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431 Cards in this Set
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Drug class: lispro
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ultra-short acting insulin
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Drug class: aspart
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ultra short acting insulin
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Drug class: regular
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short acting insulin
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Drug class: lente
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delayed onset, extended duration insulin
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Drug class: NPH
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delayed onset, extended duration insulin
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Drug class: ultralente
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delayed onset, extended duration insulin
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Drug class: glargine
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delayed onset, extended duration insulin
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Drug class: Exubera
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inhaled insulin
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Drug class: glyburide
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Insulin secretagogue (sulfonylurea)
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Drug class: Glipizide
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Insulin secretagogue (sulfonylurea)
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Drug class: Glimepiride
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Insulin secretagogue (sulfonylurea)
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Drug class: repaglinide
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Insulin secretagogue (meglitinide)
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Drug class: netaglinide
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D-phenylalanine (insulin secretagogue)
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Drug class: metformin
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biguanide
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Drug class: rosiglitazone
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Thiazolidinedione
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Drug class: Pioglitazone
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Thiazolidinedione
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Drug class: Acarbose
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alpha-glucosidase inhibitor
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Drug class: miglitol
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alpha glucosidase inhibitor
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MOA sulfonylureas
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increases insulin secretion
decreases glucagon in circulation |
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MOA meglitinides
(which type of hyperglycemia does it affect) |
increased insulin secretion
fast/brief onset and duration Reduces **post-prandial** hyperglycemia (NOT fasting) |
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MOA thiazolidinedione
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decrease insulin resistnace, increase insulin uptake and use in muscle, adipose, and liver
No insulin resistance Decreaesd visceral fat deposits, but can cause modest weight gain, fluid retention, and anemia |
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MOA exenatide
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stimulates insulin secretion
decreaes glucagon slows gastric emptying increases satiety and suppresses post-prandial plasma gluccagon and hepatic glucose output |
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MOA pramlintide
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--> weight loss
slows gastric emptying 2nd line agent |
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Chemical constituents of echinacea
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flavonoids
lipophilic constituents (alkamides, polyacetylenes) water soluble polysaccharides water soluble caffeoyl conjugates (echiacoside, chicoric acid, caffeic acid) |
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What are the uses of echninacea
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colds
immune stimulation eczema wound healing respiratory infections anti-oxidation effects |
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Effects of echinacea on the immune system?
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increased phagocytosis, but not immunostimulation
increased production of IL-1, 6, 10, and TNF-alpha Enhanced NK cell activity and AB dependent cellulary toxicity Cytokine activation |
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Effects of echinacea on anti-inflammation
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COX inhibition
5-lipoxygenase might be involved reduced edema in animal s Too few clinical trials to warrant wound healing in animals |
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Results of clinical trials of echinacea
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favorable results in reducing cold and flu symptoms if agent is given in first 24 hrs of a cold
Decreased sx and duration by 25-30% No prophylactic effect in preventing upper respiratory infection Ineffective in treating recurrent genital herpes |
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Drug interactions reported with echinacea
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NONE, although preps with high alcohol content should not be used with meds that cause disulfiram like reaction
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Active constituents of feverfew
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parthenolide, but amount varies depending on growing conditions, manufacturing process, duration of storage
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Common uses for feverfew
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fever
H/A menstrual irregularities allergies arthritis asthma general stimulant |
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Pharm effects of feverfew
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proph for migraines, related to 5HT hypothesis
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What is the active compound in garlic?
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allicin (gives garlic its smell)
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what are the common uses for garlic
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preventing vascular dz, lowering BP and cholesterol, treating colds, flu, and sinus infection
rheumatism hemorrhoids asthma low blood sugar |
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What are the pharmacologic effects of garlic on CV system?
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in vitro, inhibits HMG-CoA reductase
anti-platelet effects and mixed effects on fibrinolysis antioxidant efefcts may effect BV elasticity and BP by opening K channels in vascular smooth muscle, NOS stimulation, and ACE inhibition |
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What effects does garlic have on endocrine system?
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Some constituents of garlic have hypoglycemic effects in nondiabetic animal models, but does nothing for human diabetics
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What are the antimicrobial effects of garlic?
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in vitro: activity against gram + and gram -, protozoa and fungi.
Inhibits thiol containing enzymes needed by microbes Not tested in clinically |
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What are the antineoplastic effects of garlic
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in clincal trials, certain populations with high dietary garlic consumption have a reduced incidence in stomach cancer
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What drugs does garlic interact with? (caused by?)
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anti-clotting medications (from the diallylsulfides that inhibit thromboxane formation and platelet aggregation)
Or: through stimulation of NO synthesis Enhanced therapeutic effect of HMG-CoA reductase inhibitors Enhanced hypoglycemic agents Can reduce the bioavailability of anti-retroviral agents (saquinavir, but not ritonavir) |
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Chemical constituents of ginko?
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Flavone glycosides and terpenoids
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Common uses for gingko?
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Dementia
Memory loss HA Tinnitus Dizziness Peripheral vascular dz |
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CV effects of gingko?
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Increases blood flow and decreases viscosity
Enhancement of endogenous NO Can relieve claudication |
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Metabolic effects of gingko?
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Antioxidant and radical scavenging properties
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CNS effects of gingko?
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Increased densities for muscarinic, alpha-2, 5HT1a receptors and decreasd B-adrenceptors
Incresad ACh and NorE Enhanced synaptosomal reuptake of serotonin Reduced corticosterone synth Enhanced GABA Treatse AD Possible AD proph |
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Drug interactions with gingko?
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Increased therapeutic effect of anticoags
If with trazadone, enhanced sedative effects Increased effect of MAOI Gingko seeds are epileptogenic and can decrease effectiveness of pts taking carbamazepine or valproic acid |
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Uses for ginseng
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increase resistance to phsyical, chem, biological stresses
Treat fatiuge Stimulates immune system Can enhance mood Improves mental and physical performance |
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Clinical trials of ginseng
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improvement in mental fxn and physical performance, or no effect
American ginseng lowers postprandial glucose Inconclusive evidence |
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Drug interactions with ginseng
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If taken with psych drugs --> sleeplessness and mia
Don't take with warfarin Cytokine stimulation occurs so be cautious in immunocompromised patients LT use --> HTN |
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what part of the plant do the extracts from kava come from? what are the active constituents called?
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root
kavalactones or kavapyrones lawain, methysticin, yangonin |
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Possible MOA of kava
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GABA receptors likely involved
kavalactones bind to GABA-A receptors, but don't compete with BZ binding sites Might inhibit norE uptake, reversible MAO-B inhibition or DA antagonism Possible COX inhibition activity |
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Results of clinical trials of kava
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improvements in anxiety in pts wiht moderate to severe anxiety
Similar anxiolytic effects when compared with oxazepam, with fewer side effects |
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Drug interactions seen with kava
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potentiates effects of other CNS depressants, impaired cognitive performance
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Chemical constituents of St. John's Wort
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hypericin
hyperforin |
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Common uses for St. John's Wort
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natural source of food flavoring
depression, nervousness, anxiety fibrositis, sciatica muscle soreness and burns |
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Pharmaceological effects of St. John's Wort
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Hyperforin inihitits 5HT, norE, DA reuptake in vitro
Downregulates expression of cortical B-adrenoceptors and upregulates the expression of 5HT receptors in rodents |
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MOA St. John's Wort
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NOT a competitive antagonist at tramitter binding sites to decrease uptake
It actually attenuates Na gradient to alter NT transport |
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Drug interactions of St. John's Wort
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drugs with similar MOA should be avoided b/c --> serotonin syndrome or MAO crisis
May induce CYP enzymes and glycoprotein drug transporter --> low levels of digoxin, OC, cyclosporin, HIV meds, warfarin, irinotecan, theophylline, and anti-convulsants |
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Uses for saw palmetto
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BPH
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Clinical studies of saw palmetto
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not as effective as a1-antagonists
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Common uses of DHEA
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slow/reverse aging changes
promote weight loss increase strenght and energy improves memory, prevents heart dz and SLE |
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Clinical trials of DHEA (weight loss, CVD, AD, SLE, DM)
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Don't use DHEA for weight loss
high and low levels fo DHEA associated with CV dz To treat AD, use still contraversial Most ppl using it for SLE discontinued use To treat DM: unknown |
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Common uses for melatonin
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insomnia
jet lag immune enhancement HA depression |
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Clinical trials for melatonin in jet lag
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Reduced daytime fatigue, improved mood, quicker recovery time, but studies were inconsistent in dosing, duration of therapy, etc
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Clinical trials for melatonin in insomnia
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improves sleep onset, duration and quality when given to healthy volunteers
increased REM |
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Clinical trials for melatonin in female reproductive function
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melatonin receptors ID in granulosa cell membranes and follicular fluid
it suppresses midcycle LH surge and secretion --> partial inhibition of ovulation If given with progestin on days 1-21, lower LH levels Dont' use melatonin if pregnant or attempting to conceive, or who are nursing (also decreases PRL levels) |
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Clinical trials for melatonin in male reproductive funcion
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decreaes sperm quality, maybe through aromatase inhibition
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Drug interactions in melatonin
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possiby alters [] of NSAIDS, antideressants, b-agonists/antagonists, scopolamie, and Na valproate
But none have been formally studied |
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What should every patient with altered mental status receive?
what if respiratory depression is present? |
dextrose
naloxone .4-2 mg to reverse respiratory depression if caused by opioids |
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What is flumazenil?
What effects does it specifically have? |
it's a BZ antagonist, but does nothing for blocking barbiturates, opioids, etc
reverses sedation from BZ, effects on resp depression less clear |
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When should flumazenil NOT be given
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should ID toxin first, since it can cause convulsions in pts with TCA
don't give to pts with h/o seizures |
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What does a toxicologic exam include
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vital signs
eyes mouth skin abdomen nervous system |
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What effect do salicylates have on respiration?
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increases it
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Which drugs will cause a horizontal nystagmus?
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phenytoin
carbamazepine EtOh barbiturates |
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Which drugs will cause a vertical nystagmus?
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phencyclidine (angel dust)
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What drugs cause icterus?
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acetaminophen
mushroom poisoning |
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Which drugs can cause seizures?
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TCA
theophylline isoniazid diphenyhdramine (in sleep preparations) |
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Which drugs can cause muscle rigidity?
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haloperidol
anti-psychotics phencyclidine |
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Which drugs can cause a combo of nystagmus, dysarthria, and ataxia?
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Anti-epileptics
EtOh sedatives |
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What makes up the difference in the anion gap?
What is a normal anion gap? |
albuminate
12-16 |
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What are the general causes of metabolic acidosis from toxins?
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Organic acid metabolites from the toxin (MeOH --> foramte, ethylene glycol --> glyoxylate and oxalate)
Toxin is an organic acid (salicylate acid) Toxin produces ischemia --> lactic acidosis (CO, ibuprofin, valproate) |
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HOw do you calculate osmolar gap?
What is the noraml value? How can it be measured (w/o calculating it)? |
2x Na + (glucose/18) + BUN/3
280-290 mosm Measure the degree to which freezing point is depressed, whci can be used to estimate the BAC |
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What does an elevated osmolar gap represent?
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Some sort of alcohol intoxication (EtOh, MeOH, ethylene glycol, isopropanol)
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What is the main value in toxicology screening tests?
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confirming or r/o a suspected intoxication
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What EKG changes are seen in TCA OD?
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Widened QRS
Prolonged QT interval (also seen in SSRI and anti-psychotics) |
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What are the ways to decontaminate GI tract? Which is the most effective method?
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emesis
gastric lavage **activated charcoal and bowel irrigation** |
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What can be used to cause emesis?
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syrup of ipecac
must be done within 1-2 hrs of ingestion or else the toxin will be into intestines |
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When should ipecac NOT be used?
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if toxicant is a corrosive agent, a petroleum distillate, or rapidly acting CNS stimulant
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What are the 2 types of lavage, and which is the preferred method?
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Orogastric** (better b/c cna use a wider diamter tube)
Nasogastric |
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How does activated charcoal work to empty the stomach?
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Adsorbs many LIPID soluble toxins but DOES NOT ADSORB HYDROPHILIC, IONIC, METALS, or HYDROCARBON agents
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What can activated charcoal be combined with to enhance the effects?
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sorbitol, to draw water into the GI tract and cause diarrhea containing charcoal and the adsorbed drug (most effective in slow-release or enteric drug formulation since the drug will still be in the intestines hours after ingestion)
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What type of compounds can be filtered out in dialysis?
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hydrophilic
most effectively removed if drug has low Vd, b/c if the toxins or drugs are bound, then they will be too large to fit through the porous filter Dialysis also effectively restores plasma electrolyte levels and pH |
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What is sorbent hemoperfusion used for?
What is the main problem associated with this? |
hydrophobic toxins
most highly lipid soluble molecules have large Vd so only a smal fraction can be cleared |
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Which drugs specifically are most effectively removed from the body using sorben hemoperfusion?
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carbamazepine
phenobarbital |
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What is one of the main complications of sorben hemoperfusion?
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Blood comes incontact with activated charcoal surface adn the platelets adhere very strongly and cause severe thrombocytopenia and bleeding
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Which drug class has the highest number of deaths attributed to its use?
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opiates
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What is the classic presentation of opiate OD?
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coma
respiratory depression pinpoint pupils needle tracks on antecubital fossa |
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Treatment for opiate OD?
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naloxone
nalmefene they reverse toxindrome within seconds to minutes |
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What is the difference between naloxone and nalmefene?
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both are identical pharmacologically, except that nalmefene has a longer duration
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What things are necessary to have a successful transdermal patch?
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highly lipid soluble
very potent drug |
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Which drugs are in transdermal patches?
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fentanyl
nitroglycerin scopolamine (for motion sickness) nicotine |
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What can make patches extremely toxic?
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if sucked on they deliver huge dosages compared to the standard therapeutic dosages
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What precautions should be taken with patches?
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Wash hands thoroughly after placing or removing a patch
throw them out in a place where children can't get to them |
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What causes liver damage in acetominophen?
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highly toxic free radical metabolite is produced in liver and detoxified by glutathione
Toxicity appears when glutathione is depleted |
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What is the antedote to acetaminophen toxicity?
how soon must it be given? |
acetylcysteine, which acts as a glutathione substitute
within 8-10 hours |
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Which of the BZ are most fatal?
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diazepam
alprazolam --> coma and respiratory arrest |
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What is the treatment for BZ OD?
What if this drug is given to patients who have taken antidepressants or barbiturates? |
Flumazenil
Can cause status epilepticus |
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Which are the antidepressants that are associated with fatal intoxications?
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SSRI (since most widely prescribed)
amitriptyline (TCA) Doxepin |
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How do TCAs cause fatalities?
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profound hypotension
centrally mediated agitation tonic-clonic seizures depress cardiac contractility --> ventricular conduction block and v-fib |
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Treatment for OD of antidepressants
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IV fluids and catecholamines for hypotension
antiarrythmics (sodium bicarbonate) |
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What is contraindicated in antidepressant OD? Why?
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Pysostigmene
Aggravates deression of cardiac conduction and exacerbates seizures |
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What is the most common cause of death from EtOH?
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hypothermia (falling asleep outside when it's cold) and increseased vasodilation --> heat loss
respiratory arrest |
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What is the metabolism of EtOH?
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Acetaldehyde by alcohol dehydrogenase using NAD --> NADH
Acetaldehyde is oxidized by aldehyde dehydrogenase to form acetate (NAD --> NADH again) Acetate --> Acetyl CoA (enters TCA cycle) --> CO2 |
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How is ethylene glycol metabolized?
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Forms glycoxylic acid and dicarboxylic acid oxalate (both of which --> metabolic acidosis)
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What is the toxidrome of ethylene glycol?
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metabolic acidosis
hypokalemia respiratory depression urinary oxalate (is an anion, so it draws the K into the urine) |
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What is the treatment for ethylene glycol OD?
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Fomepizole (inhibits alcohol dehydrogenase and diminishes the formation of the metabolic acids)... oxalate crystals in the urine --> acute renal failure
hemodialysis |
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What extra precaution must be taken with ethylene glycol OD treatment?
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it binds Ca, so if muscle spasms develop administer Ca
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What is the metabolism of methanol?
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forms formaldehyde and formic acid (--> blindness)
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What is the toxidrome of methanol toxicity?
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metabolic acidosis
hypokalemia respiratory arrest vision changes NO oxalate in urine |
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What is the treatment for methanol toxicity?
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fomepizole to prevent the formation of formic acid
hemodialysis |
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MOA of disulfiram?
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inhibits aldehyde dehydrogenase so acetaldehyde accumulates --> flushing, severe vasodilation, N/V
Lasts for 48 hrs |
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How can disulfiram be fatal?
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if it taken after EtOH consumption --> accumulations of acetaldehyde
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MOA of cocaine?
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blocks the reuptake of DA, NorE, 5HT
--> profound euphoria --> incrases BP, HR (w/ arrhythmias, increses work load and O2 requirements of heart) --> lowers seizure threshold |
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Treatment for cocaine OD?
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Diazepam for seizures
beta-blockesr and Ca channel blockers for arrhythmias nitro for HTN |
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What are the lethal effects experienced from ca channel blockers?
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dramatically reduces CO and BP
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How is OD from CCB treated?
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give whole bowel irrigation adn oral activated charcoal... these drugs are given in extended release forms and they persist in GI tract following OD
There is NO antidote!!! |
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What is the major side effect of CCB?
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constipation (Ca enntry through channels drives peristalsis --> paralytic ileus and gastroparesis
charcoal and irrigation must be administered before bowel motility is lost |
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Is the Vd high or low in CCB?
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high
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What is the most important maintenance strategy while treating someone on CCB?
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maintenace of CO (pacing and placing an intraaortic balloon counterpulsation and maintenance of BP using catceholamines
give Ca IV since entry is driven by Ca concentration gradient and increasing the extracellular Ca drives mroe Ca in |
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What happens to beta selectivity in beta blockers at high doses?
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the selectivity is lost
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what are the most common manifestations of beta blocker OD?
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bradycardia with AV block and hypotension
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what is the treatment for beta blocker OD?
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Glucagon works on cardiac myocytes through elevating cAMP but through a different receptor, acts as a positive inotropic and chronotropic agent to restore CO, BP, and liver perfusion
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What causes death from CO?
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hypoxia d/t formation of carboxyhemoglobin adn a decreased O2 carrying capacity in blood
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Treatment for CO poisoning
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transfer pt to fresh air
give 100% pure O2 ASAP with mechanical assist if necessary monitr CV status |
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how long does it take to treat CO poisoning
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320 minutes if pt is in room air
80 mins if pts are in 100% O2 Under hyperbaric conditions, can be <25 mins |
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What is the advantage to hyperbaric chambers when treating ppl with CO poisoning
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recovery rate is father, but survival rate is still the same
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What are the different forms of lead
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inorganic lead salts
organic lead (in gasoline) lead oxide in dust (most common) |
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How does lead spread throughout body?
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taken up by RBC, distributed to soft tissues, then to sub-periosteal surfaces of bone and to bone matrix
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What type of anemia is caused by lead poisoning
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mycrocytic hypochromic (blocks incorporation of Pb into protoporphyrin IX to form heme) also blocks other enzymes in heme synth pathway
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What are the major signs of inorganic lead poisoning?
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colic
encephalopathy hemolytic anemia |
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treatment for inorganic lead poisoning?
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Use of chelators
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How is lead poisoning diagnosed?
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atomic absorption spectrophotometry
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How can lead poisoning treatment be monitored?
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urinary measruement of lead loss
declining plasma concentrations |
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Where is arsenic exposure commonly from
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semiconductors
herbicines cotton desiccants nonferrous alloys glass insecticides vet drugs |
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how is arsenic excreted?
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undergoes methylation in the liver and subsequent urinary excretion
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how does arsenic exert its effects
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binds sulfhydryl groups of proteins, interfering with their catalytic and structural competencies
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which form of arsenic is more toxic?
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trivalent (10x more toxic)
the other form is a pentavalent |
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presentation of acute arsenic poisoning
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abrupt gastroenteritis
hypotension metabolic acidosis |
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treatment for acute inorganic arsenic poisoning
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gut decontamination
intensive supportive care prompt chelation |
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arsine gas poisoning presentation
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massive hemolysis
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treatment for arsine gas poisoning
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exchange transfusion
mannitol infusion (to protect from porphyrin induced acute renal failure) chelators don't help |
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what is the primary source of Hg exposure
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inhalation, it then gets concentrated in the kidneys
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what effects does Hg have on the body?
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interacts with sulfhydryl groups in protins... it inhibits enzymes
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presentation of acute Hg intoxication
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pneumonitis
pulmonary edema acute gingivostomatitis neurological sx |
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What is seen with acute ingestion of inorganic mercury salts
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corrosive hemorrhagic gastroenteritis --> ATN and oliguric renal failure
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What is dimercaprol?
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classic chelator used to treat acute poisoning wiht
arsenic Hg severe Pb poisoning (when combined wiht EDTA) |
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Advantage of dimercaprol
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readily x cellular membranes and can remove intracellular and extracellular deposits of toxic metal
the complex of metal and dimercaprol is lost in the urine |
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Adverse effects of dimercaprol
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HTN
tachycardia N/V lacrimation salivation pain at injection site |
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What is succimer?
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water analog if dimercaprol
approved for Pb poisoning and has supplanted EDTA in outpatient tx also used to treat arsenic and Hg poisoning |
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Adverse reactioins to succimer?
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rare
GI dz rashes and neutropenia can occur |
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EDTA
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strong chlator
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how is EDTA administered?
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IV infusion
excreted by glomerular filtration, bringinng lead into teh urine from plasma and exchanged from soft tissue |
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Unithiol-DMPS uses
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binds and increases excretion of Hg, arsenic, and Pb
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Effectiveness of Unithiol-DMPS
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more effective than succimer and dimercaprol for inorganic Hg or arsenic
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Adverse effects of Unithiol-DMPS
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Rare
Stevens-Johnson syndroem urticaria |
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Penicillamine
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Cu chelator (treats Wilson's dz and copper poisoning )
Also used to treat severe RA |
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Adverse effects of penicillamine
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50% experience
hypersensitivity rxn nephrotoxicity pancytopenia |
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Deferoxamine
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binds Fe avidly
removes Fe from hemosiderina dn ferritin, but not from heme iron proteins |
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Deferoxamine treats?
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ironing poisonings (from treating Fe-deficiency anemia
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Administration of deferoxamine
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parenterally (poorly absorbed orally)
Excreted in urine (turns urine orange-red) |
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Adverse effecs from deferoxamine
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ARDS
neurotoxicity esp if infusions last more than 24 hrs |
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Examples of SERMS
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tamoxifen
toremifene raloxifene |
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Examples of anti-estrogen drugs
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clomiphene
fulvestrant |
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exampes of anti-progestins
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mifepristone (RU-486)
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examples of androgen drugs
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danazol
testosterone DHT testosterone cypionate testosterone enanthate |
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examples of anabolic steroids
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fluoxymesterone
oxandrolone oxymetholone stanozolol nandrolone |
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examples of anti-androgens
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flutamide
bicalutamide nilutamide |
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GnRH analogs
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leuprolide
abarelix |
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DA agonist
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bromocriptine
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pituitary hormone
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urofollitropin (FSH)
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examples of aromatase inibitors
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anastrozole
exemestane letrozole |
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examples of 5-a reductase inhibitors
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finasteride
dutasteride |
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What is the most potent estrogen? next most potent? last?
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E2 (17-beta-estradiol)
E1 (estrone) E3 (estriol) |
|
|
What is the principle structural feature of the estrogens?
|
phenolic A ring
|
|
|
What is DES?
|
nonsteroidal compound similar to estradiol, but has a longer t1/2
|
|
|
What is ethinyl
|
it is a substitution on the D ring of estrogens that increases oral potency by inhibiting first pass hepatic metabolism
|
|
|
What do gonadotropins do?
|
Increase the activity of aromatase and cholesterol side chain cleavage enzymes and facilitates the transport of cholesterol and steroid biosynthesis
|
|
|
In post-menopausal women, what is the source of estrogen?
|
adipose stroma (estrogen is made from DHEA secreted by the adrenals)
|
|
|
Where is estrogen produced in men?
|
testes
also, extragonadal production by aromatiziation of C19 steroids (accounts for most) |
|
|
What is the link between esetrogen production and breast CA?
|
mammary tumors contain aromatase and hydrolytic enzymes
|
|
|
Where does estrogen come from in the fetus?
|
fetal DHEA forms E1 and E3
|
|
|
What does estrogen do for girls?
|
responsible for pubertal changes and secondary sex characteristics
Molds body contours Shapes skeleton Causes pubertal growth spurt of long bones and epiphyseal closure growth of axillary and pubic hair |
|
|
What does estrogen do to pregnant women?
|
pigments genital region
pigmentations of nipples and areoae after 1st trimester |
|
|
What role do estrogens play in males?
|
If deficient --> diminished pubertal growth spurt and delays in skeletal maturation
delays in epiphyseal closure increased gonadotropins increased testosterone macroorchidism can affect lipid and carb metabolism affects fertility |
|
|
What does FSH do in women?
|
growth and maturation of graafian follicle in ovary
ovarian production of estrogen and progesterone |
|
|
How does estrogen interact with FSH/LH?
|
decreases amount of LH and FSH released during most of hte cycle, but triggers a surge of LH release during midcycle (after the estrogens get above a certain threshold)
|
|
|
How is FSH controlled, other than with estrogens?
|
inhibit
activin follistatin |
|
|
What do follicles produce?
|
E2
|
|
|
What happens when FSH levels drop?
|
all the smaller follicles not chosen to mature, regress
|
|
|
What does the FSH/LH surge do?
|
Causes follicular rupture and ovulation within 1-2 days
|
|
|
What happens to the ruptured follicle?
|
develops into corpus luteum, which produces large amounts of progesterone and a little bit of estrogen
|
|
|
What enzyme does aspirin inhibit?
|
postaglandin synthase (aka COX)
|
|
|
Adverse effects of NSAIDS
|
GI disturbances
inhibit platelet aggregation inhibit uterine motility inhibit PG mediated renal fxn hypersensitivity |
|
|
what are general therapeutic actions of NSAIDS
|
relieve pain
reduce fever reduce inflammation (all except acetaminophen) |
|
|
Sites of acetaminophen action
|
may have better COX inhibition in nervous system
|
|
|
why is acetaminophen not effective in inflammation
|
COX inhibition is low int eh presence of high [peroxide] found in inflammatory lesions
does not inhibit neutrophil activation (other NSAIDS do) |
|
|
Adverse rxns to acetaminophen
|
NO respiratory or cardiovascular systems
NO acid-base probs NO GI disturbances NO changes in bleeding time 6% cross-reactivity with aspirin --> AIS |
|
|
Therapeutic uses of acetaminophen
|
antipyretic
analgesic good substitute when aspirin is contraindicated NOT an anti-inflammatory, but can be a useful adjunct for pain |
|
|
Acetaminophen toxicity causes?
|
fatal hepatic necrosis
|
|
|
Treatment of acetaminophen toxicity
|
emesis or gastric lavage with activated charcoal
N-accetylcysteine to replenish glutathione in liver |
|
|
What does acetaminophen get broken down to?
|
sulfate derivative
glucuronide derivative toxic intermediates (via p450) |
|
|
What combines with toxic intermediates of acetaminophen?
|
glutathione --> mercapturic acid
nucleophilic macromolecules -->damaged macromolecules --> cell death |
|
|
What does COX do?
|
converts arachidonic acid --> PGG2 (short lived) --> PGH2 by peroxidase
|
|
|
What does PGH2 form?
|
prostacyclins
thromboxanes |
|
|
What enzyme do NSAIDS inhibit?
Is this reversible? |
COX
All except aspirin inhibit reversibly Aspirin inhibits irreversibly through acetylation |
|
|
What effects does aspirin have on platelets?
|
depletion of COX for the lifetime of the platelet
|
|
|
What effects do other NSAIDS (opther than aspirin) have on COX?
|
COX inhibition is related to the turnover rate of COX in each tissue
|
|
|
Structure of COX-1?
|
Homodimeric membrane protein
4 alpha helices with exposed hydrophobic surfaces rests within the lipid bilayer Helices form an entrance to COX channel and arachidonic can enter through the channel |
|
|
What exactly does acetylation by aspirin do to the COX channel?
|
blocks the access to the channel, so arachidonic acid can't enter
|
|
|
How do non-aspirin NSAIDS affect the COX channel?
|
it competitively excludes arachidoniate from the channel
|
|
|
What is COX2?
What is difference btwn that and COX 1? |
induced during inflammation in response to cytokines, endotoxins
COX 1 is ubiqitously expressed in GI, kidney, and platelets |
|
|
What is the anti-inflammatory activity of NSAIDS?
|
inhibits chemotaxis
down-regulates IL-1 Decreased production of free radicals and superoxide Interferes with Ca-mediated cellular events Decreased sensitivy of vessels to bradykinin and histamine affects lymphokine production from T cells reverses vasodilation |
|
|
Effects of highly selective COX2 inhibitors
|
edema
HTN |
|
|
Most important route of elimination for NSAIDS
|
kidney
|
|
|
How long does it take for salicylates to enter bloodstream
|
15-30 mins
|
|
|
What effects do aspirin and other salicylates have on respiration?
|
respiratory stim (stimulates medullary center, and increases O2 consumption/CO2 production in skeletal muscles by uncoupling ox-phos)
also respiratory depression at toxic doses (central resp paralysis, circulatory collapse, and renal failure) |
|
|
What is the relationship between aspirin and ibuprofen?
|
If using both, ibuprofen inhibits aspirin's cardioprotenctive effects (competes for access t o acetylation site on platelet COX)
But, if you take aspirin 2 hrs prior to ibuprofien, then negative effect gone IF ibuprofen taken regularly, then antiplatelet benefit of aspirin is lsost |
|
|
Which drugs don't interfere with aspirin
|
acetaminophen
diclofenac celecoxib rofecoxib |
|
|
Mechanism behind unwanted GI effects from NSAIDS?
|
local irritation
decreased PGE2 and PGI2 production (all except acetaminophen and salicylate) --> loss of cytoprotection |
|
|
What do NSAIDS do to platelet fxn? What do COX2 inhibitors do to platelets?
|
decrease TXA2 production and increase bleeding time (ESP ASPIRIN, NOT ACETAMINOPHEN OR SALICYLATE)
TXA2 is COX-1 mediated, so not really a problem with COX-2 inhibitors |
|
|
What effect does NSAIDS have on gestation?
|
decreases production of PGE2 and PGF2 which are usually increased prior to partiution
it prolongs gestation |
|
|
How do NSAIDS affecct renal fxn
|
decrease PGE2 (made in kidneys) for vasodilation
decreases RBF Can lead to fluid retention and may cause renal failure or HTN Both only occur if the patient is at risk |
|
|
Who is at risk for renal side effects from NSAIDS?
|
elderly
CHF renal insufficiency ascites volume depletion those on diuretics |
|
|
What are some effects of NSAIDS on pregnant mother?
|
prolongation of gestation (decreased PGE2 and PGF2)
during late pregnancy, chronic use --> pulmonary HTN in fetus from pulm smooth muscle proliferation fro DA closure Advantageous for smal preterm infants with PDA and respiratory distress syndrome |
|
|
What is aspirin intolerance syndrome?
|
vasomotor rhinitis
angioneurotic edema urticaria bronchial asthma hypotension shock |
|
|
who is at risk for AIS?
|
middle aged adults with asthma, chronic urticaria or nasal polyps
|
|
|
mechanism for AIS?
|
shunting of arachidonic acid towards 5-lipoxygenase (for increased LT production)
|
|
|
Features of salicylism
|
HA
tinnitus CNS depression thirst sweating GI probs hyperventilation |
|
|
treatment for salicylism
|
cut back on dose
|
|
|
Features of severe salicylate poisoning
|
hyperventilation and respiratory alkalosis
CNS and GI probs fever dehydration marked alterations in acid-base status and electrolyte composition |
|
|
Treatment for severe salicylate poisoning
|
emesis or gastric lavage with charcoal
sponging with tepid water, alcohol or fluids HCO3 Vitamin K or transfusion dialysis or exchange transfusion |
|
|
How do salicylates affect acid-base status
|
increase rate and depth of ventilation --> primary respiratory alkalosis --> eventual renal compensation
Metabolic acidosis occurs b/c ox-phos gets decoupled --> decreased ATP --> increased glycolysis |
|
|
What role do salicylates play in clotting
|
inhibit vitamin K dependent synthesis off prothrombin and other clotting factors --> prolonged PT
|
|
|
Which NSAID is contraindicated in Children? Why?
|
aspirin --> Reye syndrome
|
|
|
Which NSAID is specficially for children?
|
acetaminophen
|
|
|
Whcih NSAID is useful for a very high fever
|
Ibuprofen (can give with acetaminophen)
|
|
|
Which drugs are indicated for antipyresis?
Which is indicated for children? Which is indicated for very high fever? |
aspirin
acetaminophen (children) ibuprofen (high fever, can be given with acetominophen) |
|
|
Why would someone use salicylates over aspirin for pain relief?
|
More favorable toxicity profile, though onset of analgeisa is slower
difference in effectiveness is not clear |
|
|
What is ketorolac?
|
only injecctable NSAID available in US
for post-op use superior to aspirin for treatment of chronic pain states |
|
|
What are the limitations on ketorolac?
|
should not be used for more than 5 days
--> peptic ulcers and renal problems it's a great analgesic, but only moderately effective as an anti-inflammatory |
|
|
What drugs can be used to treat IBD?
|
mesalamine
olsalazine sulfasalzine |
|
|
How is mesalamine given?
|
poorly absorbed when given orally, so administer rectally or give formulation in pH sensitive polymer coating
|
|
|
How is olsalazine metabolized?
|
hydrolyzed in lower intestine to mesalamine
|
|
|
How is sulfasalazine metabolized?
|
poorly absorbed orally
cleaved into its 2 constituents by bacteria in colon, both portions are anti-inflammatory |
|
|
What is the utility of sulfasalazine in IBD and RA?
|
good for sulfasalazine
it is partially effective for RA?? |
|
|
Which drugs are indicated for dysmenorrhea?
|
fenamic acids
meclofenamate mefenamic acid |
|
|
MOA of fenamic acids
|
COX inhibition
phospholipase A2 inhibition |
|
|
adverse effects of meclofenamate
|
diarrhea and abdominal pain
enhances effects of oral anticoagulents contraindicated in pregnancy NOT for children |
|
|
adverse effects of mefenamic acid
|
more toxic than aspirin
NOT for children only use for 1 week |
|
|
How is choice made in general for pain relief in rheumatalogic dzs?
|
choice is empirical
|
|
|
What drugs are children restricted to in rheumatic dzs?
|
aspirin
naproxen tolmetin ibuprofen |
|
|
what drugs can be given to treat rheumatologic dzs in pregnancy?
|
DO NOT USE NSAIDS
low doses of aspirin are ok, but discontinue prior to partuition |
|
|
What is dilfunisal?
|
derivative of salicylic acid, though not converted to salicylic acid in vivo (so salicylism not observed)
|
|
|
what is dilfunisal used for?
|
analgesic for OA, musculoskeletal strains, sprains, RA
NOT good antipyretic (poor CNS penetration) |
|
|
What is indomethacin?
|
first NSAID developed
COX1 inhibitor poorly tolerated (35-50% of pts have averse rxns) |
|
|
adverse reactions from indomethacin?
|
salt and water retention (antagonizes diuretic effects of drugs)
GI pros hematopoietic rxns AIS (100% cross-reactivity with aspirin) |
|
|
Contraindications for indomethacin?
|
pregnancy
nursing mothers children psych d/o epilepsy Parksinson's |
|
|
uses for indomethacin
|
acute tx for Bartter syndrome
PDA closure in premature infants acute gouty arthritis RA (efficacy ~ aspirin) refractory fever of Hodgkin's dz don't use reoutinely for analgesic or antipyretic |
|
|
What does sulindac treat?
|
RA
OA akylsing spondylitis |
|
|
Adverse reactions to sulindac
|
mild GI effects
CNS effects (drowsiness, HA, nervousness) skin rxns (rash, pruritis) |
|
|
uses for etodolac
|
post-op anagesia
OA RA |
|
|
adverse rxns to etodolac
|
GI irritation and ulceration
|
|
|
what is a benefit of etodolac
|
arge difference btwn doses that --> anti-inflamatory effects and those that cause gastric irritation
|
|
|
what is diclofenac?
|
more potent COX inhibitor than indomethacin
decreases intracelular [] free arachidonate in WBC |
|
|
adverse rxns to diclofenac?
|
GI
reversible increase in hepatic aminotransferases |
|
|
uses of diclofenac
|
long-term RA, OA, ank spond tx
short-term acute musculoskeletal injury post-op ophthalmic inflammation |
|
|
How can GI toxicity be reduced in diclofenac?
|
add PGE1 analog (misoprostol)
|
|
|
What is nabumetone
|
weak COX inhibitor
active anti-inflammatory with analgesic and antipyretic activities |
|
|
adverse reactions to nabumetone
|
lower bowel complains
skin rash HA/dizziness heartburn tinnitus pruritis doesn't interfere with platelet aggregation decreaesd GI ulceration |
|
|
uses of nabumetone
|
RA
OA short-term soft tissue injuries |
|
|
General info with regard to proprionic acid derivatives
|
COX inhibition
anti-inflammatory, analgesic, and anipyretic activity prolong bleeding time AIS high degree of binding to albumin |
|
|
adverse rxns of proprionic acid derivatives
|
GI (less severely than aspirin)
some CNS effects |
|
|
uses for propionic acid derivatives
|
RA
OA ankylosing spondylitis acute gouty arthritis analgesics for acute probs (incl primary dysmenorrhea) |
|
|
which propionic acid derivative has been shown to be safe and effective in children
|
ibuprofen
|
|
|
which propionic acid derivative has the longest half life?
Shortest? |
oxaprozin
ibuprofen/ketoprofen |
|
|
Which propionic acid derivative is associated iwth interstitial nephritis
|
fenoprofen
|
|
|
Which propionic acid derivative is available in topical formuation? What is it used for?
|
flurbiprofen
prevents miosis during ophthalmic surgery |
|
|
Which propionic acid derivative is preferred for analgesia and relieve of morning stifffness?
|
naproxen
|
|
|
what are the propinoic acid derivatives
|
ibuprofen
naproxen flurbiprofen oxaprozin fenoprofen ketoprofen |
|
|
what are the enolic acid derivatives?
|
piroxicam
meloxicam |
|
|
How long does it take for maximal therapeutic response to occur in piroxicam?
|
2 weeks
|
|
|
adverse rxns ot piroxicam?
|
GI effects
peptic ulcers |
|
|
therapeutic uses for piroxicam
|
RA
OA akylosing spondyltisi acute musculoskel d/o dysmenorrhea post-op pain acute gout |
|
|
adverse rxns to meloxicam
|
COX2 selective inhibition
|
|
|
adverse rxn to meloxicam?
|
diarrhea
dyspepsia nausea increase aminotransferases serious GI disturbances (but less than piroxicam) |
|
|
What is the main advantage to COX 2 inhibitors compared to non-selective COX inhibiton?
|
they are NOT any more effective, they just have decreased side effects (esp GI toxicity!!)
Increased risk of CV events |
|
|
What are the disadvantaes of COX 2 inhibitors?
|
inbalance of prostanoids in kidneys --> salt and water retention
this interferes with ovulation, bone remodeling, healing of gastric ulcers, PROTHROMBIC effects COX2 KO mice have histologically deranged kidneys |
|
|
COX 2 inhibitors and pregnancy?
|
should not be given in 3rd trimester or pregnancy
they have decreased fetal survival in pregnant animals |
|
|
mechanism behind the COX inhibitors and CVD risk
|
COX1 mediates platelet TXA2 production in platelets (--> decreased aggregation, reduced platelet proliferation, and vasodilation)
PGI2 is mediated by COX1 and COX2, so there is decreased PGI2 and TXA2 is unaffected In non-selective COX inhibition, both TXA2 and PGI2 are reduced equally |
|
|
What does PGI2 do?
|
vasodilation
inhibits platelet aggregation |
|
|
What does TXA2 do?
|
vasoconstriction
promotes platelet aggregation |
|
|
uses of celecoxib
|
OA
RA moderate to severe pain dysmenorrhea dental pain |
|
|
what is the initially favored treatment for RA
|
methotrexate (esp if severe) b/c of relatively rapid response, hihg repsonse rate, and longest sustained efficacy
can also be used for mild-moderate dz |
|
|
what DMARD drug is sometimes preferred for mild dz
|
hydroxychloroquine
sulfasalazine |
|
|
MOA MTX
|
folate antagonist
supplement with folate |
|
|
adverse rxn to MTX
|
nausea
mucosal ulcers hepatotoxicity with LE changes, cirrhosis rare (toxicity reduced by giving leucovorin 24hrs after MTX) |
|
|
contraindication of MTX
|
pregnancy (teratogenic)
decreased fertility in men and women |
|
|
uses of MTX
|
RA
juvenile chronic arthritis psoriasis psoriatic arthritis polymyositis dermatomyositis WEgener's giant cell arteritis SLE vasculitis |
|
|
features of hydroxychloroquine
|
may decrease RF
may not slow progression of erosive bone lesions 3-6 months to work |
|
|
adverse rxn to hydorxychloroquine
|
CNS and GI disturbances
skin rxns peripheral neuropathies retinal damage |
|
|
use of sulfasalazine in RA
|
IgA and IgM RF production decreased
|
|
|
adverse rxns to sulfasalazine
|
N/V
HA rash |
|
|
MOA leflunomide
|
inhibits pyrimidine synthesis
critical step for rUMP production induces cell cycle arrest of activated autoimmune lymphocytes |
|
|
adverse rxns leflunomide
|
diarrhea
elevated LE alopecia weight gain increased BP rash teratogenic and carcinogenic |
|
|
what class of drug is leflunomide
|
DMARD
|
|
|
use of glucocorticoids in RA
|
used orally when pts are waiting for onset of DMARD action or during brief flares of multiple joints
|
|
|
examples of gold compounds
|
aurothioglucose
gold sodium thiomalate auranofin |
|
|
adverse rxns to gold compounds
|
1/3 of pts suffer
skin and mucous membranes proteinuria nephrosis severe blood dyscriasis (incl aplastic anemia) choestatic jaundice perpheral neuropathies pulmonary infiltrates |
|
|
therapeutic uses of gold compounds
|
RA if early and active (nto for mild dz)
usually of little behefit if dz is advanced |
|
|
contraindications of gold compounds
|
renal dz
hepatic dysfxn hematological d/o recent radiation tx condomitant use of anti-malarials, immunosupressant s uritcaria eczema colitis elderly |
|
|
What do TNF-alpha and IL-1 do?
|
stimulate PGE and collagenase production
stim cartilage resorption inhibits proteoglycan synth --> inflamm cell recruitment, neoangiogen, and joint damage |
|
|
where are TNF-alpha and IL-1 found
what are they derived from |
rheumatoid synovial fluid and tissues
macrophages and fibroblasts |
|
|
which drugs are the TNF inhibitors
|
etanercept
infliximab adalimumab |
|
|
what is etanercept
|
recombinant fusion protein made of 2 soluble TNF receptor moieties linked to Fc portion
it binds TNF-alpha wiht high affinity and neutralizes it's bio activity |
|
|
what does etanercept treat?
|
RA
juvenile chornic arthritis psoriatic arthritis ank spond |
|
|
what is infiximab?
|
MAB to TNF-alpha
Fc region of human IgG and Fab sequences reduces TNF-alpha level may dislodge TNF-alpha bound to cells |
|
|
What does infliximab treat?
|
Crohn's
RA |
|
|
What is adalimumab?
|
recombinent human MAB to TNF-alpha
complexes with soluble TNF-alpha and prevents interaction with p55 and p75 |
|
|
what does adalimumab treat?
|
RA
|
|
|
adverse effects common to TNF inhibitors?
|
risk of macrophage-dependent infection increaes
must monitor for lymphoma newly formed dsDNA AB and ANA documented, but does not contradict use if clinical lupus symptoms don't occur |
|
|
what is anakinra?
|
recombinant non-glycosylated IL-1Ra for moderate to severe active RA pts who have failed 1 or more DMARD
Might be less effective than anti-TNF agents |
|
|
administration of anakinra?
|
daily subQ injection
|
|
|
what is abatacept?
|
fusion protein of cytotoxic T lymphocyte associated Ag 4, linke to IgG1
inhibits binding of ligants to CD28, which prevents Tcell activation and lowering serum concentrations of inflammatory markers, cytokines, and RF |
|
|
what does abatacept treat?
|
moderate to severe RA pts who haven't responded to 1+ DMARD
|
|
|
what is rituximab
|
anti-CD20 MAB
selectively depletes CD20+ B cells, which play a role n autoimmune response and in chronic syndovitis seen in RA |
|
|
uses for rituximab
|
B-cell non-hodgkin's lymphoma
can be used with MTX to treat mod-severe RA in pts who haven't responded to TNF inhibitors |
|
|
what is gout?
|
syndrome caused by an inflammatory response to the formation of monosodium urate monohydrate crystals that develop 2/2 hyperuricemia (either environmental or genetic)
|
|
|
what can cause increaed uric acid in body?
|
under-elimination of uric acids by kidneys (impaiared fxn or EtOH interference)
increased intake of foods with purines (meats, seafood, dried peas and beans) |
|
|
are men or women more likely to get gout?
|
men
|
|
|
what are some of the associated risk factorS for gout?
|
obesity
HTN hyperlipidemia DM |
|
|
Dx for gout?
|
needle aspiration --> uric acid crystal in the joint fluid during an acute attack
|
|
|
what % of ppl with hyperuricemia develop gout?
|
10-20%
|
|
|
How is acute gout treated?
|
disabling leukocyte migration and phagocytosis (colchicine)
COX inhibition (indomethacin and oxaprozin) |
|
|
long-term management of gout?
|
increase uric acid excretion with uricosuric agents (probenecid adn sulfinpyrazone)
reducing uric acid synth (allopurinol) |
|
|
pharmacodynamics of colchicine
|
ibnds tubulin and prevents tubulin polymerization
inhibits WBC migration and phagocytosis inhibits formation of LT B4 relieves pain and inflammation w/i 24 hrs |
|
|
indications for colchicine
|
alleviates inflammation of acute gouty arthritis
proph for recurrent episodes of gouty arthritis and Med fever |
|
|
adverse effects of colchicine
|
diarrhea and N/V
abdominal pain |
|
|
what is the dosing for colchicine
|
.5-1 mg
8mg in 24 hrs = lethal |
|
|
Which NSAIDS are not used to treat gout?
|
aspirin
salicylates tolmetin |
|
|
what is the mechanism of NSAIDS in gout
|
inhibits COX and urate crystal phagocytosis
|
|
|
When should indomethacin be used to treat gout?
|
can be used initially or as a 2nd choice if colchicine is unsuccessful
|
|
|
how does exaprozin treat gout?
|
lowers serum uric acid by increasing excretion
not to be used in pts iwht uric acid stones |
|
|
whihc drugs are the uricosuric agents?
|
probenecid
sulfinpyrazones |
|
|
use of the uricosuric drugs?
|
for pts with the tophaceous gout or in those wiht increasingly frequent attacks
use when plasma tissue levels are high start tx 2-3 weeks after acute attack |
|
|
who should not use the uricosuric agents?
|
those that excrete large amounts of uric acidin order to avoid uric acid calculi
|
|
|
MOA of uricosuric acids?
|
act at anionic transport sites of the renal tubule
|
|
|
metabolism of probenecid
|
completely resorbed by the renal tubules
metabolized very slowly |
|
|
metabolism of sulfinpyrazone
|
rapidly excreted by the kidneys
|
|
|
pharmacodynamics of uricosuric drugs?
|
affect active transport sites in middle segments of prox tubules to net resoprtion of uric acid is decreased
|
|
|
what role does aspirin play in the treatment of gout?
|
should not be used in small doses b/c it encourages the retention of uric acid by the kidneys
it's ok in large doses |
|
|
how can formation of renal uric acid stones be avoided in treatment of gout
|
maintain high urine output
keep urine pH >6 esp early in treatment |
|
|
adverse effects of uricosuric drugs
|
GI irritation (esp sulfinpyrazone)
allergic dermatitis (probenecid) rash (both) nephrotic syndrome (probenecid) aplastic anemia (rare, both) |
|
|
how should uricosuric drugs be administered?
|
in beginning give with colchicine or NSAIDS to avoid precipitating acute gouty attack
|
|
|
How is uric acid formed?
How does allopurinol work? |
hypoxanthine --> xanthine (via xanthane oxidase) --> uric acid (xanthine oxidase)
allopurinol --> alloxanthine (whcih inhibits xanthine oxidase) |
|
|
dosing of allopurinol?
|
long duration of action
dose once a day 80% absorbed orally |
|
|
indications for allopurinol?
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chronic tophaceous gout
in pts with gout whose 24 hr urine on purine-free diet exceeds 1.1 g when uricosuric drugs can't be used b/c of adverse rxns for recurrent renal stones pts with fxnal renal impairment gross elevations of serum urate levels |
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adverse effects of allopurinol?
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acute attacks of gouty arthritis occur early with allopurinol when urate crystals are being removed and plasma urate levels are below normal
(administer with colchicine and/or indomethacin) GI intolerance peripheral neuritis and necrotizing vasculitis depression of BM elements aplastic anemia hepatic toxicity interstitial nephritis allergic skin rxn exfoliative dermatitis cataracts |
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drug interactions iwth allopurinol
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mercaptopurine and azathioprine doses should be reduced ot 25%during CA chemo
increased risk fo BM suppression inhibits metabolism of prbenecid and oral anticoags increases hepatic ion [] safety not est in children and pregnancy |
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what is pseudogout?
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Ca pyrophosphate deposition in joints
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what is familial mediterranean fever?
how is it treated? |
recurrent episodes of unprovoked episodes in joints, peritoneal cavity, and skin
colchicine |
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innate immunity
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skin
granulocyes monocytes NK cells mast cells basophils |
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adaptive immunity
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AB from B cells
T cells (helper, regulatory, cytotoxic |
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uses of immunosuppressants
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preventing graft rejection
treatment of autoimmune dzs |
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is monotherapy or combination therapy more effective when treating transplant rejection
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combination
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purpose of biological induction therapy
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delays the use of nephrotoxic calcineurin inhibitors or to intensify initial immunosuppressive tx in pts of high risk rejection
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who is at high risk for transplant rejection
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repeat transplant
african american s peds |
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what are the 2 types of drugs for biologic induction therapy
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depleting agents
immune modulators |
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what comprises the depleting agents
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antithymocyte globuliesn
muromonab CD3 MAB |
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what drugs are immune modulators
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anti-IL-2R MAB blocsk IL-2 mediated T cell activation
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which drugs are included in maintenance immunotherapy?
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calcineurin inhibitor
glucocorticoids mycophenolate mofetil |
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Which drugs are used for maintenance in transplants?
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GCs
azathioprine cyclosporine tacrolimus mycophenolate mofetil sirolimus monoclonal and polyclonal AB |
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what tx is there for established rejection?
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use of agents against activated T cells (GC in high doses)
polyclonal antilymphocytes or muromonab CD-3 MAB |
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classes of immunosuppressant drugs
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depletion of lymphocytes (AB, cytotoxic drugs)
Ag recognition by Ag presenting cells (MAB) Production of pro-inflammatory cytokines (GCs) T cell activation and IL-2 production (AB and calcineurin inhibitors) Proliferation and differentiation of T and B cells (ABs, cytotoxic drugs, GCs and mTOR inhibitors) |
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Which drugs are calcineurin inhibitors?
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cyclosporine
tacrolimus |
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what is calcineurin?
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Readily diffuse into cytoplasm of target T cells and inhibit T cell receptor activated signal transduction pathway
T cell receptor activation --> increase in intracellular Ca --> calcineurin, which dephosphoyrlates NF-AT that increases the transcription of IL2 and other lymphkines |
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MOA of calcineurin inhibitors
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they complexes with their cytoplasmic receptors and bind calcineurin and inhibits calcineurin activiyt n T cells
NFAP translocation is blocked --> interleukin production inhibition and T cell proliferation |
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pharmacokinetics of cyclosporine
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hydrophobic
given Iv or PO metabolized by p450 |
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Pharmakinetics of tacrolimus
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IV or oral admin
met by p450 |
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receptor for cyclosporine? tacrolimus?
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cyclophilin
FKBP12 |
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Uses of cyclosporine and tacrolimus?
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kidney, heart, liver, BM, lung and pacreas trasplant
treats psoirasis, RA, Crohn's dz |
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which calcineurin inhibitor is more potent?
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tacrolimus (by 100x)
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toxicity of calcineurin inhibitors?
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nephrotoxicity in 70%
HTN altered mental status tremor hirsutism DM hyperglycemia increased risk of malignancy and opportunistic infectinos |
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drugs that are mTOR inhibitors
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sirolimus
everolimus |
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what is sirolimus?
what is everolimus |
macrolide AB
derivative from sirolimus |
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MOA of sirolimus
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inhibits IL-2 induced T and B cell expansion
Forms a complex with FKBP12 that inhibits mTOR activity |
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what is mTOR
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protein kinase that plays a central role in the growth and expansion of T and B cells
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pharmacokinetics of sirolimus
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given orally
hihg fat diet decreases absorption CYP3A4 metabolism transported by p-glycoprotein |
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difference between sirolimus and everolimus in terms of pharmacokinetics?
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shorter half life in everolimus
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therapeutic uses for sirolimus and everelimus
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organ transplant
can be used alone or in combo with other immunosuppressants some dermatologic d/o uveoretinitis (in combo with cyclosporine) |
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when is the use of sirolimus recommended?
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if pt has calcineurin inhibitor associated nephrotoxicity, can be used with GC and mycophenylate mofetil
it will avoid permanent renal damage |
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toxicity of mTOR inhibitors
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dose dependent cholesterol and TG increases
lymphocele can develop (complication from renal transplant) anemia, leukopenia GI effects delayed wound healing opportunistic infections |
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drug interactions with sirolimus
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interacts with cyclosporine --> renal toxicitym, hyperlipidemia, and myelosuppression
Interacts with other drugs metabolized by CYP3A4 and transported by glycoprotein |
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what is azathioprine?
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purine anti-metabolite
preodrug of mercaptopurine but is mroe potent than it for immunosuppression |
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MOA of azathioprine
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cleave to mercaptopurine and gets converted to thio-GTP, which gets incorporated in DNA, inhibiting cell prolif --> cell death
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how is azathioprine metabolized?
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excreted by urine
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therrapeutic uses of azathioprine
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prevents transplant rejection
used in pts who don't respond ot cyclosporine or glucocorticoids can treat RA, CD, and MS |
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toxicity of azathioprine
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affects rapidly growing cells in BM adn GI
--> leukopenia and thrombocytopenia hepatotoxicity mutagenic and carcinogenic |
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drug interactions with azathioprine
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metabolized by xanthine oxidase, so administration with allopurinol --> toxicity
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What is structure of mycophenolate mofetil
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2 morpholinoethyl ester of mycophenolic acid (MPA)
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MOA of mycophenolate mofetil
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inhibits inosine monophosphate dehydrogenase
B and T cells depend on this enzyme for cell prolif MPA suppresses lymphocyte prolif and fxns (including migration, adhesion, and AB production) |
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Pharmacokinetics of mycophenolate mofetil
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rapidly absorbed orally
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therapeutic usees of mycophenolate mofetil
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following renal transplant
used in combo with calcineurin inhibitor and GCs lupus nephritis RA some dermatologic d/o |
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toxicity of mycophenolate mofetil
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leukopenia
diarrhea vomiting increased incidence of infection sepsis CMV |
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drug interactions with mycophenolate mofetil
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antacids with Al or MgOH --> decreased absorption
don't give wiht cholestyramine or drugs that affect enterohepatic circulation b/c they decreae MPA conecntrations by binding free MPA in intestines |
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how are poly and MAB used in preventing transplant rejection
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ABs abainst lymphocyte cell-surface Ags are effective in interfering with activation and fxn of lymphocytes
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examples of ABs used to prevent organ rejection
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antithymocyte globulins
anti-CD3 monoclonal ABs Anti-CD25 MAB anti-TNF-alphha agents |
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MOA of antithymomcyte globulins
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deplete thymocytes by cytotoxicity and by blocking lymphocyte fxns by binding to cell surface molecules
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side effects of antithymocyte globulins and how can these side effects be prevented
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fever, chills, hypotension (from giving a foreign protein)
leukopenia and thrombocytopenia these rxns can be minimized by giving slow infusion or pretreatement with corticosteroids, acetaminophen and/or anti-histamines |
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what is muromonab and how does it work?
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mouse monoclonal AB against CD3 receptor complex on T cell surface
Causes depletion of mosmt T cells from blood and peripheral lymphoid organs AB reduces fxn of remaining T cells |
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uses of muromab
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prevents acute rejection of heart kidney, and liver transplants
depletes donor bone marrow prior to BM transplant |
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adverse rxns to muromonab
|
allergenicity to foreign mouse AB
toxicity associated with immunosuppression repeated treatment is contraindicated cytokine release syndroem from increase in cytokines, manifests as fever, chills, HA, tremor, N/V, diarrhea, abdominal pain, malaise, myalgias, arthralgias, and generalized weakness |
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which drug is used mroe frequently: muromonab or antithymocyte globulins
|
muromonab is obsolete b/c of toxicity and availability of antithymocyte globulins
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What is daclizumab
|
MAB against CD25 of IL-2 receptor, specific to acivated but not resting T cells
competitive antagonism of IL2 induced T cell prolif |
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uses for daclizumab
|
proph for acute organ rejection in adults
better than mouse ABs b/c of improved effector function, low potential for immunogenicity and long elimination half life can be used for maintenance triple therapy regimen |
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what are the drugs included in the maintenance triple therapy given with daclizumab
|
cyclosporine or tacrolimus steroids
mycophenolate mofetil (MMF) |
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toxicity associated with daclizumab
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rare, except those associated with immunosuppression
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what is basiliximab
|
CD25 MAB, combo murine-human
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what is infliximab
|
anti-tnf-alpha agent
humanized anti-TNF alpha MAB binds to TNF alpha and prevents it from binding to its receptosr |
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uses for infliximab
|
CD
RA |
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adverse rxns to infliximab
|
urticaria
hypotension dyspnea fever all within 1-2 hrs |
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MOA of GCs
|
exACT MOA unknown
may inhibit T cell prolif T cell dependent imunity and expression of cytokines IL2 |
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advantages of GCs over other immunosuppressants
|
no BM suppression or GI toxicity
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