Module 5 Pharmacology

Front 1

Where is the major storage site of histamine?

Back 1

In most tissues, found in mast cells or its circulating counterpart, the basophil. In these cells, histamine is syn and stored in granules

Front 2

Where do the largest numbers of mast cells exist?

Back 2

Skin
Nasal mucosa
Lungs
**these storage sites are the ones most involved

Front 3

Where else is histamine synth?

Back 3

-- In non-mast cells of the gastric mucosa and epidermis
-- appears to be neurotransmitter in parts of CNS
-- turnover is also very high in rapidly growing tissues (embryonic tissue and granulation assoc w/ wound healing)
-- been suggested that hist exerts anabolic effect on growth and repair

Front 4

What about histamine ingested in the diet?

Back 4

It is rapidly degraded by the GI tract and does not reach systemic circ
-- inhibition of enzyme monoamine oxidase does not affect degradation of histamine

Front 5

How is histamine released from mast cells and basophils?

Back 5

-- re-exposure to an offending Ag causes IgE bridges to form on the surface of the mast cell
-- bridging results in increase in the intracellular conc of the Ca (probably via IP3) which in turn causes degranulation of the mast cell
-- degranulation results in release of histamine and other inflamm promoters (eosinophil and PMN chemotactic factors) and destructive enzymes (proteases and acid hydroxylases)
-- also causes de novo synth of bronchoconstrictors PGD2, LTC4, and LTD4 (latter two being slow reacting substance of anaphylaxis)

Front 6

The majority of the inflamm and tissue damage caused by mast cell degran is actually mediated by…?

Back 6

Heinous cmpds OTHER THAN histamine
-- other cmpds account for fact that antihistamines are only partially effective in reversing inflamm rxns involved in hypersensitivity

**Thus it is better to prevent degranulation

Front 7

What about mechanical injury?

Back 7

If mech injury produces destruction of mast cells, it also causes histamine release
-- scratching of the skin causes cytolytic release of histamine resulting in redness and itching

Front 8

What type of drugs can elicit histamine release?

Back 8

Radiocontrast media
Dextran plasma expanders
Morphine
d-tubocurarine

Front 9

How can we inhibit AG-induced histamine release?

Back 9

Epinephrine
Selective B2-adrenoceptor agonists such as albuterol
Theophylline
Chromolyn sodium, nedocromil, and olopatadine

Front 10

How does epinephrine and albuterol inhibit histamine release?

Back 10

They stimulate an adrenoceptor-sensitive adenylate cyclase in the mast cell mbrn
-- Resulting increase in cAMP blocks histamine release by preventing the increase in intracellular Ca concentration caused by formation of IgE bridges

Front 11

How does theophylline inhibit histamine release?

Back 11

Increases cAMP conc by inhibiting cAMP phosphodiesterase
-- increased cAMP prevents the increase in intracellular Ca conc caused by formation of IgE bridges

Front 12

How does cromolyn sodium, nedocromil, and olopatadine inhibit histamine release?

Back 12

It inhibits mast cell degran by preventing the increase in intracellular Ca conc caused by formation of IgE bridges

Front 13

Histamine and second messenger systems: H1 receptors

Back 13

H1 receptors: ↑IP3 --> ↑ intracellular Ca causing contraction of:
1. vascular endothelial cells of postcapillary venules --> extravasation of plasma

2. bronchial smooth muscle --> decreased ventilation

3. GI smooth muscle --> bowel cramping, involuntary defecation

Front 14

Histamine and second messenger systems: H1-receptors on vascular endothelial cells of resistance arterioles

Back 14

Causes synth of NO --> activation of guanyl cyclase --> ↑CGMP --> relaxation of vascular smooth muscle --> vasodilation --> decreased TPR --> hypotension

Front 15

Histamine and second messenger systems: H2 receptors coupled to adenyl cyclase

Back 15

1. vascular smooth muscle cells of arterioles --> ↑cAMP --> relaxation --> vasodilation --> decreased TPR --> hypotension

2. gastric parietal cells: ↑cAMP  ↑calcium  ↑ acid secretion

Front 16

Histamine and vasodilation: H1 receptor mediated vs. H2 receptor mediated

Back 16

H1-receptor mediated = rapid onset and offset

H2-receptor mediated = slow onset and offset

Front 17

Where do we find H1 histamine receptors?

Back 17

1. vascular smooth muscle

2. capillary endothelial cells

3. bronchial smooth muscle

4. GI smooth muscle = food allergy

5. sensory nerve ending

Front 18

Result of H1 histamine receptors in vascular smooth muscle?

Back 18

1. relaxation of resistance arterioles and venules

2. vasodilation causes hypotension and reflexly-mediated tachycardia

3. rapid vasodilation is mediated by stimulation of H2-receptors

Front 19

Result of H1 histamine receptors in capillary endothelial cells?

Back 19

1. contraction increases capillary permeability

2. extravasation of plasma causes local edema

Front 20

Result of H1 histamine receptors in bronchial smooth muscle?

Back 20

1. contraction causes bronchoconstriction

2. FEV1 and PEFR are decreased

Front 21

Result of H1 histamine receptors in GI smooth muscle?

Back 21

1. contraction enhances peristalsis

2. bowel cramping and diarrhea result

Food allergy

Front 22

Result of H1 histamine receptors in sensory nerve endings?

Back 22

stimulation causes pain and itching

Front 23

H2 histamine receptor locations?

Back 23

Gastric parietal cells

Front 24

Result of H2 histamine receptors in gastric parietal cells?

Back 24

1. increased secretion of gastric acid, pepsin and intrinsic factor

2. acid secretion exacerbates GI ulcers caused by H. pylori

Front 25

Explain the “triple response of Lewis”

Back 25

FLUSH, FLARE, WHEAL

Intradermal release of histamine produces:
Flush – localized red spot at the site of injury which appears in a few seconds

Flare – diffuse flush of the skin extending 1cm around the site of injury which appears more slowly

Wheal – edema localized at the original red spot which develops after several minutes

Front 26

What, exactly, are the causes of the triple response of Lewis?

Back 26

All are mediated by H1-receptors

Flush – arteriodilation caused by histamine at the site of release

Flare – activation of axonal reflexes in the branches of the sensory nerves shich cayses the surrounding blood vessels to dilate

Wheal – localized edema resulting from the increase in capillary perm caused by histamine

Histamine, PGs and bradykinin stimulate sensory nerve ending to cause sensations of pain, itching, and burning = ALGESIA

Front 27

The “triple response of Lewis” can be produced by…?

Back 27

1. trauma
2. sunburn
3. animal venoms and toxins
4. plant toxins (poison oak and ivy)
5. plant allergens

Front 28

Describe an immediate HSN (acute allergic) rxn

Back 28

1. bronchoconstriction causing severe dyspnea

2. laryngeal edema – DOC is epi which constricts laryngeal vessels

3. hypotension – (may be severe) Tx w/ i.v. combo of H1-blocker and H2-blocker (diphenhydramine + cimetidine)

Front 29

Describe seasonal allergic rhinitis

Back 29

1. allergic rxn of nasal mucosa and conjunctiva to pollen

2. increased nasal and ocular secretion and vasodilation

Front 30

Describe asthma

Back 30

1. re-exposure to allergen causes bridging of reaginic Abs (IgEs) on the surface of mast cells, including those of the nasal mucosa and bronchioles, causing degranulation

2. degranulation of mast cells elicits bronchoconstriction, respiratory tract congestion (vasodilation, increased secretion and edema) and chemotaxis of eosinophils

Front 31

Describe urticaria (hives) and pruritis (itching)

Back 31

1. local allergic responses

2. red itchy patches of hives represent the flush, flare, and wheal caused by local histamine release w/in the skin

Front 32

Describe mast cell tumors

Back 32

1. skin tumors (urticaria pigmentosa) cause local hives after mech pressure releases histamine

2. degran of mast cells in deeper tumors (mastocytosis) can produce systemic effects including increased aPTT from heparin release

Front 33

Describe gastric and duodenal ulcers

Back 33

1. stim of H2-receptors increases gastric acid secretion: acid promotes and/or exacerbates ulceration

2. increased acid secretion causes “stress” ulcers (i.e. in severe trauma such as burns)

Front 34

Describe GERD

Back 34

Gastric acid damages the mucosa of the esophagus

Front 35

Name the inhibitors of mast cell degranulation

Back 35

Cromolyn sodium

Olopatadine

Front 36

Cromolyn sodium use?

Back 36

1. inhalation for asthma

2. ophthalmic for allergy

3. nasal for allergy

4. oral for food allergy

Front 37

Olopatadine use?

Back 37

1. ophthalmic for allergy

prevents mast cell degran AND blocks H1-histamine receptors

Front 38

Non-prescription H1-histamine receptor antagonists?

Back 38

1. brompheniramine – class B

2. chlorpheniramine – class B

3. diphendydramine – class B

4. dimenhydrinate – class B

5. loratadine – class B

Front 39

Oral prescription H1-histamine receptor antagonists?

Back 39

1. hydroxyzine – class C

2. cyproheptadine – class B

3. cetirizine – class B

4. fexofenadine – class C

5. desloratadine – class B

6. meclizine – class B

Front 40

Other prescription H1-histamine receptor antagonists?

Back 40

1. olopatadine (eye drops) – class C

2. promethazine (i.m. or rectal suppository) – class C

Front 41

Pharmacological properties of antihistamines?

Back 41

See pg. 46 of the syllabus

Front 42

Pharmacokinetics of cetirizine, fexofenadine, loratadine, and desloratadine?

Back 42

half life (h) and clearance

Cetirizine 8 50% renal 50% hepatic

Fexofenadine 14 95% renal

Loratadine 8 hepatic

Desloratadine 28 renal

Front 43

Pharm effects of H1-receptor blockades?

Back 43

1. prevents constrictor response to histamine at most smooth muscle (bronchial and GI)

2. inhibit the pain and itching caused by histamine at sensory nerve ending

3. antagonize the increase in capillary permeability

Front 44

Pharm effects of a cholinergic muscarinic receptor blockade?

Back 44

1. depresses CNS (sedation, etc)

2. inhibits nasopharyngeal secretion

3. prevents motion sickness (action in vestibular nuclei)

4. exerts an antiemetic effect

Front 45

Local anesthetic pharm effect is only caused by…?

Back 45

Topical diphenhydramine

-- blocks Na channels in afferent sensory pain fibers

Front 46

Therapeutic uses of antihistamines?

Back 46

1. seasonal and allergic rhinitis
2. acute HSN rxns
3. motion sickness
4. pre-op sedation
5. nausea and vomiting
6. vertigo (Meniere’s disease)
7. Parkinson’s disease

Front 47

Tx of seasonal and allergic rhinitis?

Back 47

Newer, non-sedating dugs preferred:
-- cetirizine
-- fexofenadine
-- loratadine

Front 48

Tx of acute HSN rxns?

Back 48

H1 blockers are adjunctive therapy
**Epi (s.c.) remains the DOC

Front 49

Tx of motion sickness?

Back 49

Prophylaxis = dimenhydrinate and meclizine

Treatment = promethazine

Front 50

Tx for pre-op sedation?

Back 50

Promethazine

Front 51

Tx for vertigo?

Back 51

If of vestibular origin
-- DIMENHYDRINATE and MECLIZINE reduce the nausea, ataxia, and nystagmus caused by spontaneous bursts of activity of the sensory nerves of the semicircular canals

Front 52

Tx for Parkinson’s disease

Back 52

DIPHENHYDRAMINE is used to treat the central motor disorder caused by antipsychotic drugs

Front 53

Why is promethazine so great?

Back 53

**antihistaminic and anticholinergic effect
** given i.m. or by rectal suppository

Used for tx of:
1. acute HSN rxns
2. allergic dermatoses (poison ivy/oak)
3. motion sickness
4. sedate anxious pts
5. prevent post-op nausea and vomiting
6. n/v assoc w/ GI infection (via rectal suppository)

Front 54

Do we use H1-receptor antagonists for serous otitis media?

Back 54

NOT effective and can cause ontoward effects (sedation, irritability, and restlessness)
-- after repeated rounds of antibiotic therapy, pressure equalization (PE) tubes usually solve the problem of recurrent OM

Front 55

Toxicity and side-effects of antihistamines?

Back 55

1. CNS depression
2. CNS excitation
3. Dizziness and tinnitus
4. Antimuscarinic effects
5. Torsade

Front 56

CNS toxicity of antihistamines?

Back 56

DEPRESSION
-- decreased alertness, slowed rxn times and somnolence
-- potentiates CNS depression caused by alcohol and other drugs and can lead to impaired psychomotor performance

EXCITATION
-- paradoxical excitation can occur w/ overdose or even normal doses in children and older adults

Front 57

Antimuscarinic effects of antihistamines?

Back 57

1. dry mouth

2. dry respiratory tract (cough may occur)

3. urinary retention in the presence of BPH

4. exacerbation of glaucoma

Front 58

Torsade effect of antihistamines?

Back 58

Parent cmpd of fexofenadine (terfenadine) inhibits K repol current in ventricular muscle
-- prolongs the QT interval and can cause torsade

**drugs such as ketoconazole and the macrolide antibiotics (erythro and clarithro – not azithro) inhibit oxidation of terfenadine to fexofenadine

-- plasma conc of terfenadine increases and may precip torsade, espec in pts w/ congenitally-prolonged Q-T syndrome or patients taking other drugs which prolong the Q-T interval

***Loratadine DOES NOT cause torsade, even in the presence of CYP3A4 inhibitors, possibly b/c it is also metab by the CYP2D6 isozyme

Front 59

H1-histamine antagonists found in OTC products?

Back 59

Diphenhydramine – Nytol, Sleepeze-3

Front 60

H2-histamine receptor antagonists?

Back 60

famotidine
ranitidine
cimetidine

Front 61

Pharm effect of H2-histamine receptor antagonists?

Back 61

These drugs inhibit:
1. both basal and nocturnal acid secretion

2. secretion of gastric acid induced by food, coffee, insulin, muscarinic agonists, increased vagal nerve activity, histamine agonists (betazole) and gastrin (pentagastrin)

Despite the fact that H2-histamine receptors are found at many sites in the body, H2-receptor antagonists have little effect on phys fxns other than inhibition of gastric acid secretion

Front 62

Therapeutic uses of H2-histamine receptor antagonists?

Back 62

1. gastric and duodenal ulcers

2. GERD

3. prophylaxis of stress ulcers (trauma, burns)

4. anaphylaxis

5. viral warts and other skin lesions

Front 63

Toxicity and S/Es of H2-histamine receptor antagonists?

Back 63

Pregnancy category B

Cimetidine inhibits hepatic CYP450
1. antiandrogenic effects (may cayse gynecomastia, azoospermia, and decreased libido in males) occur b/c it prevents brkdwn of estrogen by CYP450

2. inhib of CYP450 also increases the half-life of other drugs such as the B-adrenoceptor antagonists, warfarin and diazepam

3. may also produce CNS effects ranging from mental confusion to overt psychosis in older pts, pts w/ prior hx of psychiatric disease and pts receiving large doses for a long period

***Ranitidine and famotidine do not exert these adverse effects

All of these drugs can cause nausea, diarrhea, and skin rash.