Tuesday 3 - memorize these sheets ILT Flashcards
what leaks large molecules
post capillary venules
what cause Redness - Vasodilation
Histamine
PGE2
PGI2
Kinins
what molecules cause Swelling - Increased vascular permeability
Histamine
Peptido leukotrienes (LTC4, LTD4, LTE4)
Kinins
what molecules cause Pain - Causes pain or reduces the pain threshold
PGE
PGI
LTB4
Kinins
What molecules are Chemotactic - Directed migration of white blood cells
LTB4 (neutrophils, etc)
Peptido leukotrienes (eosinophils)
what molecule induces fever
PGE
What molecules cause bronchoconstriction
Histamine Peptido leukotrienes*** Kinins PGD2 Thromboxane
what cause Hypotension
Kinins!!!!
Histamine
Histamine
Redness, heat, swelling and airway constriction – but not chemotaxis.
PGE2 and PGI2
vasodilate, increase vascular permeability and cause pain
PGD2 and thromboxane
bronchoconstriction
TXA2
causes platelet aggregation (and vasoconstriction)
PGI2
opposes platelet aggregation (and causes vasodilation)
LTB4
is chemotactic (PMNs) and reduces pain threshold
Kinins (Bradykinin and kallidin)
Everything
Also very strong vasodilator with resulting hypotension!!!!
Not a major chemotactic agent.
WHAT TYPE OF AGONISTS ARE ANTIHISTAMINES
inverse agonists - they lower levels of activity when bound to histamine receptors (historically called competative agonists)
H1 histamine receptor stimulation
Bronchoconstriction
Contraction of GI smooth muscle
Increased capillary permeability (wheal)
Pruritis (itch) and pain
Release of catecholamines from the adrenal medulla
H2 receptor stimulation by histamine will cause
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
H3 and H4 receptors
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.
Mixed H1 and H2 receptor mediated responses. Cardiac effects (H1 and H2)
- increased heart rate
- increased force of contraction
- increased arrhythmias
- Slows AV conduction (primarily H1)
“triple response of histamine”
- 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…….?
Metabolism and excretion of first generation antihistamines
Transformed to inactive metabolites in the liver and excreted in the urine.
Side effects of first generation antihistamines
Sedation
Drying of secretions
GI disturbances
first gen anti hista Acute poisoning
Resembles atropine poisoning
Fixed - dilated pupils, Flushed face and fever with dry mouth
Dominant effect - excitation, hallucinations, incoordination, convulsions
Terminally - coma and cardiorespiratory collapse
ftwo first gen antihistamines and SE
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
Second generation antihistamines
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)
Prostanoids - what makes them
Synthesis By Phospholipase A2
Cyclooxygenase (COX)
makes what
• key enzyme for the two step synthesis of PGH2 in the cell
COX-1
- Found in platelets
* Constitutively expressed in most cells and is thought to protect the gastric mucosa
COX-2
- 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.
What prostaglandin receptor causes platelet aggregation
what are it’s natural agonists
TP
TXA2, PGH2
all the non selective NSAIDS
• 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
• Selective COX2 inhibitor
or ‘coxib’
differences between it and nonselectives
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
disease associated with aspirin in children
Reye syndrome - encephalopathy and fatty liver following viral infection
The peptide leukotrienes
LTC4, LTD4, LTE4
HETEs
Arachadonic acid product
enhance directed and random migration of white blood cells
LTB4
Chemotaxis of white cells
leukocyte adhesion
hyperalgesia
LTC4, LTD4, LTE4
what do they do
The peptide Leukotrienes
Cause increased vascular permeability and swelling, leading to bronchoconstriction - important in asthma and anaphylaxis
Also recruit eosinophils
leukotriene inhibitors
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.
Kinins
how they act on their different receptors
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
how is histamine made
how is it broken down
histidine > L-histidine decarboxylase in mast cells and basophils, etc > histamine
enzymes for metabolism are widely distributed, metabolites have little/no activity
What happens if you give oral histamine
nothing, it is inactivated in intestinal wall or liver or by bacteria
Sx of intravenous administration of histamine
BP drops tachycardia bronchoconstriction flushing headache wheal mucus production gastric acid secretion
Do H1 antagonists help with congestion?
NO
Sudafed, an alpha agonist that constricts blood vessels, however, does.
how long does it take to see the effects of nasal steroids?
days.
they need to regulate transcription factors in order to work
what type of receptor does prednisone bind
What are some adverse effect that she talked about in class
glucocorticoid receptor
osteoporosis, immunosuppresion, hyperglycemia
diphenhydramine -
works on what symptoms of an allergic reaction
doesn’t work on inhibiting the release of what
blocks H1, primarily works against the itching effect
doesn’t inhibit the production of prostanoids
most potent bronchoconstricor of the peptide leukotrienes
LTC4
What shifts the histamine curve but not the acetylcholine curve?
Loratadine! The non drowsy antihistamines
enzyme incubated with LTA4 causes production of substance that causes very potent bronchoconstriction. what enzyme is it?
LTA4 -> glutathione transferase -> LTC4
function of angiotensin converting enzyme
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!
Mech of aspirin hypersensitivity
shunting of AA enzyme metabolites to the Leukotriene pathway
What enzyme receptors is critical for neutrophil migration into the lung
C5a Receptor
Mycophenolate Mofetil
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
Fexofenadine’s effects on a dose response curve of Acetylcholine
No change
fexofenadine is a second generation anti histamine
What drugs can you use to pretreat someone who is going to possibly have an anaphylactic shock
Any of the Leukotriene inhibitors, Zileuton, Montelukast, the other “kast”
also prednisone
what is the major enzyme that forms leukotrienes from arachidonic acid
lipoxygenase
What synthesizes bradykinin and kallidin and where is it found
Kallifrein
found outside of cells in tissues and plasma
Carboxypeptidase N
– found in plasma, modifies bradykinin by removing the terminal arginine
important in breaking down kinins
LTA4 hydrolase
found in myelomonocytic cells (basophils and mast cells)
o Converts leukotriene A4 (cannot interact with any receptors) to leukotriene B4 (biologically functional substrate)
glutathione transferase
Makes the peptide leukotrienes (C,D,E4) from LTA4 by adding glutathione AA (a peptide)
Why is thrombosis a risky side effect of celecoxib?
because it doesn’t stop the formation of thromboxane, which is made via COX1 inside platelets
What is the biggest difference betwee prednisone and cortisol
prednisone only acts on glucocorticoid receptors
‘cortisol work on mineralcorticoid receptors as well
