Tuesday 3 - memorize these sheets ILT

Question 1

what leaks large molecules

Answer 1

post capillary venules

Question 2

what cause Redness - Vasodilation

Answer 2

Histamine
PGE2
PGI2
Kinins

Question 3

what molecules cause Swelling - Increased vascular permeability

Answer 3

Histamine
Peptido leukotrienes (LTC4, LTD4, LTE4)
Kinins

Question 4

what molecules cause Pain - Causes pain or reduces the pain threshold

Answer 4

PGE
PGI
LTB4
Kinins

Question 5

What molecules are Chemotactic - Directed migration of white blood cells

Answer 5

LTB4 (neutrophils, etc)

Peptido leukotrienes (eosinophils)

Question 6

what molecule induces fever

Answer 6

PGE

Question 7

What molecules cause bronchoconstriction

Answer 7

Histamine
Peptido leukotrienes***
Kinins
PGD2
Thromboxane

Question 8

what cause Hypotension

Answer 8

Kinins!!!!

Histamine

Question 9

Histamine

Answer 9

Redness, heat, swelling and airway constriction – but not chemotaxis.

Question 10

PGE2 and PGI2

Answer 10

vasodilate, increase vascular permeability and cause pain

Question 11

PGD2 and thromboxane

Answer 11

bronchoconstriction

Question 12

TXA2

Answer 12

causes platelet aggregation (and vasoconstriction)

Question 13

PGI2

Answer 13

opposes platelet aggregation (and causes vasodilation)

Question 14

LTB4

Answer 14

is chemotactic (PMNs) and reduces pain threshold

Question 15

Kinins (Bradykinin and kallidin)

Answer 15

Everything
Also very strong vasodilator with resulting hypotension!!!!
Not a major chemotactic agent.

Question 16

WHAT TYPE OF AGONISTS ARE ANTIHISTAMINES

Answer 16

inverse agonists - they lower levels of activity when bound to histamine receptors (historically called competative agonists)

Question 17

H1 histamine receptor stimulation

Answer 17

Bronchoconstriction
Contraction of GI smooth muscle
Increased capillary permeability (wheal)
Pruritis (itch) and pain
Release of catecholamines from the adrenal medulla

Question 18

H2 receptor stimulation by histamine will cause

Answer 18

Gastric acid secretion****
Inhibition of IgE-mediated basophil histamine release
Histamine release by antigen feeds back to turn off its own release
Inhibition of T lymphocyte mediated cytotoxicity
Suppression of Th2 cells and cytokines

generally slower

Question 19

H3 and H4 receptors

Answer 19

Present on histaminergic nerve terminals (H3) and many immune cells (H4; eosinophils, dendritic cells, T cells, neutrophils). Histamine can regulate activity of all of these cells through the H3 and H4 receptors.

Question 20

Mixed H1 and H2 receptor mediated responses.
Cardiac effects (H1 and H2)

Answer 20

• increased heart rate
• increased force of contraction
• increased arrhythmias
• Slows AV conduction (primarily H1)

Question 21

“triple response of histamine”

Answer 21

• Vasodilation (H1 & H2)
• Flare - H1 (probably H2 also)
• Wheal - increased capillary permeability (edema) is primarily H1 but may also involve H2
• Pain and itching (primarily H1)

then why are there four bullet points and five different Sx…….?

Question 22

Metabolism and excretion of first generation antihistamines

Answer 22

Transformed to inactive metabolites in the liver and excreted in the urine.

Question 23

Side effects of first generation antihistamines

Answer 23

 Sedation
 Drying of secretions
 GI disturbances

Question 24

first gen anti hista Acute poisoning

Answer 24

Resembles atropine poisoning
Fixed - dilated pupils, Flushed face and fever with dry mouth
Dominant effect - excitation, hallucinations, incoordination, convulsions
Terminally - coma and cardiorespiratory collapse

Question 25

ftwo first gen antihistamines and SE

Answer 25

```  Diphenhydramine (OTC) Low incidence of GI side effects Sedation If you want sedative actions as well, use diphenhydramine  Chlorpheniramine (OTC) Most suitable for day time use ``` ANTICHOLINERGIC ANTIMUSCARINIC

Question 26

Second generation antihistamines

Answer 26

Minimal anticholinergic properties Do not cause sedation and drying of secretions Cetirizine (OTC) Fexofenadine Loratadine (OTC) (claratin) Only small amounts cross the blood-brain barrier and they cause less sedation than first generation H1 antagonists DONT HAVE ANTICHOLINERGIC EFFECTS (DON'T STOP THE SYMPATHETIC NERVOUS SYSTEM)

Question 27

Prostanoids - what makes them

Answer 27

Synthesis By Phospholipase A2

Question 28

Cyclooxygenase (COX) | makes what

Answer 28

• key enzyme for the two step synthesis of PGH2 in the cell

Question 29

COX-1

Answer 29

* Found in platelets | * Constitutively expressed in most cells and is thought to protect the gastric mucosa

Question 30

COX-2

Answer 30

* Not found in platelets * Expressed constitutively in the brain and kidney, but can be induced by certain serum factors, cytokines and growth factors in other tissues and at sites of inflammation. * The more important isozyme in the production of prostaglandins and thromboxane in inflammation.

Question 31

What prostaglandin receptor causes platelet aggregation what are it's natural agonists

Answer 31

TP TXA2, PGH2

Question 32

all the non selective NSAIDS

Answer 32

• Aspirin – irreversibly acetylates COX • tNSAIDs or traditional NSAIDS or non-selective COX inhibitors o Older inhibitors of both COX1 and COX2 Ibuprofen- fewer GI side effects than aspirin, OTC Naproxen, OTC Ketorolac – promoted primarily for analgesia but is also anti-inflammatory Ketoprofen - related to ibuprofen Indomethacin, most potent NSAID, severe frontal headache & blood disorders Sulindac Piroxicam - once a day administration, can cause dose related serious GI bleeding

Question 33

• Selective COX2 inhibitor or ‘coxib’ differences between it and nonselectives

Answer 33

Celecoxib (Celebrex) – 200 mg/day, 10-20X more selective for COX2 COX 2 is not in platelets, so COX 2 inhibitors dont inhibit clotting less likely to cause gastic ulceration and intolerane, as well as hypersensitivity reaction

Question 34

disease associated with aspirin in children

Answer 34

Reye syndrome - encephalopathy and fatty liver following viral infection

Question 35

The peptide leukotrienes

Answer 35

LTC4, LTD4, LTE4

Question 36

HETEs

Answer 36

Arachadonic acid product enhance directed and random migration of white blood cells

Question 37

LTB4

Answer 37

Chemotaxis of white cells leukocyte adhesion hyperalgesia

Question 38

LTC4, LTD4, LTE4 what do they do

Answer 38

The peptide Leukotrienes Cause increased vascular permeability and swelling, leading to bronchoconstriction - important in asthma and anaphylaxis Also recruit eosinophils

Question 39

leukotriene inhibitors

Answer 39

used for chronic asthma Zileuton - inhibits 5-lipoxygenase, preventing the synthesis (!) of LTB,C,D,E4 DOES NOT SHIFT THE DOSE RESPONSE CURVE OF LEUKOTRIENES Zarfirlukast and Montelukast - leukotriene receptor antagonist (LTD4 receptor) - Zarfirlukast inhibits a cytochrome P450 and may have drug interactions - Montelukast is prescribed more because of once daily administration without restrictions with regard to meals.

Question 40

Kinins how they act on their different receptors

Answer 40

Bradykinin and Kallidin Via B1 receptor - Bradykinin and kallidin are more active WITHOUT the terminal arg • Chronic inflammatory effects • induced after trauma** • maybe involved with cytokine production and more long term effects • Hypotension and pain Via B2 Receptor - Kallidin and Bradykinin are more active here if they have terminal arginine • potent vasodilators - ******Hypotension******* • increased capillary permeability and edema formation • algesic agents - cause pain and stimulate nerve endings

Question 41

how is histamine made how is it broken down

Answer 41

histidine > L-histidine decarboxylase in mast cells and basophils, etc > histamine enzymes for metabolism are widely distributed, metabolites have little/no activity

Question 42

What happens if you give oral histamine

Answer 42

nothing, it is inactivated in intestinal wall or liver or by bacteria

Question 43

Sx of intravenous administration of histamine

Answer 43

``` BP drops tachycardia bronchoconstriction flushing headache wheal mucus production gastric acid secretion ```

Question 44

Do H1 antagonists help with congestion?

Answer 44

NO Sudafed, an alpha agonist that constricts blood vessels, however, does.

Question 45

how long does it take to see the effects of nasal steroids?

Answer 45

days. | they need to regulate transcription factors in order to work

Question 46

what type of receptor does prednisone bind What are some adverse effect that she talked about in class

Answer 46

glucocorticoid receptor osteoporosis, immunosuppresion, hyperglycemia

Question 47

diphenhydramine - works on what symptoms of an allergic reaction doesn't work on inhibiting the release of what

Answer 47

blocks H1, primarily works against the itching effect doesn't inhibit the production of prostanoids

Question 48

most potent bronchoconstricor of the peptide leukotrienes

Answer 48

LTC4

Question 49

What shifts the histamine curve but not the acetylcholine curve?

Answer 49

Loratadine! The non drowsy antihistamines

Question 50

enzyme incubated with LTA4 causes production of substance that causes very potent bronchoconstriction. what enzyme is it?

Answer 50

LTA4 -> glutathione transferase -> LTC4

Question 51

function of angiotensin converting enzyme

Answer 51

AKA ACE ACE degrades bradykinin (Bradykinin lowers BP) also converts angiotensin 1 into 2, which constricts blood vessels, driving up blood pressure 2 fold effect!

Question 52

Mech of aspirin hypersensitivity

Answer 52

shunting of AA enzyme metabolites to the Leukotriene pathway

Question 53

What enzyme receptors is critical for neutrophil migration into the lung

Answer 53

C5a Receptor

Question 54

Mycophenolate Mofetil

Answer 54

Used to prevent organ transplat rejection • Mechanism: A metabolite is an inhibitor of inosine monophosphate dehydrogenase (IMPDH), an important enzyme in the de novo pathway of guanine nucleotide synthesis. B and T cells are highly dependent on this pathway for cell proliferation, while other cell types can use salvage pathways

Question 55

Fexofenadine's effects on a dose response curve of Acetylcholine

Answer 55

No change fexofenadine is a second generation anti histamine

Question 56

What drugs can you use to pretreat someone who is going to possibly have an anaphylactic shock

Answer 56

Any of the Leukotriene inhibitors, Zileuton, Montelukast, the other "kast" also prednisone

Question 57

what is the major enzyme that forms leukotrienes from arachidonic acid

Answer 57

lipoxygenase

Question 58

What synthesizes bradykinin and kallidin and where is it found

Answer 58

Kallifrein found outside of cells in tissues and plasma

Question 59

Carboxypeptidase N

Answer 59

– found in plasma, modifies bradykinin by removing the terminal arginine important in breaking down kinins

Question 60

LTA4 hydrolase

Answer 60

found in myelomonocytic cells (basophils and mast cells) o Converts leukotriene A4 (cannot interact with any receptors) to leukotriene B4 (biologically functional substrate)

Question 61

glutathione transferase

Answer 61

Makes the peptide leukotrienes (C,D,E4) from LTA4 by adding glutathione AA (a peptide)

Question 62

Why is thrombosis a risky side effect of celecoxib?

Answer 62

because it doesn't stop the formation of thromboxane, which is made via COX1 inside platelets

Question 63

What is the biggest difference betwee prednisone and cortisol

Answer 63

prednisone only acts on glucocorticoid receptors 'cortisol work on mineralcorticoid receptors as well