaxis, epinephrine is required \*\*diphynhydramine often used as an adjunct to block the H₁ effects of release histamine

Question 49

effects of epinephrine

Answer 49

beta-2 agonist effect opens the airways alpha-1 effect produces vasoconstriction to oppose the vasodilation associated with anaphylaxis and reduces mucosal edema inhibits release of mediators from mast cells

Question 50

Where are the muscarinic vs. adrenergic receptors in the lungs?

Answer 50

adrenergic (beta-2) in the fine branches muscarinic in the large airways

Question 51

corticosteroids in asthma treatment

Answer 51

used by themselves for mild to moderate asthma and together with a long-acting beta-agonist such as salmeterol and formoterol for severe asthma

Question 52

corticosteroid mechanism of action

Answer 52

blocks cyclooxygenase pathway and production of prostaglandins and PGD₂ blocks the lipoxygenase pathway, which produces leukotrienes LTC₄, LTD₄, and LTE₄ blocks cytokine release and recruitment of inflammatory cells blocks PAF, bradykinin, and adenosine production

Question 53

effects of leukotrienes

Answer 53

bronchoconstriction (LTD4 is 1000x more potent than histamine) increase vascular permeability mucus secretion inflammatory cell infiltration

Question 54

montelukast

Answer 54

competitive antagonist of the cys-LT1 leukotriene receptor used for prophylaxis of exercise induced asthma in children

Question 55

effects of leukotriene B4

Answer 55

causes attraction of neutrophils and subsequent release of damaging factors not blocked by montelukast

Question 56

zileuton

Answer 56

inhibits the 5'-LOX enzyme and thus inhibits the synthesis of leukotrienes including LTB4 used for prophylaxis of asthma with a neutrophilic phenotype

Question 57

cromolyn Na⁺

Answer 57

stabilizes the mast cell membrane, preventing disease of granules inhibits eosinophils in airway nerves used for prophylaxis of exercise induced asthma, and asthma-induced by animal dander also used for rhinitis and mastocytosis

Question 58

theophylline

Answer 58

competitive inhibitor of adenosine at adenosine receptors at the lowest doses at slightly higher doses, inhibits phosphodiesterases (and thus increases cAMP) suppresses inflammatory genes and proteins used to treat disorders of the bronchioles - asthma, COPD by relaxing airway smooth muscle, suppressing mediator release, and improving diaphragm contractility