Test 2: Autocoids

Front 1

Which histamine receptor works via Gq through phospholipase C synthesis or release of nitric oxide depending upon site of action

Back 1

H1

Front 2

How does H1 receptors act on bronchiole and GI smooth muscles?

Back 2

has a direct CONTRACTILE action (spasm of bronchi and gut) and neuronal actions mediated by Gq through phospholipase C and thus the breakdown of inositol phospholipids

Front 3

How does H1 receptors act on vascular smooth muscles?

Back 3

It RELAXES vascular smooth muscle in small blood vessels (leads to hypotension, blushing, etc.) and INCREASES vascular permeability. Both are mediated by synthesis and release of nitric oxide

Front 4

Which of the histamine receptors has the highest affinity for histamine (has a rapid and short lived dilator response)?

Back 4

H1

Front 5

Which histamine receptor works via action of Gs?

Back 5

H2

Front 6

How H2 receptor acts on:
1. gastric acid secretion
2. vascular smooth muscle
3. neurons
4. basophil degranulation
5. myocardial contractility
6. skin

Back 6

1. release of gastric acid secretion
2. relaxation of vascular smooth muscle (mild relaxation of bronchi)
3. neuronal excitation
4. inhibition of basophil degranulation
5. increases in myocardial contractility
6. cutaneous vasodilation (blushing)

Front 7

Which of the histamine receptors has a low affinity for histamine?

Back 7

H2. Activation of H2 receptors causes slower and more sustained vasodilation

Front 8

Name H2 antagonists that are used in the treatment of peptic ulcer

Back 8

Cimetidine (Tagamet)
Ranitidine (Zantac)

Front 9

Which histamine receptors modulates Ca2+ entry into nerve endings and inhibits neurotransmitter release?

Back 9

H3

Front 10

How is histamine primarily stored?

Back 10

in mast cells (most tissues) and basophils (blood) as ionic complexes with proteoglycans and protein molecules

Front 11

Where is the highest concentration of histamine located?

Back 11

in skin, lungs, and mucosa in the GI tract

Front 12

How is histamine metabolized/degraded?

Back 12

Metabolized by ring methylation and then further converted by MAO into metabolites that have little or no activity

Front 13

Both basophils and mast cells have a high-affinity for what?

Back 13

IgE

Front 14

What can cause histamine release from mast cells and basophils?

Back 14

1. allergic disorders
2. endogenous polypeptide-induced release
3. drug induced (pseudoallergic) release

Front 15

What are the two general processes of degranulation?

Back 15

1. cytolytic release
2. non-cytolytic release

Front 16

What can cause cytolytic release of histamine?

Back 16

1. disruption or damage of plasma membrane of mast cells
2. high (non-therapeutic) concentration of drugs such as, phenothiazines, H1-antagonists, some narcotic analgesics, antibiotic bases, experimental compounds (polyamine 48/80), basic polypeptides (polymixin B, bradykinin and substance P)

Front 17

Cytolytic release:

1. is it energy dependent?
2. does it require Ca2+ influx
3. does it cause leakage of cytoplasmic contents?

Back 17

1. NOT energy dependent
2. does NOT require Ca2+ influx
3. causes leakage of cytoplasmic contentsq

Front 18

What can cause non-cytolytic release of histamine?

Back 18

1. allergic response to antigens through generation of cross-bridging of adjacent IgE molecules
2. Nonimmune mechanism such as those caused by polybasic substances: polyamine 48/80, basic polypeptides (polymyxin B, bradykinin, and substance P) and bee venom
3. Drugs such as tubocurarine, succinylcholine, doxorubicin, vancomycin, morphine and codeine, antibiotics

Front 19

Non-cytolytic release:

1. is it energy dependent?
2. does it require Ca2+ influx?
3. is it accompanied by leakage of cytoplasmic contents?

Back 19

1. IS energy dependent
2. does REQUIRE Ca2+ influx
3. is NOT accompanied by leakage of cytoplasmic contents

Front 20

What is the most acute and potentially severe allergic reaction that could happen following histamine release?

Back 20

Anaphylaxis

Front 21

What happens during anaphylaxis?

Back 21

hypotension, vasodilation, myocardial depression, dysrhythmias, urticaria (hives), angiodema, and bronchospasm

Front 22

Describe how histamine can effect the vascular system.

Back 22

Most vascular beds respond with vasodilation by either H1 or H2 receptors. However, some vessels like coronaries constrict. The predominant effect is dose-dependent vasodilation resulting from relaxation of smooth muscles located in aterioles, capillary sphincters and muscular venules. Generally, there is a fall in blood pressure.

Front 23

What is the "Triple Response"?

Back 23

occurs after an intra/subdermal injection. You see a small red spot (verticaria), flushed area around spot, wheal

also called a wheal and flare response

Front 24

At lower doses of histamine, which effect (direct or indirect) predominates?

Back 24

indirect

at lower doses of histamine, it produces a decrease in blood pressure

Front 25

Describe the indirect effects of histamine on the heart.

Back 25

1. increase in heart rate and force of contraction
2. It results from a response to decrease blood pressure: increased sympathetic tone from baroreceptor discharge

Front 26

Describe the direct effects of histamine on the heart

Back 26

1. increase heart rate, force of contraction, and automaticity (atrial and ventricular)
2. primarily mediated by H2 receptors

Front 27

What is the "histamine shock"?

Back 27

when histamine produces a coronary vasoconstriction via H1 receptors leading to dysrhythmia.

-> greatly lowers cardiac output

Front 28

Describe how histamine effects the respiratory system.

Back 28

1. marked bronchiolar constriction mediated by H1 receptors
2. increases pulmonary airway fluid and electrolyte secretions due to leakage from vascular tree. May cause pulmonary edema.

Front 29

Drugs that are mast cell membrane stabilizers.

Back 29

- Chromolyn sodium
- nedocromil

Front 30

Pharmacological properties of Mast cell membrane stabilizers

Back 30

1. for asthma, chromolyn sodium is given by inhalation since it is poorly absorbed orally
2. has no effect on bronchiolar smooth muscle
3. good as a prophylactic agent; has little effect in ongoing reaction
4. clinical effectiveness is delayed from the first administration of the drug

Front 31

Mechanism of action of mast cell membrane stabilizers

Back 31

1. primary action is membrane stabilization and inhibition of degranulation of mast cells: release of histamine and other granular content is markedly reduced
2. cellular mechanism thought to result from receptor activation and subsequent phosphorylation of cytoplasmic protein

Front 32

Side Effects of mast cell membrane stabilizers

Back 32

airway irritant
bad taste
headache
tolerance

Front 33

METHYLXANTHINES

Pharmacological properties

Back 33

1. Direct relaxation of smooth muscle (bronchodilation)
2. Does NOT stabilize mast cells
3. Stimulates CNS, cardiac muscle
4. produces diuresis

Front 34

METHYLXANTHINES

Mechanisms of action

Back 34

1. block cyclic nucleotide phosphodiesterases: both cAMP and cGMP phosphodisterases which lead to increases in cAMP and cGMP
2. block receptors for adenosine

Front 35

METHYLXANTHINES

Side Effects

Back 35

Insomnia
Anxiety

Front 36

METHYLXANTHINES

Examples of

Back 36

Theophyllines
Caffeine

Front 37

BETA2 SELECTIVE AGONISTS

Example of

Back 37

Albuterol

Front 38

BETA2 SELECTIVE AGONISTS

Pharmacological properties

Back 38

1. inhalation preferred route of administration
2. more selective and longer lasting than beta 1 or beta 2 agonists (ex. isoproterenol)
3. stimulates beta 2 receptors on bronchioles resulting in bronchodilation

Front 39

BETA2 SELECTIVE AGONISTS

Mechanism of action

Back 39

stimulates beta2 receptors on mast cells which results in increase of cAMP by action on Gs

Front 40

MAST CELL MEMBRANE STABILIZERS

Pharmacological Properties

Back 40

1.for asthma, chromolyn sodium is given by inhalation since it is poorly absorbed orally
2. has no effect on bronchiolar smooth muscle
3. good as a prophylatic agent; has little effect on ongoing reaction
4. clinical effectiveness is delayed from the first administration of the drug

Front 41

MAST CELL MEMBRANE STABILIZERS

Mechanism of action

Back 41

1. primary action is membrane stabilization and inhibition of degranulation of mast cells: release of histamine and other granular content is markedly reduced

2. cellular mechanism thought to result from receptor activation and subsequent phosphorylation of cytoplasmic protein

Front 42

MAST CELL MEMBRANE STABILIZERS

Side Effects

Back 42

1. airway irritant
2. bad taste
3. headache
4. tolerance

Front 43

H1 RECEPTOR ANTAGONISTS or ANTIHISTAMINES

Primary use

Back 43

Used for management of non-severe chronic Type 1 hypersensitivity reactions. Very effective agents in histamine-induced itching, anaphylaxis but NOT vewry effective DURING anaphylaxis and allergy

Front 44

H1 RECEPTOR ANTAGONISTS or ANTIHISTAMINES

Why does this drug have a wide-spread therapeutic use?

Back 44

With varying degree, it also exhibits sedative, antiemetic, anti-motion sickness, antiparkinsonism, antitussive, and local anesthetic actions

Front 45

H1 RECEPTOR ANTAGONISTS or ANTIHISTAMINES

What does it inhibit? What does it activate?

Back 45

Inhibit broncospasm and coronary artery vasoconstriction

Increases vascular permeability

Front 46

H1 RECEPTOR ANTAGONISTS or ANTIHISTAMINES

What does the relative effectiveness of these drugs depend on?

Back 46

their tissue concentration

Front 47

H1 RECEPTOR ANTAGONISTS or ANTIHISTAMINES

What is it often used with?

Back 47

often used in combination with decongestant (e.g. pseduoephrine HCl, phenylpropanolamine HCl)

Front 48

H1 RECEPTOR ANTAGONISTS or ANTIHISTAMINES

Tolerance generally develops with most effects. What should you do when this occurs?

Back 48

Switch to another chemical class

Front 49

H1 RECEPTOR ANTAGONISTS or ANTIHISTAMINES

What do you do in cases of severe allergic reactions?

Back 49

must be used in conjunction with epinephrine

Front 50

H1 RECEPTOR ANTAGONISTS or ANTIHISTAMINES

There are two subclasses based on body distribution: first-generation and second-generation.

Describe their differences

Back 50

First-generation is distributed throughout the body and the CNS.

Second-generation does not readily penetrate the CNS

Front 51

H1 RECEPTOR ANTAGONISTS or ANTIHISTAMINES

Pharmacokinetic properties

Back 51

1. well absorbed orally
2. onset of most is 30-60 minutes
3. duration form most is 3-6 hours (except meclizine duration 12-24 hours)
4. metabolized by P450 system in liver: can induce P450; some also substrates for MAO
5. excreted by the kidney

Front 52

H1 RECEPTOR ANTAGONISTS or ANTIHISTAMINES

Mechanism of action for first generation

Back 52

1. Primary action is competitive antagonists at the H1 receptors
2. All agents exhibit weak to strong anti-AChM action
3. cyproheptadine: also potent antagonist of 5HT2 and L-type Ca2+ channels
4. Promethazine: weak alpha-receptor antagonist and moderate D2 receptor antagonist

Front 53

H1 RECEPTOR ANTAGONISTS or ANTIHISTAMINES

Side effects

Back 53

1. Sedation is the most common
2. First generation agents cause CNS depression, hallucination, excitement, ataxia, convulsions (Die hard exams are confusing)
3. GI upset
4. Atropine like side effects: dry mouth, blurred vision
5. Cyclizine may cause teratological effects and thus should not be used in pregnant women
6. Potentiate the effects of MAO inhibitors, sedative-hypnotics, alcohol, narcotic analgesics, general anesthetics

Front 54

H1 RECEPTOR ANTAGONISTS or ANTIHISTAMINES

Name the First-Generation Drugs

Back 54

Brompheniramine (Dimetane)
Chlorpheniramine (Chlortrimeton)
Cyclizine
Meclizine (Antivert, Bonine)
Diphenhydramine (Benadryl)
Hydroxyzine (Atarax)
Promethazine (Phenergan)
Tripelennamine (PBZ)

[Benny could count many days he packed turkey]

Front 55

H1 RECEPTOR ANTAGONISTS or ANTIHISTAMINES

Name the Second-Generation Drugs

Back 55

Astemizole (Hismanal) -- withdrawn
Acrivastine (Semprex)
Cetirizine (Reactine, Zyrtec)
Loratidine (Claritin)
Terfenadine (Seldane) -- withdrawn
Fexofenadine (Allegra)

[Anny acts cool like the fox]

Front 56

ARACHIDONIC ACID

Name the three pathways in which arachidonic acid is converted into active metabolite

Back 56

1. Cytrochrome P450 (CYP450) monooxygenases --> epoxides (HPETEs and HETEs) --> Na+/K+-ATPase inhibition or stimulation, changes in vascular permeability inflammation

2. Cyclooxygenases --> prostaglandins and thrombaxanes --> inflammation

3. Lipoxygenases: three distinct cytosolic isoforms have been identified
a. 5-lipoxygenase --> several different leukotrienes --> phagocytic mobilization, increase vascular permeability, inflammation
b. 15-lipoxygenase --> leukotriens --> ?
c. 12-lipoxygenases --> 12(S)-HETE --> Activates Na+/K+-ATPase and proinflammatory (exp. in cornea)

Front 57

ARACHIDONIC ACID

1. Which CYP metabolizes arachidonic acid to active metabolite 12(R)-HETE?

2. What does 12(R)-HETE do?

Back 57

1. CYP1A1
cl
2. is present in the cornea and rod photoreceptor cells. Inhibits Na+/K+-ATPase in cornea, also potent inhibitor of vascular reactivity

Front 58

ARACHIDONIC ACID

1. Name the two distinct cyclooxygenase isoforms that have been identified and describe them.

2. What inhibits cyclooxygenases?

Back 58

1. a. COX-1
- constituitively expressed
- involved with blood vessels, kidneys, and the stomach
b. COX-2
- inducible during inflammation
- corticosteroids suppress this induction

2. nonsteroidal anti-infllammatory drugs (NSAIDs)

Front 59

ARACHIDONIC ACID

LIPOXYGENASES
Mechanism of action

Back 59

1. active in leukocytes, including mast cells, eosinophils, neutrophils, monocytes and basophils

2. when these cells are activated, arachidonic acid is liberated from cell membrane phospholipids by PLA2, and donated by the 5-lipoxygenase activating protein (FLAP) to 5-lipoxygenase. 5-lipoxygenase converts it in two steps to leukotriene A4 (LTA4), an unstable epoxide

Front 60

ARACHIDONIC ACID

What is leukotriene A4 (LTA4) converted to in:

1. neutrophils and onocytes?

2. mast cells and eosinophils?

Back 60

1. LTA4 --> LTB4, which is a powerful chemoattractant for neutrophils acting at BLT1 and BLT2 receptors on the plasma membrane of these cells

2. LTA4 --> LTC4 (cysteinyl-leukotrienes) by a LTC4 synthase. If released from the cells, LTC4 can be converted by ubiquitous enzymes to from successively other cysteinyl-leukotrienes LTD4 and LTE4, which retain biological activity

Front 61

ARACHIDONIC ACID

What is the mechanism of action of cysteinyl-leukotrienes found in the lipoxygenase pathway?

Back 61

They act at their cell-surface receptors CysLT1 and CysLT2 located on mast cells, eosinophils and endothelial cells. They:
1. contract bronhcial and vascular smooth muscle
2. increase vascular permeability of small blood vessels
3. enhance secretion of mucus in the airway and gut
4. recruit leukocytes to sites of inflammation

Front 62

ARACHIDONIC ACID

How is lipoxygenase excreted from the body and what can inhibit lipoxygenases?

Back 62

LTB4 and the cyseinyl-leukotrienes are partly degraded in local tissues, and ultimately to inactive metabolites in the liver.

Some NSAIDs inhibit them.

Front 63

LEUKOTRIENES

What are the pharmacological effects of the cysteinyl-leukotrienes (LTC4, LTD4, LTE4)?

Back 63

1. produce contraction of bronchiolar smooth muscles (asthma): airflow obstruction

2. increased secretion of mucous: mucousal accumulation

3. increase vascular permeability

Front 64

LEUKOTRIENES

What are the pharmacological effects of LTB4?

Back 64

1. increase chemotaxis of polymorphonuclear lymphocytes in airway walls

2. release lysosomal enzymes

3. causes adhesions of WBCs

Front 65

LEUKOTRIENES

What happens when cysteinyl-leukotriene binds to the CysLT1 and CysLT2 receptors?

Back 65

They can stimulate proinflammatory activities such as endothelial cell adherence and chemokine production by mast cells. As well as mediating inflammation, they induce asthma and other inflammatory disorders.

Front 66

LEUKOTRIENES

What are the two oral therapeutic approaches to blocking the action of leukotrienes for prevention and chronic treatment of asthma in adults and children over 12 years of age as well as seasonal allergic rhinitis?

Back 66

1. inhibit the 5-lipoxygenase pathway

2. block the CysLT1 receptor (antagonists of)

Front 67

LEUKOTRIENES

What drugs inhibit the 5-lipoxygenase pathway?

Back 67

1. Zileuton (Zyflo)
2. MK-866

Front 68

LEUKOTRIENES

Which CYPs metabolizes Zileuton and what is it's half life?

Back 68

CYP1A2, CYP3A4, CYP2C9

half-life = 2.5 hours

Front 69

LEUKOTRIENES

How does MK-866 work and what can be another use for it?

Back 69

it inhibits FLAP and may also be useful in the treatment of artherosclerosis

Front 70

LEUKOTRIENES

Name the drugs that are antagonists of CysLT1 Receptor

Back 70

1. Montelukast (Singulair)
2. Zafirlukast

Front 71

LEUKOTRIENES

Which CYPs metabolizes Montelukast and what is it's half life?

Back 71

CYP1A2 and CYP3A4

half-life = 2.7 - 5.5 hours

Front 72

LEUKOTRIENES

Which CYPs metabolizes Zafirlukast and what is it's half-life?

Back 72

CYP2C9

half-life = 10 hours

Front 73

LEUKOTRIENES

How does antagonists of CysLT1 receptors work?

Back 73

1. block LTD4 action on the CysLT1, which is an orphan G-coupled protein receptor

2. normally used as adjuncts to the standard therapy of inhaled steroids with inhaled long- and/or short-acting beta-agonists

Front 74

PROSTAGLANDINS AND THROMBAXANES

Mechanism of action

Back 74

1. Prostaglandins are not stored but are synthesized in response to diverse stimuli and released into the extracellular space. Prostaglandin release is stimulated by histamine and kinins.

2. Prostaglandins and thrombaxane A2 (TXA2) act primarily as local hormones (autocoids)

3. Prostaglandins are potent vasodilators - they also cause constrictor effects on selected sites

Front 75

PROSTAGLANDINS AND THROMBAXANES

What are the pharmacological effects of thrombaxane A2 (TXA2)?

Back 75

1. produced mostly by platelets
2. promotes platelet aggregation
3. cause vasoconstriction. Half-life of 1 minute.
4. mobilize intracellular calcium and cause contraction of smooth muscle

Front 76

PROSTAGLANDINS AND THROMBAXANES

What are the pharmacological effects of PGE2?

Back 76

1. produced by most tissues: especially the kidneys
2. causes vasodilation
3. relaxes smooth muscle
4. used to induce labor

Front 77

PROSTAGLANDINS AND THROMBAXANES

What are the pharmacological effects of PGF2-alpha?

Back 77

1. produced by most tissue
2. vasoconstriction
3. contraction of smooth muscle (stimulates uterine contraction)
4. regulation of IOP

Front 78

PROSTAGLANDINS AND THROMBAXANES

What are the pharmacological effects of PGI2 (Prostacyclin)?

Back 78

1. produced by endothelium of vessels
2. cause vasodilation: more potent vasodilator than PGE2
3. inhibit platelet aggregation
4. inhibit gastric acid and pepsin secretion and stimulates mucus secretion

Front 79

NSAIDS

Clinical uses of

Back 79

1. acute and chronic rheumatoid arthritis
2. osteoarthritis
3. analgesia
4. primary dysmenorrhea
5. ophthalmic: post-operative inflammation after cataract extraction

Front 80

NSAIDS

Major GI side effects

Back 80

1. Prostaglandins inhibit gastric acid secretion and have a protective effect on the mucosal lining (mediated via prostacyclin)

2. All NSAIDs interfere with platelet aggregation by inhibiting formation of Thrombaxaine A2. This prolongs bleeding time and can cause a gastric ulceration, bleeding and perforation.

Front 81

NSAIDS

Major kidney side effects

Back 81

1. prostaglandins are synthesized mainly in the renal medulla, ascending loop of Henle and cortex. The renal prostaglandins influence several important renal functions: total blood flow, distribution of blood flow, sodium and water retention, and renin release.

2. Inhibition, mainly COX-1, causes decreased glomerular filtration rate, and sodium and water excretion. These can lead to acute renal failure, increased blood pressure, loss of pharmacological control of hypertension, and lithium intoxication for patients on lithium therapy.

Front 82

NSAIDS

Mechanism of action

Back 82

A. Analgesic
- block generation of pain signal by inhibiting synthesis of PGE2
- arachidonic acid metabolites, including prostaglandins and leukotrienes, do not directly stimulate nerve endings on nocio receptors. Rather they sensitize nociceptors to bradykinin or histamine, which then interact with substance P to stimulate free nerve endings

B. Anti-inflammatory
- inhibition of COX-1 and COX-2

C. Anti-pyretic
- inhibition of prostaglandin synthesis in the CNS: hypothalamic heat-regulating center

Front 83

NSAIDS

What is the difference between the old classification of drugs and the new classification?

Back 83

Old classification based on chemical structure and new classification based on COX inhibition

Front 84

NSAIDS

Name the drugs based on the old classification

Back 84

SALICYLATES
aspirin
salicyclic acid

PARA-ACETO-AMINOPHENOLS
acetominophen (Tylenol)

PROPIONIC ACIDS: largest group
ibuprofen (Advil, Motrin, Nuprin)
naproxen (Naprosyn)
naproxen sodium (Aleve)
fenoprofen (Nalfon)
ketoprofen (Orudis, Oruvail)

Front 85

NSAIDS

Name the drugs based on the new classification

Back 85

SELECTIVE COX-1 INHIBITORS
low dose aspirin

NON-SELECTIVE COX INHIBITORS
high dose aspirin
NSAIDS

SELECTIVE COX-2 INHIBITORS
meloxicam (Mobic)

HIGHLY SELECTIVE COX-2 INHIBITORS
rofecoxib - withdrawn
valdecoxib - withdrawn
celecoxib (Celebrex)

Front 86

NSAIDS

What is Celecoxib (Celebrex)?

Back 86

-a highly selective COX-2 inhibitor.

-Used in treatment of: osteoarthritis, rheumatoid arthritis, acute pain, painful menstruation and menstrual symptoms, and reduces the number of colon and rectum polyps in patients with familial adenomatous polyposis (also decreases colorectal cancer risk)

-minimizes GI adverse reactions

- reduced affect on platelet aggregation compared to traditional NSAIDs

- halfe-life = 11 hours

- metabolized mainly by CYP2C9

- contains a sulfonamide