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143 Cards in this Set

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theopyhylline
-site of action?
Note: aminophylline works just like theophylline

-site of action: direct effect b/c works inside cell, thus it dilates normal lungs and if pt has taken propanolol (B blocker) b/c theophylline doesn't need B-receptor to work

S/E: seizures

MOA: (~sildenafil)
inhibits PDEase
==>inhibits degradation or cAMP
==>cAMP becomes cAMP protein kinase
==>cAMP protein kinase adds phosphate to MLC-K to become MLCK-P (inactive)
==>less MLCK-P to convert MLC to MLC-P, which is req for bronchial SmM contraction
==>less bronchial SmM contraction (easier to breathe)

S/E: seizures

Note: theo is metabolized by CYP450, so if person on theo develops a sinus infxn which req Tx with AB, which AB would require decr in daily dose of theo?
==>erythromycin (inhibits CYP450)

-similarly, asthmatic on theo develops seizure after taking OTC drug for heartburn. Rx?
==>Cimetidine (blocks CYP450, which metabolizes theo)
person is treated w/propanolol. which drug will still bronchodilate?
theophylline or aminophylline b/c their MOA=inhibits PDEase (in which intracellular, does not act via Beta receptors, which would be blocked by propanolol)

S/E: seizures
asthmatic pt taking theophylline develops sinus infxn that req Tx with AB. What AB would require lowering of daily dose of theo?
Erythromycin (b/c it blocks CYP450, which metabolizes theo)
asthmatic pt taking theophylline develops seizures after taking OTC drug for heartburn. drug?
cimetadine (b/c it blcoks CYP450, which metabolizes theophylline)
aminophylline
Note: aminophylline works just like theophylline

-site of action: direct effect b/c works inside cell, thus it dilates normal lungs and works even if pt has taken propanolol (B blocker) b/c theophylline doesn't need B-receptor to work

MOA: (~sildenafil)
inhibits PDEase
==>inhibits degradation or cAMP
==>cAMP becomes cAMP protein kinase
==>cAMP protein kinase phosphorylates MLC-K to MLCK-P (inactive)
==>less MLCK-P to phosphorylate MLC to MLC-P, which is req for bronchial SmM contraction
==>less bronchial SmM contraction (easier to breathe)

Note: theo is metabolized by CYP450, so if person on theo develops a sinus infxn which req Tx with AB, which AB would require decr in daily dose of theo?
==>erythromycin (inhibits CYP450)

-similarly, asthmatic on theo develops seizure after taking OTC drug for heartburn. Rx?
==>Cimetidine (blocks CYP450, which metabolizes theo)
cromolyn sodium
-site of action
inhibits mast cell degranulation by preventing Ca++ influx into mast cells when no IgE bridges form
==>no mast cell degran
==>no histamine release to bind H1-R

Normally:
H1-R activates IP3 (Inosine TriPhosphate (P3)), which activates MLCK, which converts MLC==>MLCK-P, which contracts bronchial SmM (hard to breathe)
ipratropium
-site of action
muscarinic antagonist
==>no muscarinic message
==>easier to breathe

Normally:
muscarinic receptor activates IP3 (Inosine Triphosphate (P3)), which activates MLCK, which converts MLC==>MLCK-P, which contracts bronchial SmM (hard to breathe)
zafirlukast
LTC4 and LTD4 receptor antagonist

Normally:
LTC4 and LTD4 receptors activates IP3, which activates MLCK, which converts MLC==>MLCK-P, which contracts bronchial SmM (hard to breathe)
beclamethasone
"--sone"=corticosteroid

Corticosteroids inhibit production of Arachidonic Acid, which is the precursor of leukotrienes and prostaglandins (which induce bronchial SmM contraction=harder to breathe).

Thus, corticosteroids make it easier to breathe (ICS lecture: Long-term Tx for Asthma=corticosteroids)

[Recall how corticosteroids decr all inflammatory substances, including LT's & PG's).

Normally:
LTC4 and LTD4 receptors (leukotrienes) & PGD4 receptor (prostaglandin) activates IP3, which activates MLCK, which converts MLC==>MLCK-P, which contracts bronchial SmM (hard to breathe)
albuterol
Tx: Asthma
("AST" drugs for Asthma:
Albuterol
Selmeterol
Terbutaline)

B2-agonist==>bronchial SmM relaxation (easier to breathe)
terbutaline
Tx: Asthma
("AST" drugs for Asthma:
Albuterol
Selmeterol
Terbutaline)

B2-agonist==>bronchial SmM relaxation (easier to breathe)
what drug causes biggest incr FEV1 with smallest incr HR?
albuterol
pt with exercise induced asthma uses cromolyn sodium prophylactically? MOA?
cromolyn prevents Ca++ influx into mast cells when IgE bridges form = no mast cell degranulation
glucocorticoids
*inhibits production of IL-1 and IL-6 by macrophages and monocytes
==>inhibits Ig synthesis by B cells (d/t decr IL-1 & IL6)
==?prevents fxns of cytotoxic T-cells (d/t decr IL-1)

*inhibits production of PG's and LT's (inflammatory substances)

*NO BM depression

Note: glucocorticoids INCR # neutrophils in blood (stim their release from BM and prevents them from moving out of blood into lymphoid tissue), but it does the opposite for all other WBC's (L, M, E, B): glucocort decr # of other WBC's in the blood by stimulating them their mvmt from blood to lymphoid tissue

S/E:
-glaucoma
-osteoporosis
-GI ulcers (d/t decr PG in stomach)
-psychosis
which drug suppresses cellular immunity, blocks synthesis of PG's and LT's, and incr #neutrophils in blood?
glucocorticoids

Note: glucocorticoids INCR # neutrophils in blood (stim their release from BM and prevents them from moving out of blood into lymphoid tissue), but it does the opposite for all other WBC's (L, M, E, B): glucocort decr # of other WBC's in the blood by stimulating them their mvmt from blood to lymphoid tissue
cyclosporine
(immunosuppressant)

inhibits calcineurin
==>prevents prod of IL2 by helper T cells
mycophenolate
(immunosuppressant)

inhibits inosine monophosphate
==>prevents purine synthesis in T and B lymphocytes
azathioprine
(cytotoxic immunosuppressant)

MOA: converted to 6-mercaptoPURINE, which is a PURINE analog
==>cannot make nucleic acids req for T and B cell prolif
cyclophosphamide
(cytotoxic immunosuppressant)

alkylates DNA

s/e: hemorrhagic cystitis
Sx:
-hypercalcemia
-hypercalcinuria;
-hyperphosphatemia
- anorexia, nausea, weight loss, weakness; dehydration

-what's the problem
-how Tx?
problem=Vit D toxicity

[dehydration develops because
hypercalcemia impairs the renal concentrating ability of the kidney]

Tx:
*aggressive hydration w/isotonic saline (goljan: first step is to restore fluids via nl saline)
*furosemide (elim Ca++)
*plicamycin (mithramycin) = cytotoxic antibiotic that prevents bone resorption
pt with renal failure has low plasma Ca++. Tx?
1,25 (OH)2 Vit D
Patient w Paget’s disease (a localized bone dx w uncontrolled osteoclastic bone
resorption and secondary in the formation of poorly organized bone) exhibits hearing loss,
bone pain, bone deformity, increased serum alkaline phosphatase, increased urinary hydroxyproline, high output HF and immobilization hypercalcemia. TX w ?
Tx w calcitonin to decrease bone pain, bone deformity, hearing loss and hypercalcemia.
Calcitonin will decrease serum Ca++ and PO4- by inhibition of osteoclastic bone resorption and
decreasing the reabsorption of Ca++ and PO4- by the kidney.
alendronate
=bisphosphanate (alendronate & etidronate)

Tx:
-glucocorticoid-induced osteoporosis
-post-meno osteoporosis
-Paget's dz (+calcitonin)

MOA: inhibit bone resorption by inhibiting osteoclasts' ability to break down hyroxyapatite crystals
post-menopausal woman requires tx to maintain bone mass, but cannot take estrogen bx her mother and sister had breast cancer. Tx w ?
alendronate or etidronate (bisphosphanates)
etidronate
=bisphosphanate (alendronate & etidronate)

Pat's mneum: Lazy 'dro smokin (hydro is a type of weed) guy named nate (smokes so much his boys call him "dro-nate") doesn't ever want to do any work or goto class--"class?? Mann fuck class!!!! I'll smoke some 'dro instead!!!"
(-dronate, “CLASS”=osteoCLASTS)


Tx:
-glucocorticoid-induced osteoporosis
-post-meno osteoporosis
-Paget's dz (+calcitonin)

MOA: incorporated into bone and inhibit osteoclast bone resorption
A patient tx with steroids develops hypocalcemia. Why?
steroids (-) Vit D's absorption of Ca++ from GI
==>low serum Ca++
==>incr PTH
==>incr renal Ca++ excretion
==>hypocalcemia & osteoporosis
Sx=pallor, fatigue, feel light-headed; craving for clay

-what's the prob?
-Tx?
Fe-def anemia

-caused by blood loss, decr GI abs of Fe, incr Fe req

-Tx:
*ferrous iron
*Vit C (incr GI abs of ferrous iron)
folate def:
-Sx?
-Tx?
Sx=
diarrhea
anorexia
sore tongue
irritability
forgetfulnes (but no neurologic Sx)

Tx?
-po folate
Sx:
-diarrhea
-anorexia
-sore tongue
-irritability
-distal parasthesias
-sensory disturbances

-Dx?
-Tx?
(mneum: think Haley)

Dx=Vit B12 def
(it's B12 def and not folate def b/c paresthesias & sensory disturbances=neurologic Sx)

-Vit B12 def causes neurologic Sx b/c B12 req to convert methylmalonyl acid==>succinyl CoA, which is req for synthesis of myelin.
-If no myelin==>demyelination of dorsolateral spinal column (dorsal column==>sensory abnl;
corticospinal tract==>UMN problems like paresthesias)

Tx: cyanocobalamin or hydroxycobalamin (cobalamin=Vit B12)
Clinical: A patient with normochromic, macrocytic anemia has distal paresthesias. The patient
is treated with p.o. folate and the anemia disppears, but the neurological S/S worsens. What happened?
Folate will correct the megaloblastic anemia, but the neurological syndrome
results from B12 deficiency because B12 is needed for the synthesis of myelin.
what Rx cause normochromic macrocytic anemia?

-why?
-how tx?
*Phenytoin
*Isoniazid
(these inhibit abs of folate in GI tract)

*TriMETHOprim (trim)
*pyramidine
*METHOtrexate
(these these inhibit DHF reductase)

--Tx with leukovorin (=folonic acid) for BM rescue
pt on hemodilaysis develops normochromic, macrocytic anemia.

-why?
-how tx?
hemodialysis clears folate out of system.

Thus, all pts on hemodialysis must be tx with:
-folate
-EPO
-ferrous iron
pt with Hct=24 is started on hemodialysis. After tx w/EPO, folate, and ferrous iron, the pt develops HTN. why?
-EPO, folate, and ferrous iron all incr viscosity of blood
==>incr viscosity of blood==>incr resistance (Poiseuille's law)

==>inct BP
what drugs can be used for "blood doping" (incr Hct) in competitive cycling?
-EPO (erythroPOETIN)
-ePOETIN alfa
-darbePOETIN
Clinical: Which synthetic glucocorticoid is used to differentiate bilateral adrenal hyperplasia from
adrenal carcinoma?
dexamethasone

(BILATERAL adrenal hyperplasia==>pituitary Cushing's
(incr ACTH causes hyperplasia of BILATERAL adrenal glands; vs. adrenal tumor usually only affects one side)

Remember the dexamethasone suppression test that you use for Cushing's! High-dose DEXA will suppress cortisol in pituitary Cushing's, but it will not suppress but will not suppress cortisol in other causes of Cushing's (adrenal carcinoma or ectopic ACTH tumor). Goljan: There are only 2 instances when an endocrine tumor can be suppressed:
-pituitary Cushing's (suppressed by high-dose DEXA)
-prolactinoma (suppressed by DOPA analogs)
which drug increases urinary excretion of 17-ketosteroids (testosterone) in pt with bilateral adrenal hyperplasia (i.e. adrenal Cushing's) hyperplasia) without incr urnary excretion of 17-OH-steroids (cortisol) in pt with adrenal carcinoma?
Metyrapone

17-ketosteroid=testosterone
17-OH-steroid=11-deoxycortisol; cortisol


Metyrapone inhibits the CYP450scc that converts 11-deoxycortisol to 11-cortisol.
==>no cortisol for negative feedback on pit
==>incr ACTH
==>stimulates entire steroidogeneis pathway
==>incr testosterone and thus urinary testosterone excretion (but no incr excretion of cortisol b/c can't convert 11-deoxycortisol to 11-cortisol)

*But in pt with adrenal carcinoma, the cortisol produced by the tumor caused negative feedback on pit
==>decreased ACTH
==>adrenal has already atrophied and thus cannot respond to incr ACTH caused by metyrapone w/incr testosterone (as in bilateral adrenal hyperplasia)
==>decr cortisol (d/t adrenal atrophy), thus no incr in urinary excretion of cortisol
what drug suppresses plasma cortisol in pt with nl pit-adrenal fxn?
ketoconazole (blocks CYP450scc)
--note, this is on Adrenal steroid genesis chart in FA Endocrine section
which drug causes "medical adrenalectomy?"
aminogluthethimide (blocks conversion of chol==>pregnenolone==>no adrenal steroidogenesis)

Tx: Cushing's
pt tx with steroids develops GI ulcer. MOA?
inhibit production of PG's to coat stomach
a patient with breast tenderness is on a drug to enhance fertility.

rx?
[breast tenderness=Sx of hyperestrogenism)

clomiphene


Blocks estrogen receptors in hypothalamus and pituitary
==>↓feedback inhibition of GnRH and gonadotropins
==>↑GnRH secretion
==>↑FSH secretion
==> ovulation
why is estradiol contraindicated in a patient w a history of thromboembolic dx (DVT's)?
estradiol incr synthesis of clotting factors
Tx breast cancer
tamoxifen (blocks est receptors)
Why do OCP's which contain an estrogen also contain a progestin?
progestin also blocks endometrial hyperplasia d/t est
Which compound can be used to maintain bone mass in a postmenopausal woman who
has had breast cancer?
raloxifene (SERM) or alendronate (bisphosphanate)
fluoxymesterone
androgen

*used for anabolic effects
*prevent catabolic action of cortisol
*stimulate erythropoiesis and protein synthesis
nandrolone
nANDROlone=ANDROgen

*used for anabolic effects
*prevents catabolic action f cortisol
*stimulates erythropoiesis and protein syn
A body builder treats himself w fluoxymesterone (an anabolic steroid). How his
spermatogenesis be affected?
suppressed

fluoxymesterone (androgen) suppress hypothalamic release of GnRH
==>less FSH from pituitary
==>less development of sperm
Clinical: A body builder has an enlarged heart and spleen, borderline DM and mild HT, but
androgenic steroids are not present in his urine. What drug is he abusing?
GH
==>increases production of IGF
Clinical: What drug will suppress the secretion of GH hormone in a patient with acromegaly?
octreotide (somatostatin analog)

or bromocriptine (DOPA analog)
Older man has arthralgia, fluid retention and hyperglycemia. What drug has the effect?
GH
Tx BPH
finasteride
==>inhibits 5α-reductase
==>decr DHT
Tx hair loss
finasteride
==>inhibits 5α-reductase
==>decr DHT
androgen receptor antagonist?
flutamide

("Unmanly men play the flute.")
Clinical: How to tx a young boy w cryptorchidism?
hCG
leuprolide
Tx:
-prostatic cancer
-endometriosis
-leiomyomas (uterine fibroid tubors)

continuous infusion via IM densensitizes GnRH receptors
==>inhibit release of LH/FSH

Tx: for in vitro

Rx is used to suppress GnRH (and thus suppress LH/FSH) Then administer exogenous gonadotropins (hCG, which looks like LH)
==>synchronized follicular development
goserelin
Tx:
-prostatic cancer
-endometriosis
-leiomyomas (uterine fibroid tumors)

=GnRH analog

("GO"nadotropin "Rel"easing Hormone= "GO"se"REL"in)

continuous infusion via IM densensitizes GnRH receptors
==>inhibit release of LH/FSH


Tx: In vitro fert

Rx is used to suppress GnRH (and thus suppress LH/FSH) Then administer exogenous gonadotropins (hCG, which looks like LH)
==>synchronized follicular development
nafarelin
*GoseRELIN
*nafeRELIN
*Leuprolide

GnRH analogs

Tx:
-prostatic cancer
-endometriosis
-leiomyomas (uterine fibroid tubors)

continuous infusion via IM densensitizes GnRH receptors
==>inhibit release of LH/FSH

Tx: for in vitro

Rx is used to suppress GnRH (and thus suppress LH/FSH) Then administer exogenous gonadotropins (hCG, which looks like LH)
==>synchronized follicular development
Tx prostatic cancer
*Leuprolide
*GoseRELIN
*NafeRELIN

Tx:
-prostatic cancer
-endometriosis
-leiomyomas (uterine fibroid tubors)

continuous infusion via IM densensitizes GnRH receptors
==>inhibit release of LH/FSH

Tx: for in vitro

Rx is used to suppress GnRH (and thus suppress LH/FSH) Then administer exogenous gonadotropins (hCG, which looks like LH)
==>synchronized follicular development
Tx endometriosis
*Leuprolide
*GoseRELIN
*NafeRELIN

=GnRH analog
("GO"se"REL"in= "GO"nadotropin "REL"easing Hormone)

Tx:
-prostatic cancer
-endometriosis
-leiomyomas (uterine fibroid tubors)

continuous infusion via IM densensitizes GnRH receptors
==>inhibit release of LH/FSH


Tx: in vitro vert

Rx is used to suppress GnRH (and thus suppress LH/FSH) Then administer exogenous gonadotropins (hCG, which looks like LH)
==>synchronized follicular development
Tx leiomyomas
*Leuprolide
*GoseRELIN
*NafeRELIN

Tx:
-prostatic cancer
-endometriosis
-leiomyomas (uterine fibroid tubors)

continuous infusion via IM densensitizes GnRH receptors
==>inhibit release of LH/FSH

Tx: for in vitro

Rx is used to suppress GnRH (and thus suppress LH/FSH) Then administer exogenous gonadotropins (hCG, which looks like LH)
==>synchronized follicular development
glucagon
secreted by pancreatic alpha cells; 29 AA protein

MOA:
*converts hepatic glycogen==>plasm glucose (no effect on SkM glycogen)
*cardiac effects: incr dp/dt d/t incr cAMP

PE:
*use to Dx T1DM; glucagon SHOULD stimulate release of insulin and C-peptide in non-diabetics; no C-peptide release in T1DM

Tx:
*severe hypoglycemia
*poisoning with BB: increases dp/dt independent of B-receptors
insulin--onset, peak, duration:
-Lispro
-Regular
-NPH (protamine)
-ultralente
-glargin
onset; peak; duration

Lispro: 10m, 60m, 3-4h
Regular: 15m, 2-4h, 5-8h
NPH (protamine):
1-2h, 6-12h,18-24h

ultralente:4-8h, 16-18h, 20-36

glargine (very slow absorption with no peak, duration=24 h)
Tx: DKA
-lispro or regular insulin IV
-IV fluids for rehydration
-K+ to prevent hypokalemia as insulin drives glucose into liver, SkM, and fat cells
sulfonylureas
"hypoglycemics"

*tolbutamide
*chlorpropamide
*glyburide
*glipizide

Tx: T2DM

MOA: blocks ATP-sensitive K+ channels in beta cells
==>depol beta cells
==>release insulin

S/E: hypoglycemia
tolbutamide
Tx: T2DM

MOA: blocks ATP-sensitive K+ channels in beta cells
==>depol beta cells
==>release insulin

S/E: hypoglycemia
chlorpropamide
Tx: T2DM

MOA: blocks ATP-sensitive K+ channels in beta cells
==>depol beta cells
==>release insulin

S/E: hypoglycemia
glyburide
Tx: T2DM

MOA: blocks ATP-sensitive K+ channels in beta cells
==>depol beta cells
==>release insulin

S/E: hypoglycemia
glipizide
Tx: T2DM

MOA: blocks ATP-sensitive K+ channels in beta cells
==>depol beta cells
==>release insulin

S/E: hypoglycemia
metformin
Tx: T2DM

MOA: decr insulin resistance primarily in SkM and fat cells

FirstAid: decr gluconeogenesis
S/E: lactic acidosis
rosiglitazone
(a glitazone)

Tx: T2DM

MOA: decr insulin resistance primarily in SkM and fat cells
which drug decr hepatic glucose production in a T2DM without enhancing the pancreatic secretion of insulin?
metformin
ipecac
ipecac induces vomiting by an action at the CTZ and by an irritant action in the stomach which is not blocked by antihistamines

(bulimics use)
Clinical: What drug induces emesis by stimulating D2-receptors in the CTZ?
apomorphine (morphine works via dopamine receptors)
lactulose
lactulose (synthetic disaccharide) – slow-acting laxative which is converted to small organic acids in the bowel; these acids exert an osmotic effect to slowly draw water into the feces.
Clinical: A patient with S/S (confusion/coma) of hepatic portal encephalopathy needs tx.
Drug =
Drug = lactulose which acidifies the bowel to trap ammonia as ammonium ion; ammonium lost in feces

==>plasma [ammonia] falls
==>coma and confusion disappear
docusate sodium
= a stool softener = an anionic surfactant: detergent action (~soap) allows water to enter feces; softens the stool wo increasing its bulk
Diarrhea – tx w
DOC=loperamide (Imodium)

-or diphenoxylate which stimulate mu opiate receptors
Ulcers – tx
*H2-receptor blockers (cimetidine)
*antacids, (Al and/or Mg hydroxides)
*PGE-receptor agonists (misoprostol)
*proton pump inhibitors (omeprazole)
*sucralfate (mixture of sucrose ("sucr") & AlOH ("al"), which forms a viscous gel at acidic pH; gel coats ulcerated tissue)

*modern tx is to eradicate Helicobacter pylori w triple AB tx =
1. clarithromycin,
2. amoxacillin,
3. omeprazole
Which antiulcer drug does not alter stomach pH? =
sucralfate
Clinical: Patient on propranolol takes cimetidine for heartburn and develops severe bradycardia.
Why?
Bx cimetidine inhibits CYP450 and thus blocks the metabolism of propranolol
antacids and GI tract
AlOH = constipation; MgOH = diarrhea
Pat being tx w doxycycline; which drug contraindicated?
Al/Mg antacids
Patient needs emergency surgery; need to empty stomach/prevent reflux. Drug = ?
metoclopramide = prokinetic in stomach and bowel and tightens the LES

FA:
MOA: prokinetic, D2-R antagonist

Tx: Diabetic and post-surgery gastroparesis

S/E: Park effects
Clinical: Cancer chemo patient has n/v and noctural acid reflux Tx w = ?
metoclopramide= prokinetic in stomach and bowel and tightens the LES
Patient has post-operative paralytic ileus Tx w = ?
A: metoclopramide, bethaneCHOL, cisapride
Patient treated with drug for Crohn’s disease or ulcerative colitis develops hepatic damage or bone marrow depression. Drug = ?
sulfasalazine=SHIP drug; patient is a slow acetylator.

SULFASALAzine consists of SULFApyridine conjugated to 5-aminoSALIcyclic acid (5-ASA).

Bacterial E's in the large bowel hydrolyze SULFASALAzine to free SULFApyridine and free 5-aminoSALIcyclic acid.

-5-ASA = NSAID ==>hepatic damage
-sulfaPYRIdine, which is metabolized by acetylation,
suppresses BM (Kat's note: recall Tx malaria: "trim-PYRImethamine: the PYRImethamine part inhibits DHF-R==>inhibits THF formation (this would probly suppress BM)
constipation, hypokalemia, muscle weakness, abnormal architecture inner GI wall

suggests what?
laxative abuse with castor oil or bisacodyl
NSAIDS
1. Inhibits platelet aggregation by acetylating & irreversibly inhibiting COX1 & COX2
==>prevents conversion of AA to PG's (TxA is a PG)
==>nl platelet count but incr BT b/c platelets don't work! (no effect on PT, PTT)

2. Aspirin blocks platelet aggregation caused by arachidonic acid but not the aggregation caused by PGG2 and PGH2 (cyclic endoperoxides)

3. Inhibition of platelet aggregation relieves chest pain in unstable angina: platelet count is normal, but bleeding time is increased

4. Aspirin converted to salicylate during first-pass metabolism in the liver
NSAIDS: how recog non-linear kinetics
Note:

Linear kinetics=1st order kinetics

**Most drugs
-[drug] falls by constant PERCENTAGE/FRACTION
-Most drugs operate this way b/c the enzymes resp for drug elimination are NEVER saturated
--------------------

Non-linear kinetics=Zero Order Metabolism

-[drug] falls by constant AMOUNT (called "nonlinear" b/c does not fall by constant fraction/percentage like most drugs do)
-Enzymes resp for drug elimination are saturated
--------------------


Large doses of aspirin exhibit nonlinear kinetics - how to recognize non-linear kinetics?

I. the disappearance of plasma salicylate:
1. plasma [salicylate] falls by constant AMOUNT during zero-order elim b/c enzymes resp for hepatic Cl are saturated with substrate

2. plasma [salicylate] falls by 50% during 1st-order elim (constant PERCENTAGE/FRACTION)

(Most drugs operate this way)

II. the apperance of plasma [salictylate] during po dosing:


When the dose is doubled, the plasma concentration should double.

If the doubling the dose causes [salicylate] to increase more than two-fold, the hepatic enzymes have become saturated and elimination has changed from first-order to zero-order; the decr in Clearance will cause the half life to incr
aspirin OD:
Sx
Tx
- n/v, tinnitus

*Respiratory alkalosis: aspirin uncouples oxidative phosphorylation in skeletal muscle
==>thus form lactic acid
==>incr pCO2
==>increases respiration
==>resp alkalosis

*metabolic acidosis: as CO2 production increases, a metabolic acidosis develops

- children skip the alkalosis step and go directly to acidosis w low blood pH and low bicarbonate

TREATMENT: make urine alkaline (acetazolamide or NaHCO3) to enhance the renal clearance of salicylate and infuse bicarbonate to correct acidosis
Clinical: half-life of aspirin as only 1 h, why does it inhibit platelet inhibition for a longer period
Aspirin irreversibly acetylates active site of COX-1 in platelets
Clinical: How does aspirin prevent platelet aggregation when it is not taken in doses large enough to maintain a steady-state plasma concentration?
Aspirin irreversibly acetylates active site of COX-1 in platelets
Clinical: patient has intermittent episodes of hemiplegia which resolve spontaneously; would like
to treat with aspirin, but patient has aspirin “hypersensitivity”;
ticlopidine:

irreversibly blocks ADP receptors
==>no GP2b/3a receptors to bind fibrinogen and cause platelet aggregation
Clinical: What is the causative compound in aspirin hypersensitivity? =
leukotrienes
Clinical: DOC for menstrual cramps
ibuprofen
Clinical: Baby has patent ductus arteriosus

Tx?
close w/indomethacin
Clinical: Want to keep ductus arteriosus open prior to surgery: what drug will do this ?
alPROSDTAdil = PGE1 (PROSTAglandin) analog dilates the ductus arteriosus
Clinical; pat tx with NSAID develops GI ulceration. MOA =
inhibit gastric PG syn
Clinical: A patient with nasal polyps who has wheezing with aspirin needs a antipyretic drug
DOC = acetaminophen
Acetaminophen
antipyretic but not antiinflammatory
Clinical: Drug OD; initially blood chemistries normal, but 36 h later see increase in AST and ALT.

Q: what is the drug?
-how tx OD?
acetaminophen; treat with n-acetylcysteine to replenish glutathione
Adverse effects of NSAID’s
*gastric ulceration – results from decreased PG synthesis in stomach; prevent or tx with misoPROstol (methyl-PGE1; PRO=PROstaglandin)

*interstitial nephritis – hematuria, proteinuria, flank pain

*decreased RBF and GFR causing oliguria
Clinical: Patient on NSAID for tendonitis for 2 weeks develops fever and hematuria: diagnosis?
acute interstitial nephritis
Clinical: Patient with CHF takes ibuprofen; effect on kidney = ?
1. Constriction of afferent arteriole lowers RBF and GFR ==>salt/water retention

2. no PG's to partially inhibit the effects of ADH in the collecting duct = water retention.
Clinical: Patient tx with NSAID for arthritis exhibits decr [Hb] and Hct and has occult blood in his stool.

Which drug could be addded to tx to reverse this pathology?
misoPROSTol (PROSTaglandin PGE analog
==>incr gastric mucosal lining
==>less bleeding from ulcer)
Colchicine
binds to tubulin to block the formation of microtubules and thus inhibit phagocytosis of urate crystals by WBC’s; used to tx the pain of acute attacks
Allopurinol
inhibits xanthine oxidase (purine degradation pathway: degrades purines==>uric acid)
Clinical: Patient with a renal transplant is taking the immunosuppressant drug azathioprine.
Patient develops gout. Which gout drug is contraindicated?
allopurinol bx azathioprine is converted to the cytotoxic agent 6-mercaptopurine (6-MP; kills antigen presenting cells and T- and B-lymphocytes). 6-MP is inactivated (metabolized) by xanthine oxidase.

Allopurinol==>inhibit xanthine oxidase
==>incr levels of cytotoxic agent 6-MP
Clinical: Patient with lymphoma tx with chemo. Which drug will prevent decr in renal function?
allopurinol--prevents the formation of urate

Chemo kills lymphoma cells ==>release nucleic acids which are converted to urate (Degredation Pathway of purines)
==>xs urate in urine crystalizes to occlude the collecting ducts, pelvis and ureters
==>rapid, progressive renal dysfunction
Probenacid
Probenecid and large doses of aspirin enhance the renal clearance of urate

==>urate (urate=uric acid=acidic) stones may form, so keep the urine alkaline with sodium citrate
Clinical: Which gout drug is not uricosuric?
colchicine, allopurinol
Clinical: patient takiing a small daily dose of aspirin may develop gout whereas a large daily dose of aspirin is used to treat gout. Why the discrepancy?
Small doses of aspirin enhance urate
reabsorption in the renal tubule whereas large doses of aspirin are uricosuric
Clinical: Patient being tx for gouty arthritic develops leukopenia. Which drug ?
colchicine (House episode)
Clinical: Pg woman develops hyperthyroidism. How to treat
PTU
Clinical: What are the usual causes of hyperprolactinemia and their treatment?
A: blockade of D2-dopamine receptors and increased TRH in hypothyroidism cause hyperprolactinemia.

A: in hypothyroidism, tx w thyroxine to suppress plasma [prolactin]
(incr T4==decr TRH==>decr PRL)
Clinical: patient w recurrent v. tach/v. fib. develops hyper- or hypothyroidism while taking
amiodarone. Why?
AmIODaroNE (Tx V tach/V fib) is 37% iodide by weight (IODiNE). This iodide can either prevent the conversion of T4 to T3 (hypothyroidism), or it can serve as a substrate for the synthesis of T3 by thyroid peroxidase (hyperthyroidism)
Central DI – tx with
desmoPRESSIN (~vasoPRESSIN=ADH)
(=DDAVP (VP=VasoPressin))

-long half-life b/c resistant to degradation by peptidases;
-very selective for renal V2-receptors
Nephrogenic DI – tx w
HCTZ;

if that doesn’t work, try indomethacin
Li+-induced DI – tx w
*DOC=amiloride (prevents entry of Li+ into principal cells of LDT/CD)

*or HCTZ
Carcinoid syndrome =

-desc
-tx
bronchospasm, GI cramping and diarrhea, "odd" flushing of the skin, hypotension and increased urinary excretion of 5-HIAA (5-hydroxyindoleacetic acid)

*tx w:
-cyproheptadine (blocks 5-HT1 and 5-HT2 receptors) or
-the somatostatin analog octreotide, which inhibits the release of 5-HT from the tumor.
increased urinary excretion of 5-HIAA (5-hydroxyindoleacetic acid
carcinoid syndrome
metoclopramide
1. Blocks D2-receptors in CTZ (block CTZ)=anti-emetic– prevents nausea;

S/E’s = EPS, hyperprolactinemia

2. Blocks 5-HT3 receptors in CTZ and at vagal afferents – prevents nausea/emesis

3. Stimulates 5-HT4 receptors on prejunctional cholinergic neurons to amplify the release of ACh, ACh stimulates muscarinic receptors in the GI tract
==>empty the stomach prior to emergency surgery

4. Tx GERD (via incr LES tone)
ondansetron
antiemetic drug which blocks 5-HT3 receptors in CTZ and at vagal afferent fibers

(“—setron”= antiemetic, blocks 5-HT3 in CTZ)
cisapride
Tx:
-GERD
-empty stomach prior to emergency surgery

agonist at 5-HT4 receptors on prejunctional cholinergic neurons - amplifies the release of ACh to increase tone in the LES
sumatriptan
agonist at 5-HT1B and 5-HT1D receptors to inhibit the release of inflammatory peptides

*used to treat migraine headache and cluster headache
buspirone
-a partial agonist at 5-HT1A (serotonin) receptors;

-opens K+ channels to hyperpolarize neurons; used to tx anxiety, slow onset of action, no drug dependence
histamine H1-receptors
-dilate arterioles
==>"rubor" & "calor" of acute inflamm

-contracts vascular endothelial cells
==>increase capillary permeability

-contract GI smooth muscle==> diarrhea

-contracts bronchial SmM==>asthma

-stimulates afferent pain receptors==>pain/itch ("dolor" of acute inflam)
H2-R
-dilate arterioles
-increases gastric H+ secretion
cromolyn sodium
inhibits mast cell degranulation by preventing incr in intracellular Ca++
olopatidine
inhibits mast cell degranulation and blocks histamine H1-receptors, used
to tx conjunctivitis assn with seasonal allergy
Sedating antihistamines =
-diphenhydramine (benadryl)
-meclizine (prophylaxis against motion sickness and n/v during pregnancy)
Non-sedating antihistamines =
terFENADINE
fexoFENADINE
clemastine
Prophylaxis of motion sickness
Prophylaxis of motion sickness (need to block central muscarinic ACh receptors)

= dimenhydrinate, meclizine and scopolamine
Tx of Meniere’s disease
Meniere’s disease (hearing loss, vertigo, tinnitus from nonsuppurative disease of the labyrinth of ear)

DOC=meclizine (prophylaxis for motion sickness & n/v during pregnancy)
H2-receptor blockers =
cimeTIDINE
famoTIDINE
raniTIDINE

(Every girl wants "to dine" (TIDINE) w/a guy who owns an H2 (Hummer))

blocks gastric acid secretion,
also blocks allergic responses in the skin
Sedating antihistamines =
diphenhydramine, meclizine (H1 blockers)
Non-sedating antihistamines =
= terfenadine, fexofenadine, clemastine
Prophylaxis of motion sickness
PROPHYLAXIS of motion sickness (need to block central muscarinic ACh receptors):

*dimenhydrinate
*meclizine
*scopolamine (“Give Scop to ppl on a Ship”)

(mneum:

“2 men (dimen) hydrate (hydrinate) their pregnant wives to prevent motion sickness.”

“The “2 men” (dimen) are named “mec” and “liz”.”
Tx of Meniere’s disease
Meniere’s disease (hearing loss, vertigo, tinnitus from nonsuppurative disease of the labyrinth in ear)

DOC=meclizine
H2-receptor blockers =
cimetidine, famotidine, ranitidine – blocks gastric acid secretion,
also blocks allergic responses in the skin
Clinical: A patient exposed to poison oak - how tx?
; To completely block the vasodilation, must give both H1 blocker (diphenhydramine) and H2 blocker (cimetidine)
Clinical: A patient w GERD is being treated with cimetidine requires allergen testing by a dermatologist.
Must d/c cimetidine to ensure accuracy of skin tests. Tx GERD w
omeprazole during allergy testing.
Clinical: Patient has insomnia from depression; tx with a TCA but patient still has insomnia. what happens if give antihistamien (i.e. diphenhydramine)
patient gets urinary retention
from combined atropine-like effect of the drug combination