Renal, Autocoids, Gout, Nsaids Physiology

Front 1

50-70% of Na is reabsorbed...

Back 1

in the proximal tubule.

Front 2

Filtrate leaving Proximal Tuble is _______. Why?

Back 2

Isomotic

Na is reabsorbed and the PT is permeable to water as well.

Front 3

Fluid leaving the PT is _________.
Filtrate leaving the Descending Loop of Henley is ________.
Filtrate leaving the thin ascending LOH is _________.
Filtrate leaving the thick ascending loop of henley is _________.

Back 3

Fluid leaving the PT is Isotonic. (Na reabsorbed and water permeable)

Filtrate leaving the Descending Loop of Henley is Hypertonic. (water permeable only)

Filtrate leaving the thin ascending LOH is Hypotonic. (Water IMpermeable, Na is passively reabsorbed).

Filtrate leaving the thick ascending loop of henley is Hypotonic. (Impermeable to water, Active Na reabsorption.).

Front 4

Sections permeable to water:

Back 4

PT
Descending LOH.

Front 5

Na reabsorption depends on...

PT
Ascending thin limb of LOH
Ascending thick Limb?
Distal convoluted Tubule?

Back 5

PT: Depends on The actions of CA (antiport with H+).

Ascending thin limb: PASSIVE REABSORPTION

Ascending thick limb: ACTIVE REABSORPTION

Distal convoluted Tubule: Coport with Cl.

Front 6

The ____ transporter in the ________ is essential in the development of a hypertonic intermedullary interstitium.

Back 6

The Na/K/Cl transporter in the thick ascending limb of the loop of henley is essential in the development of a hypertonic intermedullary interstitium. Absorbed Na is pumped into the intersititum.

Front 7

5% of Na is reabsorbed in the..

Back 7

Distal convoluted Tuble (NaCl transporter).

Site of action of thiazide diuretics.

Front 8

3% of Na is reabsorbed in the

Back 8

Collecting Duct.

Front 9

Electrolyte disturbances assoc with diuretics occur where in the kidneys?

Back 9

The collecting duct.

Front 10

T/F

Water reabsorption in the collecting duct is passive.

Back 10

True

Via the concentrated medullary interstitium and aquaporins inserted by ADH.

Front 11

Describe the steps to forming Uric Acid in the Blood.

Uric acid is an end product of _____ _____ metabolism.

Back 11

Uric Acid is an endproduct of PURINE NUCLEOTIDE metabolism.

1) Nucleic Acids (Adenosine monophosphate (AMP) and Guanosine Monophosphate (GMP)) get converted to Hypoxanthine & Guanine respectively, and then to Xanthine in the blood.

2) The enzyme Xanthine Oxidase (blocked by Allopurinol) converts Xanthine to Uric Acid.

3) Uric Acid can precipitate in the joints and cause GOUT.

PRIMARY CAUSES
* Metabolic: Over producers of Uric Acid
* Renal (under excretors due to a problem at the OAT transporter. )

SECONDARY CAUSES
* DRUGS
---> Diuretics/ Low Dose ASA: Competition at OAT sites
---> Ethanol: Increased production of purine nucleotides, Decreased secretion of purine nucleotides
* LESCH-NYHAN SYNDROME: Mutation in the enzyme that recycles purine nucleotides. Cannot salvage them. Leads to hyperuricemia, gout, and self mutilation (chewing fingers).
* TUMOR LYSIS SYNDROME: Cell lysis causes dumping of purine nucleotides AMP and GMP. This can precipitate gouty arthritis.

Front 12

Hyperuricemia is defined as

Men: > __ mg/dl uric acid
Women: > __ mg/dl uric acid

Is this a disease (gout?)

Back 12

Hyperuricemia is not a disease unless it leads to gouty arthritis.

Men > 7 mg/dl uric acid
Women > 6 mg/dl uric acid

Front 13

How gout forms...

Back 13

Hyperuricemia leads to formation of URATE CRYSTALS in joints and cartiledge.

INITIAL RESPONSE: Phagocytosis of urate crystals increases synthesis and release of inflammatory mediators (cytokines, LTs, PGs, lysosomal enzymes, etc).
SECONDARY RESPONSE: Migration of polymorphonuclear leukocytes and macrophages exacerbate ongoing inflammatory responses.

PRIMARY CAUSES
* Metabolic: Over producers of Uric Acid
* Renal (under excretors due to a problem at the OAT transporter. )

SECONDARY CAUSES
* DRUGS
---> Diuretics/ Low Dose ASA: Competition at OAT sites
---> Ethanol: Increased production of purine nucleotides, Decreased secretion of purine nucleotides
* LESCH-NYHAN SYNDROME: Mutation in the enzyme that recycles purine nucleotides. Cannot salvage them. Leads to hyperuricemia, gout, and self mutilation (chewing fingers).
* TUMOR LYSIS SYNDROME: Cell lysis causes dumping of purine nucleotides AMP and GMP. This can precipitate gouty arthritis.

Front 14

How is Gout treated?

Back 14

ACUTE ATTACKS: Decrease the inflammation

CHRONIC ATTACKS:
1) Increase UA excretions and decrease it's production.
2) Decrease dietary intake of purines: LOW CARB, HIGH PROTEIN, UNSATURATED FAT DIET
3) Avoid Alcohol!!

Front 15

Is aspirin used to tx gouty arthritis? Why or why not?

Back 15

NO!

Low dose ASA competes with UA at OAT transporters, decreasing PT secretion of UA!!!

High dose ASA dose the opposite...but you still don't use it because of the low dose effects.

Front 16

What are some adverse effects of Chronic drug therapy for Chronic Gouty Arthritis?

Back 16

* They do not help an acute attack

* They can precipitate acute attacks as uric acid is mobilized from joints.

* Can cause renal stone formation from urate or xanthine in the urine. This can be tx with increased fluids and alkalinized urine (bicarb).

Front 17

Acute gouty arthritis is tx with ....

Chronic gouty arthritis is tx with...

Back 17

ACUTE
* NSAIDS and Colchicine

CHRONIC
* Colchicine
* Probenecid
* Sulfinpyrazone
* Allopurinol

Front 18

Over producers of UA are treated with ______.

Under secretors of UA are treated with _______.

Back 18

Over producers of UA are treated with allopurinol.

Under secretors of UA are treated with probenecid.

Front 19

List some autocoids

Back 19

Act locally on demand

Histamine
Serotonin
Eicosanoids: Prostaglandins and Leukotrienes
Cytokines.

Front 20

Drugs that decrease histamine release

Back 20

A. Mast cell stabilizers
Cromolyn sodium
Nedocromil

 
B. H1 receptor antagonists
Diphenhydramine
Fexofenadine
Loratadine
 
C. H2 receptor antagonists
Cimetidine

Front 21

The highest concentrations of histamine in the body are in the _____, ____, _________. _____ ____ are the primary storage site for histamine in the body. The drugs _______ and _______ block histamine release from mast cells by...

Back 21

The highest concentrations of histamine in the body are in the lungs, skin, and intestinal mucosa. Mast cells are the primary storage site for histamine in the body. The drugs Cromolyn Sodium and Nedocromil block histamine release from mast cells by blocking Ca dependent degradation of the these cells.

Front 22

Other storage site for histamine (other than mast cells) are ______, and _______.

Back 22

Other storage site for histamine (other than mast cells) are basophils, and enterochromaffin-like (ECL) cells in the stomach, brain, and synaptic vesicles.

Front 23

Histamine formed by the enzyme...

Back 23

Histamine decarboxylase.

Front 24

What is the key role of histamine in the CNS?

Back 24

Arousal.

So antihistamines make you sleepy.

Front 25

Roles of histamine

Back 25

Gastric Acid Secretions (H2 on ECLs)
Arousal (H3)
Acute Inflammatory Responses (mast cell release)
Neurotransmitter
Bronchoconstriction (H1)
Wheals/ Hives (H1)
Urticaria (H1)

Front 26

What things stimulate Ca dependent degradation of Mast Cells, causing Histamine release?

Back 26

* Allergies (Type 1 Sensitivity Rxns) - This is an immunological response.

* Drugs: Morphine, Tubocurare, Atracurium

This causes the following response:

Allergen (A) exposure
-->production of IgEs (sensitization)
--> Allergen (A) re-exposure
-->activation of IgE receptors
-->stimulation of second messenger systems
-->increases in intracellular Ca++ levels
-->histamine release

Front 27

Histamine to H1 receptors causes:

Back 27

Bronchoconstriction
Wheals/ Hives - Edema
Urticaria

Front 28

Histamine release from _____ in the GI tract is stimulated by 1) ____ to _____ receptors and by _____ release from G cells. Gastrin is inhibited by ______ release from the gastric antrum. This decreases histamine release.

Back 28

Histamine release from ECL cells in the GI tract is stimulated by 1) ACh to M1 receptors and by Gastrin release from G cells. Gastrin is inhibited by Somatostatin release from D cells in the gastric antrum. This decreases histamine release.

Front 29

Activation of H2 receptors on the _____ cells of the stomach stimulates the ________ by increasing _____. This can also be stimulated by _____ and ______ via non-______ dependent mechanisms.

Back 29

Activation of H2 receptors on the Parietal cells of the stomach stimulates the H+/K+ ATPase proton pump by increasing cAMP. This can also be stimulated by ACh-M3 and Gastrin via non cAMP dependent mechanisms.

Front 30

How does H. Pylori affect histamine release?

Back 30

. In H pylori infection, there is a decrease in the # of D cells in the stomach…this means decr somatostatin levels, no inhibitory tone. Excessive histamine release.

Front 31

Things that increase gastric acidity, leading to ulcers

Things that decrease gastric mucosal defense...leading to ulcer

Back 31

INCREASE ACID
* Zollinger Ellison Syndrome (gastrin secreting tumor)
* Smoking (increase histamine release)
* Alcohol

DECREASE MUCOSA
* H. Pylori
* NSAIDS
* Stress
* Smoking
* Ethanol

Front 32

What causes GERD and how is it treated?

Back 32

GERD is caused by a hypomotility disorder of the Lower Esophageal Sphincter.

GERD means decr LES tone. Reflux can lead to esophagitis.

Tx GERD by incr pH of the gastric contents:
* H2 antags (act on parietal cells).
* PPIs


There is a delay in the clinical efficacy of the the PPI’s(3-7 days to provide symptomatic relief) so H2 antagonists are still effective..

Front 33

What drugs can cause impotence in men?

What drugs can cause infertility and gynecomastia in women?

Back 33

Loop Diuretics cause impotence in men due to the dehydration.

Spirinolactone and H2 antagonists causes anti-androgen effects in men and women: decrease sperm count, gynecomastia, decrease fertility in women.

Front 34

The pharmacological action of HIstamine?

Back 34

1) Relaxation of vascular smooth muscle
2) Stimulation of non-vascular smooth muscle
3) Stimulation of glandular tissue
4) Arousal

Front 35

T/F H1 antags are ineffective in tx of systemic anaphylaxis

Back 35

True

Only used as an adjunct med in these cases because autocoids other than histamine (cytokines, leukotrienes) are causing the bronchoconstriction and anayphylaxis.

Front 36

________ decrease basal and stimulated secretion of gastric acid
and are used therapeutically to treat and prevent reoccurrence of gastric
and duodenal ulcers.

Back 36

H2 antagonists decrease basal and stimulated secretion of gastric acid
and are used therapeutically to treat and prevent reoccurrence of gastric
and duodenal ulcers.

Front 37

What is the drug of choice for treating ACUTE gouty arthritis?

Back 37

Indomethecin

(An NSAID)

Front 38

How is serotonin formed?

Back 38

L-tryptophan is converted to L-5-Hydroxytryptophan by the enzyme TRYPTOPHAN HYDROXYLASE. (This is the rate-limiting step.)

L-50Hydroxytryptophan is converted to 5-Hydroxytryptamine (Serotonin) by the enzyme AROMATIC AA DECARBOXYLASE.

Front 39

What is the rate limiting enzyme in the synthesis of serotonin (5-Hydroxytryptamine, 5-HT)?

Back 39

Tryptophan Hydroxylase

Front 40

5-HT3 (serotonin) receptors

(where are they and how do they work?)

Back 40

Ligand gated Ion Channels

In the GI tract they FACILITATE PERISTALSIS

In the CTZ of the brain they CAUSE NAUSEA

Front 41

G-protein coupled serotonin (5-HT) receptors

Back 41

Everything BUT 5-HT3

Front 42

The roles of serotonin

Back 42

A) Gastrointestinal tract: entoerochromaffin cells are site of synthesis and storage. Here they increase peristalsis.
 
B. Platelets: have 5Ht receptors on them…serotonin must be taken up into the plts for them to be able to aggregate. They rely on serotonin reuptake…which depends on serotinin transporters.

C. Cardiovascular system: vasoconstriction (also in cerebral vasculature causing migraines). Serotonin name came from “serum tonic”
 
D. CNS: neurotransmitter. : regulates mood, pain, etc.

Front 43

Most serotonin in the body is found where?

Back 43

In the GI tract. (ECL cells produce and store it.).

Front 44

Platelet aggregation depends on what aspect of serotonin physiology?

Back 44

Depends on serotonin TRANSPORTERS, which transport serotonin into plts. This allow them to aggregate.

Front 45

Serotonergic Drugs

Back 45

Ergot alkaloids /Derivatives
* Ergotamine --Partial agonist at 5-HT-1Rs
* Ergonovine --Partial agonist at 5-HTRs
* Methyl ergonovine --Partial agonist at 5-HTRs

Triptans: 5-HT1B/5-HT1D agonists
* Sumatriptan

Front 46

Migraines are more common in

Back 46

* Females (3:1)
* Stress

* Caused by steroids: Estrogen during periods, stress hormones during stress.

* Cerebral Vasodialtion - Inflammatory mediators found.

Front 47

Differentiate a common migraine from a Classic migrane (tension headache).

Back 47

COMMON MIGRAINE
* Unilateral Headache
* Progressively worsens
* Absence of an Aura

CLASSIC MIGRAINE
* Aura present (hallucinations, Speech Abnormalities, Photophobia)
* Nausea/ Vomiting present
* can last hours to days.

Front 48

T/F

We are certain that serotonin causes migraines.

Back 48

False

the role of serotonin in the pathogenesis
of migraine remains to be determined.

Front 49

_____ is the product of a fungus that grows on grains.

Back 49

Ergot is the product of a fungus (Claviceps purpurea) that grows on grains.

Front 50

what is the Drug of Choice for prophylactic tx of migraines?

What about for acute migraines?

Back 50

Propanolol - Prophylactic DOC

Ergotamine and Triptophans - Acute tx.

Front 51

Drugs used for prophylactic tx of migraines

Back 51

Beta-receptor blockers (propranolol; drug of choice)
Valproic acid
TCAs (amitriptyline)
Verapamil.

Front 52

Explain the cascade for EICOSANOIDS: phospholipid derived autocoids

Back 52

* Membrane Phospholipids in the endothelial cell are converted to Arachidonic Acid by Phospholipase A2. This enzyme is Ca sensitive and needs Ca to be activated. (Steroids block this enzyme).

*Arachidonic Acid is converted to Prostaglandins by Cyclooxygenase 1 and 2, and to Leukotrienes by Lipoxygenase.

* Prostaglandins are then converted into:
--> Prostaglandins A-F
---> Prostacyclins (VDrs)
---> Thromboxane A2 (VCr).

Front 53

Glucocorticoids inhibit the enzymes ________ and ________.

NSAIDS inhibit the enzyme _________.

Back 53

Glucocorticoids inhibit the enzymes Phospholipase A2 and Cyclooxygenase.

NSAIDS inhibit the enzyme COX 1 and 2. .

Front 54

Actions of Prostaglandins

Back 54

PGE2 /PGI2(Prostacyclin)
-->cytoprotective: decr gastric acid secretion, inr mucus secretion, incr blood flow, incr bicarb secretion

PGE2 /PGFs/PGI2/TXA2
--->contraction of GI smooth muscle (peristalsis)

PGE2/PGF2
--->contraction of uterine muscle

PGE2 maintains patency of the Ductus Arteriosus

PGE2/PGI2
---> Renal vasodilation: incr GFR, incr renal blood flow; natriuresis; diuresis
---> Systemic VD: incr blood flow, decr BP

Front 55

Pharmacologic Roles of NSAIDS

Back 55

ANTI-INFLAMMATORY
* Inhibit prostaglandin synthesis.

ANTI-PYRETIC (CNS)
* Fever is caused by increased cytokine and prostaglandin levels (PGE-2), which activate the hypothalamus to increase body temp.

ANTI-ANALGESIA (CNS and peripery)
* Prostaglandins produce pain via inflammation and by decr pain threshold via c-fiber activation.
* Thermal injury and body injury leads to an incr in bradykinen and cytokines, which leads to the production of prostaglandins and pain.

Front 56

Differentiate Osteoarthritis and Rheumatoid Arthrits

Back 56

RHEUMATOID ARTHRITIS
* Autoimmune disorder that causes inflammation of joints.

OSTEOARTHRITIS
* Not autoimmune, NO Inflammation. Loss of articular cartiledge causes bone on bone contact. Happens in weight bearing joints.

Front 57

Reyes Syndrome

Back 57

Reyes Syndrome is a potentially fatal disease that causes numerous detrimental effects to many organs, especially the brain and liver, as well as causing a lower than usual level of blood sugar (hypoglycemia).[1] The classic features are liver damage, aspirin use and a viral infection. The exact cause is unknown, and while it has been associated with aspirin consumption by children with viral illness, it also occurs in the absence of aspirin use.

Front 58

Explain Hypersenstivity Reactions to ASA

Back 58

Symptoms similar to anaphylactic shock. But are NOT immunological in natures. In patients with hypersensitivity reaction to aspirin, ALL NSAID use is contraindicated!! Exception: nonacetylated salicylates (salsalate, sodium salicylate).

--> Asthma patients/patients with nasal polyps appear particularly susceptible: may result from shift towards synthesis of leukotrienes when COX is blocked.

Front 59

What are the two arms of the coagulation cascade? Which one does thromboxane stimulate?

Back 59

INTRINSIC PATHWAY
The intrinsic pathway, which is triggered by elements that lie within the blood inself (intrinsic to the blood), occurs in the following way. Damage to the vessel wall stimulates the activation of a cascade of clotting factors (for the sake of simplicity we will not consider the individual factors). This cascade results in the activation of factor X. Activated factor X is an enzyme that converts prothrombin to thrombin. Thrombin converts fibrinogen to fibrin monomers, which then polymerize in fibrin fibers. Fibrin fibers form a loose meshwork that is stabilized by crosslinks created by factor XIII. The stabilzed meshwork of fibrin fibers is now a clot that traps red blood cells and platelets and thus stops the flow of blood.

EXTRINSIC PATHWAY
The extrinsic pathway is triggered by tissue damage outside of the blood vessel. This pathway acts to clot blood that has escaped from the vessel into the tissues. Damage to tissue stimulates the activation of tissue thromboplastin, an enzyme that catalyzes the activation of factor X. At this point the intrinsic and extrinsic pathways converge and the subsequent steps are the same as those described above.

Thromboxane increases plt activation, so I'd say ASA effects the intrinsic pathway only.

Front 60

T/F

OTC NSAIDS are better than ASA and Ibuprofen

Back 60

FALSE

Not more efficacius than ASA
Ibuprofen has equal or LESS side effects.

So they have NO CLINICAL ADVANTAGE.

Front 61

What NSAIDS are good for pts with compromised renal function?

Back 61

Sulindac: metabolized back into it's prodrug form when it reaches the kidney to no active metabolites reach the kidney! :)

Non-acetylated salicylates (weaker than ASA).

Front 62

What types of NSAIDS are best for pts taking thiazide diuretics?

Back 62

Sulindac: metabolized back into it's prodrug form when it reaches the kidney to no active metabolites reach the kidney! :)...no effect on prostaglandins.

Non-acetylated salicylates.

Front 63

Differentiate b/c COX 1 and COX 2

Back 63

COX1
* Expressed in the stomach, kidney, plts, vasculature.
* "Housekeeping Prostaglandins" - play a role in normal physiological functions.
* Thromboxane synthesis.

COX2
* An inducible enzyme by cytokines. Responsible for prostaglandisn that are released in pain, fever, and inflammation.
* COX2 plays an important role in the kidney.