Histamines and Antihistamines Flashcards Preview

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Flashcards in Histamines and Antihistamines Deck (59):
1

name the H2 blockers

cimetidine

ranitidine

famotidine

nizatidine

1

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

L-histidine decarboxylase

2

Describe the structure of histamine and its important components.

ethylamine chain is important for drug behavior at H1 receptors

imidazole ring is important for action at H2 receptors

3

Discuss the metabolism of histamine.

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

finally turned into an acetic acid derivative

histaminase (diamine oxidase) is another pathway

4

diamine oxidase

found in high concentrations in the digestive tract

important for metabolizing ingested histamine

5

general sites of action of histamine

non-vascular smooth muscle

vascular smooth muscle (and sensory nerve endings in man)

gastric acid secretion

isolated heart peparations

possible neurotransmitter roles

6

effect of histamine on non-vascular sooth muscle

all are H1 effects

bronchoconstriction - smooth muscle very sensitive

intestinal smooth muscle contracts - high doses can cause diarrhea

7

effect of histamine on vascular smooth muscle

effects all mediated by H1

triple response of lewis due to skin trauma

8

triple response of Lewis

redness - direct dilatation

flare - indirect dilatation

wheal - edema

9

triple response of Lewis - redness

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

10

triple response of Lewis - flare

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

11

triple response of Lewis - wheal

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

12

effect of histamine on gastric acid secretion

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

13

enterochromaffin-like (ECL) cells

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

14

effect of histamine on isolated heart preparations

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

15

the effect of histamine on neurons

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

16

What cells contain histamine?

mast cell and the basophilic leukocyte

17

What makes up the secretory granules of mas cells?

histamine

proteases

heparin

cytokines

18

alpha-tryptase

a neutral protease found in the mast cell granule

19

What cytokines are found in mast cell granules?

ECF-A - eosinophil chemotactic factor of anaphylaxis

TNFs - tumor necrosis factors

20

anaphylaxis

the physiological stimulus to secretion of mast cells

leads to type I immediate hypersensitivity

21

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

  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

22

urticaria pigmentosa

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

23

mechanism of insect stings and bites

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

G-protein induced histamine release

24

histamine release inhibitors

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

25

evokers of histamine release

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

26

signaling mechanism for H2 receptors

G-protein coupled receptor

increases cAMP and thus PKA phosphorylation

27

mechanism of H1 receptor antagonists

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

28

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

classical

phenothiazines

piperazines

**CNS effects and thus sedating

**peripheral anti-muscarinic effects

29

chlorpheniramine

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

30

diphenhydramine

*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

31

dimenhydrinate

first generation, classical

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

32

doxylamine

first generation, classical

another ethanolamine of similar structure

used OTC by itself or witho ther agents as a sedative

33

hydroxyzine

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

34

promethazine

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

35

meclizine

first generation, piperazine

OTC to treat motion sickness

36

cyclizine

first generation, piperazine

OTC to treat motion sickness

37

second generation H1 antagonists

agents are used because they have minimal sedative effects as they do not cross the blood-brain barrier

also largeley devoid of muscarinic effects

38

loratidien

*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

39

desloratadine

second generation

a single isomer (active metabolite) of loratadine

no evidence that it is superior

40

fexofenadine

*Allegra

second generation

a derivative of terfenadine

no cardiac effects

non-sedating and devoid of anti-muscarinic effects

excreted unchanged in the urine

41

cetirizine

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

42

levocetirizine

second generation

same uses as cetirizine with generally comparable effectiveness

43

azelastine

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

44

Doxepin

used clinically as a combined H1 and H2 blocker

45

appropriate therapeutic uses of H1 blockers

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

46

side effects and contrainidications of H1 blockers

dry mouth

constipation

urinary retention

narrow-angle glaucoma

47

toxicity of H1 blockers at high doses

Dry as a bone

Hot as a stove

Red as a beet

Blind as a bat

Mad as a hatter

48

treatment of an acute asthmatic attack or anaphylactic shock

for anaphylaxis, epinephrine is required

**diphynhydramine often used as an adjunct to block the H1 effects of release histamine

49

effects of epinephrine

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

50

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

adrenergic (beta-2) in the fine branches

muscarinic in the large airways

51

corticosteroids in asthma treatment

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

52

corticosteroid mechanism of action

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

53

effects of leukotrienes

bronchoconstriction (LTD4 is 1000x more potent than histamine)

increase vascular permeability

mucus secretion

inflammatory cell infiltration

54

montelukast

competitive antagonist of the cys-LT1 leukotriene receptor

used for prophylaxis of exercise induced asthma in children

55

effects of leukotriene B4

causes attraction of neutrophils and subsequent release of damaging factors

not blocked by montelukast

56

zileuton

inhibits the 5'-LOX enzyme and thus inhibits the synthesis of leukotrienes including LTB4

used for prophylaxis of asthma with a neutrophilic phenotype

57

cromolyn Na+

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

58

theophylline

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