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795 Cards in this Set

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  • Back
what is the natural hormone we refer to as "estrogen"?
17-B-estradiol - other natrual estrogens are are estrone, estriol
what is premarin and what is its use?
equilin sulfate and estrone sulfate, from pregnant mare urine, used in HRT
what chemically modified natural progestin must we know, and what is it used for?
medroxyprogesterone - most common for HRT, also depot contraception
what is the most common therapeutic regimen for contraception (specific estrogen, and type of progestin)?
a synthetic estrogen, ethinyl estradiol (EE), and one of the five synthetic progestins
what are the five synthetic progestins we must know, and what generation is each?
1st generation: norethinedrone (NE); 2nd generation: levonorgestrel (LNG); 3rd generation norgestimate (NGM) and desogestrel (DSG); 4th generation drosperinone
what is the most common therapeutic regimen for HRT?
premarin (two equine estrogens) plus medroxyprogesterone - together called prempro
what is the rate limiting step in biosynthesis of E and P?
conversion of cholesterol to pregneolone
what is the function of aromatase (2 conversions)?
androstenedione --> estradiol; testosterone --> 17-B-estradiol
what is the source of estrogens in men and postmenopausal women, and what estrogen do they have?
adipose tissue takes DHEA from adrenals and converts it to estrone
what hormonal change causes ovulation?
E peaking adt midcycle, causing surge in LH and FSH
what happens to hormone levels after this?
E levels decline, but P levels rise
how do oral contraceptives inhibit ovulation?
by creating an environment which inhibits the FSH and LH surge
what concentrations suppress the LH and FSH release?
high concentrations of E and P
what are the relative concentrations of E to P in luteal phase?
P >>> E - P is measured in mg, while E is measured in ug
how does estrogen level affect transport of E in blood?
it increases the level of the binding globulin SHBG
which hormone, E or P, binds with high affinity and specificity to its receptors?
besides P receptors, what else does B bind to and agonize (3)?
1) PR; 2) GR; 3) ER
what are the two estrogen receptors, and which does E bind with more affinity?
ER-alpha and ER-beta, E binds with same affinity
what hormone(s) prefer alpha and what hormone(s) prefer beta?
estrone prefers alpha, estriol and genstein prefer beta
where does beta receptor predominate?
prostate, GIT
where does alpha receptor predominate (3)?
breast, endometrium, liver
which hormone, E or P, modulates many metabolic processes?
what are other functions of estrogen (3)?
development of female secondary sex characteristics, control of ovulatory cycle control of pregnancy
what are effects of progesterone (list)?
mammary development, prepare uterus for implantation, increases bosal body temp, sloughing of endometrium, maintains pregnancy, inhibits uterine contractility
how does estrogen affect coagulation?
increases clotting factors and decreases coagulation factors
how does estrogen affect lipid profile/
increases HDL, increases TG, decreases LDL
what other metabolic effects does estrogen have (2)?
increases Na+ retention, stimulates cell proliferation
how do types of estrogens rank in potency, and which are used in oral contraceptives?
synthetic > conjugated > equine > natural - synthetic (ethinyl estradiol) used in oral contraceptives
what should be known about pharmacokinetics of natural vs. conjugated and synthetic estrogens?
natural estrogens are affected by first pass (some metabolized and excreted by liver), and have short half life, while conjugated and synthetic estrogens can be taken orally and have long half lives (synthetic longest)
what pharmacokinetic properties cause prolonged effects of estrogen in body?
enterohepatic effects - metabolized to E-glucuronide in liver, then cleaved in intestine by bacteria, and reabsorbed
what is the primary metabolite of progestins and how are they metabolized/excreted?
primary metabolite is pregnanediol - progestins are glucuronidated, and excreted by kidney
how do the potency of progenstins rank?
levonorgestrel, desogestrel, norgestamate, norethindrone
what is the benefit if triphasic oral contraceptives?
less exposure to progestin component minimizes possible progestin-related side effects
when are monophasics better (2)?
1) when woman has signs of progestin deficiency (late cycle bleeding); 2) if woman experiences mood swings on triphasic
how long is "backup" required when there is a Sunday start for oral contraceptives?
one week
what should patient be told about taking pills, and missing one pill?
take same time every day, and if you miss a pill take two on day remembered
what if two pills are missed in week one or two?
tmust take 2 on day remembered and 2 on day after, and use backup for one week
what if two pills are missed in a row in week three?
discard pack and start new pack same day, or for Sunday starters keep taking a pill/day until Sunday, discard pack, and start new pack
what is the mini pill, and what is in it?
progestin only pill (POP)
what forms of progesterone might be in the mini-pill?
norethindrone or norgestrel
how should it be taken, and what is the most common use?
taken at same time every day, with no pill-free interval - most commonly used in lactating women
what are two forms of extended progestin-only contraception (what is each and how is it given) and how long does contraception last?
1) depo-provera - three months - IM injections of medroxyprogesterone acetate; 2) norplant - subdermal tubes of levonorgestrel - provides contraception up to 5 years
what are adverse effects of oral progestin only contaception (3)?
1) irregular bleeding (50% amenorrhea after one year); 2) acne; 3) depression
when should depo-provera be used, and why (3)?
only when other methods are not suitable - side effects including: 1) bone loss; 2) weight gain in heavier women; 3) delayed return to fertility >1 year
what are the mechanisms of action and effects of oral contraceptives (both COCs and progestin only) (3)?
1) inhibit ovulation (by suppresing FSH and LH release); 2) thicken cervical mucosa (sperm barrier); 3) altered endometrial lining blocks implantation
what increases risk of pregnancy when POPs are missed?
>3 hr delay in taking pill (need to miss 2 doses with COCs)
what cancers do COCs decrease risk of (2)?
endometrial, ovarian
what diseases do COCs decrease risk of (3)?
1) fibrocystic disease; 2) fibroadenomas; 3) PID
what other benefits do COCs provide (2)?
greater cycle regularity, lower blood loss during menses
how much is the risk of thrombosis increased in COC users, who is it increased in the most again, and what can be done to avoid it?
2-6x higher in COC users, increases clotting factors and decreases anti-clotting factors, risk greatest in smokers, to avoid thrombosis use lowest estrogen pill available (20ug)
what is the single greatest risk factor for breast cancer?
lifetime exposure to estrogen
who is this more of a risk in?
long term users
what type of use showed the most seroius increased risk in breast cancer?
4 or more years before first full-term pregnancy
besides increased breast cancer and thrombosis, what other increased risks are associated with estrogen (5)?
1) hypertension (1-5% of users, develops slowly); 2) cervical dysplasia/cancer (issue in promiscuous women, HPV); 3) impaired glucose tolerance (less an issue with low dose estrogen pills); 4) gall bladder disease (E increases bile stasis); 5) stroke and CVD (primarily on older smokers)
what specific hormone form is most associated with stroke and CVD?
levonorgestrel (most potent progestin)
what are risks associated with progesterone (3)?
1) unfavorable lipid profile; 2) impaired glucose tolerance; 3) thrombosis
what progesterone decreases the HDL:LDL ratio the most?
levonorgestrel is the worst
which progesterones have other effects on lipid profiles, and what effects does each have?
noregestimate or desogestrel increase HDL, desogestrel also lowers LDL (positive)
how do progestins affect glucose tolerance?
decrease insulin receptors
what is the worst progestin in causing IGT?
what progestins were said to have no effect on IGT?
norgestimate or desogestrel
what progestins are associated with higher risk for DVT?
newer 3rd generation progestins (desogestrel)
what are mild/moderate effects associated with estrogen?
N/V, cramping, fluid retention, dizziness, headache, breast discomfort, changes in quality of tears, corneal edema
what are mild/moderate effects associated with progesterone?
spotting and breakthrough bleeding, weight gain, acne, hirsutism
what progestins have an effect on glucose tolerance (2) and what is the effect of each?
levonorgestrel - exacerbates; norgestimate - slight improvement
what progesterone has a lot of androgenic effects, and what has moderate?
levonorgestrel - most androgenic effects, norethindrone - minimal/moderate, rest minimal
what progesterone has no effect on lipid profile?
which progesterones have positive effects on lipid profiles?
desogestrel (increase LDL, lower LDL), norgestimate (increases HDL)
what are contraindications for COCs (list)?
thrombotic disease, smokers over 35, hormone sensitive tumors, genetic predisposition to breast cancer, history of stroke/MI, HT, migraines with focal enurological symptoms, surgery w/immobilization, pregnancy
what types of women should get progestin only pills?
migraineurs, >35yr/smoker, thromboembolic disease, cardiac disease (especially CAD), CVD, early postpartum, hypertension with vascular disease or over 35, diabetes with vascular disease or over 35, hypertriglyceridemia
what new progestin reduces problems with Na+ and water retention, and what drug does it resemble?
drospirenone - resembbles spironolactone
what problems may it cause and who is it contraindicated in (3)?
may elevate potassium, contraindicated in those with liver, kidney, and adrenal problems
what free hormone do all OC's lower?
free testosterone
what are five characteristics of an ideal local anesthetic?
1) reversible nerve block (no permannet damage); 2) non-irritating; 3) low systemic toxicity; 4) effective whether injected or paplied topically; 5) rapid onset, sufficient duration, and prompt recovery
what are local anesthetics like chemically?
weak bases that exist in both ionized and unionized form at physiologic pH
what are two major classes of local anesthetics distinguished by?
either an ester or an amide group linking aromatic and amine portions of molecule
what form of local anesthetics can cross limpid membranes?
only base form (unionized)
what is the prototype amide anesthetic, and how does acidic pH affect its action?
lidocaine is the prototype amide, and if tissue pH is lower, the proportion of unionized form decreases dramatically, slowing the onset of local anesthetic effect
what three things affect the onset of local anesthetic action?
1) tissue pH, 2) pKa of drug; 3) nerve fiber type
what is the order of sensations lost (what is first, next, etc…five things)?
pain, cold, warmth, touch, pressure (B and C fibers most sensitive, A alpha and A beta the least, A gamma and A delta intermediate)
where is the site of action for local anesthetic drugs?
deep within sodium channels
what forms of the sodium channel have higher affinity for local anesthetics?
open or inactive channels (closed have lower affinity) - so frequency of nerve stimulation enhances access of ionized local anesthetics to their receptor
what form of local anesthetics can only access the receptor under certain conditions, and what are those conditions (2)?
the ionized form can only access the receptor from inside the nerve, and only when the channel is briefly open
what are the actions of local anesthetics on the CNS?
initial excitaiton (tremors, restlessness, possible convulsions) followed by CNS depression, respiratory failure, and death
how should convulsions/CNS toxicity be treated?
convulsions treated with diazepam, also administer oxygen
what do local anesthetics do to the cardiovascular system?
decreased excitability of myocardium, decreased conduction rate, decreased contractility, possible ventricular fibrillation
what are the effects of local anesthetics on ganglia and NMJ, and why?
decreased transmission due to actions of local anesthetics at nicotine receptors
what type of local anesthetics can cause allergic reaction, and how common is it?
very rare, only ester anesthetics
what is metabolism of ester type and amide type like?
ester type hydrolyzed rapidly by plasma esterases, amide type more slowly degraded by liver enzymes
what metabolic problem can occur, and with what type of anesthetics?
ester type anesthetics - some patients who metabolize ester anesthetics poorly due to a rare mgenetic defect in plasma cholinesterase
how do local anesthetics cause death by overdose?
due to ventricular fibrillation and cardiac arrest, or by CNS depression with respiratory failure
how can lidocaine be administered?
oral, parenteral, surface application
what is a potent, long-acting amide local anesthetic, frequently used epidurally or spinally (for partirution, lower limb orthopedics)?
what is an amide anesthetic similar to bupivicaine, but with a supposed advantage, and what is that advantage?
ropivicaine, similar but supposedly less cardiotoxic
what is a prototype ester anesthetic, and how does its action compare to lidocaine?
procaine (novocain) - less potent and shorter acting than lidocaine
how is it administered, and by what method is it not active?
rapidly absorbed after parenteral injection, but not effective topically
what is the duration of action of lidocaine?
40-90 minutes
what is the duration of action of bupivicane?
120-240 minutes
duration of procaine?
20-60 minutes
what is an ester that is more active and more toxic than procaine, and how else does it differ?
tetracaine - 10x as active and more toxic, but slower onset and longer duration
what ester is useful as a topical anesthetic, and what else should we know about this?
benzocaine - useful as topical anesthetic, has no ionizable amine group, so exists only in an unionized state
besides local anesthetic activity what does cocaine do?
inhibit reuptake of catecholamines / potentiation of indirect-acting sympathomimetics
what do moderate doses of cocaine cause in the CNS?
emesis, tremors, and possibly convulsions
what do high doses cause in CNS?
CNS stimulation followed by CNS and respiratory depression
what is cocaine's effect on the hypothalamus?
what does cocaine do to the heart at high doses?
what should cocaine not be coadministered with?
other vasoconstrictors
what amide anesthetic can be used topically?
what is the AE of bupivicaine?
can cause significantly greater CV toxicity compared to lidocaine
where is lidocaine metabolized (and other amides)?
how does potency/duration of ropivicane compare to other amides?
longer lasting and more potent than lidocaine, but less potent and shorter acting than bupiviciane
what anesthetic is most likely to cause allergies?
procaine (novocain) - short duration of action
what anesthetic lacks amine group, and only exists unionized?
how is benzocaine administered?
topical only
what are four factors affecting the actions of general anesthetics (4)?
1) concentration in gas; 2) pulmonary ventilation; 3) transfer of gas from lungs to blood; 4) release of anesthetic agent from blood to body tissues
what is used to define the amount of anesthetic gas?
partial pressure
what is the partition coefficient?
relative solubility in blood vs. gas phase
what is the main method of elimination of anesthetic gases?
if a patient has achieved equilibrium with a gas at high partial pressure, what can sudden discontinuation of gas delivery cause?
rapid exchange of gas into alveolar air - can cause diffusional anoxia if remaining air contains insufficient oxygen, such as breathing room air
what is therapeutic index/dose repsonse curve like in general anesthetics?
very low therapeutic index, steep dose response curve (99% of patients anesthetized at 1.3 MAC - MAC is concentraiton at which 50% are unconscious)
what can reduce MAC (3)?
reduced by presence of other CNS depressants, in the elderly, and in pregnant women
when is MAC increased?
infants and children
how does anesthetic potency to lipid:gas particion foefficent rule relate to mechanism of anesthetic action?
does not seem to relate to it
how does structure of gas relate to activity?
does not - even inert gases like xenon have anesthetic effects
what is the postulated mechanism?
action at specific membrane proteins
what is the prototype inhaled anesthetic?
what is its potency and speed of induction/recovery like?
high potency (MAC <1%) - moderately prompt induction and recovery
what is the metabolism of halothane?
mostly eliminated in air, but undergoes significant liver metabolism (20%)
what is the most important cardiovascular effect of halothane (bold) and other CV effects?
increases sensitivity of myocardium to catecholamines (tachyarrhythmias, primarily PVCs), decreased heart rate and cardiac output, inhibition of baroreceptor mediated tachycardia, decreased blood flow to liver and kidneys
what are the respiratory effects of halothane?
if not adequately ventilated patient can get hypoxia (rapid, shalow breathing, reduced response to CO2, impaired oxygen exchange)
what is the CNs effect besides anesthesia?
1) dose dependent depression of autonomics; 2) increases secrebral blood flow; 3) increases intracranial pressure; 4) decreases oxygen consumption in brain
what are rare instances of severe adverse effects with halothane (2)?
1) malignant hyperthermia; 2) halothane hepatitis (50% mortality)
how is malignant hyperthermia treated?
with the calcium channel blocker, dantrolene
what inhaled anesthetic has a very high MAC, and what is its MAC?
nitrous oxide - MAC 105.00
what other drug has very rapid onset and recovery like nitrous oxide, but is much more potent?
what anesthetic has similar CV, CNS, and respiratory effects to desflurane?
how does isoflurane compare to halothane in induction and recovery speed, and potency?
faster induction and more rapid recovery, but slightly lower potency
what is isoflurane a DOC for and why?
DOC for neuroanesthesia, because it does not increase intracranial pressure
what else does halothane do that isoflurane was said not to do (2)?
1) sensitize heart to catecholamien-induced arrhythmias; 2) still get dose-dependent hypotension (but still get dose-dependent hypotension)
what are two other advantages of isoflurane over halothane?
1) no reported hepatotoxicity; 2) better muscle relaxation (no convulsive activity)
what drug has rapid onset and recovery, but is not irritating to the airways and does not cause tachycardia?
what else should be remembered about sevoflurane?
hepatic metabolism 100x greater than desflurane, with some release of fluoride ion
so, what drugs have significant hepatic metabolism (2)?
halothane, sevoflurane
how is nitrous oxide useful for anesthesia?
only in combination with other inhalational or IV anesthetics
how is it metabolized?
not metabolized
how effective is nitrous oxide in muscle relaxation?
no significant relaxation
what property does it have that other inhalation anesthetics do not, and what is the mechanism behind this effect?
analgesic effect at less than 1.0 MAC - caused by release of endogenous opioids
what adverse effects can nitrous oxide cause (2 major, other)?
1) interferes with B12 function; 2) diffusional anoxia after sudden discontinuation of long use, unless oxygen is administered - also can cause nausea or dysphoria (CNS-related)
what IV anesthetic is an ultrashort acting barbiturate, and what is it good for?
thiopental - causes loss of consciousness 10-20 seconds after IV injection
how quickly does consciousness return with thiopental, and why?
returns slowly due to redistribution from brain to other tissues (fat)
where is thiopental metabolized?
in the liver
what is the MOA of thiopental?
allosteric regulation of GABA-a coupled chloride channels (increase opening time, allowing more influx of Cl- and nerve hyperpolarization
what is this the most frequently used drug for?
rapid sequence induction of anesthesia
what problem can thiopental cause, and how can it be avoided?
can cause painful tissue necrosis at injection site when used in concentrations >2.5% (use in lower concentrations)
what is an ultrashort acting, nonbarbiturate sedative and anisthetic agent, which can cause unconsciousness (5 minutes worth) in a single IV injection?
what problem can etomidate cause?
1) muscle spasm (treat with diazepam); 2) dose-dependent decrease in plasma cortisol levels
who should etomidate be avoided in?
prolonged sedation of critically ill patients
what is a rapid acting intravenous anesthetic (nonbarbiturate) that can be given by continuous infusion for surgical procedures, and has rapid emergence after infusion is stopped?
what else is propofol used for?
IV sedative for regional anesthesia
what side effects does it cause (2)?
1) hypotension (30%); 2) slows respiration / decreases response to CO2
what is propofol's effect on hepatic/renal function and intracranial pressure?
no impairment of hepatic or renal function, and generaly decreases intracranial pressure
what adverse effect of propofol occurs, but with low incidence?
PONV (post-operative nausea and vomiting) possibly to intrinsic antiemetic actions
what IV anesthetic causes dissociative anesthesia?
what other effects does ketamine have?
analgesia, amnesia (and others like hallucination, delirium)
what was it said not to affect (2)?
laryngeal reflexes, respiratory responses
what are the cardiovascular effects of ketamine (must know)?
increases CO, BP, and HR, possibly due to increased sympathetic outflow
what is the site of action of ketamine, and what does it do there?
cortex, limbic system - blocks glutamate (NMDA) receptors - also has high affinity for opioid sigma receptors
what is ketamine useful for (3)?
1) trauma/emergency surgeries; 2) radiological procedures in children; 3) cardiac surgeries
what general anesthetic is used for very short procedures (<10 min)?
what IV anesthetic is useful for induction of anesthesia?
thiopental - causes loss of consciousness 10-20 seconds after IV injection
what drugs reduce Ca++ absorption (2)?
anticonvulsants, glucocorticoids - other factors are intestinal disease, phytates and oxalates, and age
what is used to treat calcium deficiency that causes rickets/osteomalacia?
100 U vitamin D/day
what is used to treat hypocalcemic tetany?
calcium chloride, IV
what is used to treat hypocalcemia related to hypoparathyroidism, what is it, and why is it used?
DHT (dihydrotachysterol) - a vitamin D2 analog - shorter duration of action and greater effect on bone mobilization than D2 or D3
what is used to treat pseudo-hypoparathyroidism (Albright's hereditary osteodystrophy, a genetic deficiency in PTH-R activation of adenylate cyclase - symptoms: short stature and short metacarpal/metatarsal bones)?
DHT (dihydrotachysterol) + calcium supplementation
what is used to treat vitamin D-dependent rickets (type I rickets - defective conversion of 25-OHD to calcitriol)?
physiologic doses of calcitriol
what is used to treat renal osteodystrophy (renal rickets - also caused by defective conversion of 25-D3 to calcitriol, secondary to CRF) if there is no dialysis (CRF) (3)?
phosphate binders, Ca supplementation
what about in late stages when there is dialysis?
what is the treatment for hereditary 1,25 dihydro vitamin D resistance, or type II vitamin D-dependent rickets (bone deformities, mainly in lower limbs) and why is this the treatment?
treatment is long-term parenteral administration of calcium
what is the treatment for hypophosphatemic vitamin D-resistant rickets (short stature, bowing of lower limbs, and rachitic changes in long bones - decreased absorption of calcium and PO4 from GIT, and decreased reabsorption)?
oral PO4, calcitriol, but not always effective
how is vitamin D effective in osteoporosis treatment?
yes, 400-800 U/day improves intestinal Ca absorption
what strategy is used to delay osteoporosis?
vitamin D, dietary Ca++ supplementation
what drug is used to slow bone resorption, what class is it, and how does it work?
alendronate (fosamax) - a bisphosphonate - binds to hydroxyapatite, and blocks ability of osteoclast to resorb bone - used in osteoporosis
what are the side effects of fosamaxx (list) and how common are they?
rare - abdominal, musculoskeletal pain, nausea, heartburn, irritation of esophagus (minimized by remaining upright)
what may be a long term problem caused by fosamax?
might induce osteomalacia by inhibiting mineralization
what other drugs can be used for osteoporosis (4) and what class is each?
1) raloxifene (SERM); 2) teriparatide (synthetic PTH); 3) calcitonin; 4) estrogens (17-B estradiol)
what is the function of 17-B-estradiol in osteoporosis?
decreases osteoblast production of IL-6, a chemoattractant for osteoclast precursors
what is raloxifine (a SERM) protective against, and what advantage does it have over 17B-estradiol?
protective against spine fractures (but not hip) - avoids most undesirable effects of 17B (but has some hot flashes, thrombophlebitis)
how is teriparatide given, and what is its effect?
appears to stimulate Ca++ conservation, when administered in low, intermittent doses
how does it stimulate Ca++ conservation (2)?
1) minimize bone resorption; 2) via intestinal absorption (calcitriol dependent)
where does teriparatide induce bone growth?
both spine and hip, but so far only demonstrated efficacy against spine fractures
what is the MOA of calcitonin, and what is the problem?
it is a powerful inhibitor of bone resorption, but there is little net bone growth
how can calcitonin be administered (2), and what side effects occur with each mode of administration?
1) nasal spray (runny nose); 2) parenteral - N/V, flushing of face, frequent urination
what may have benefit in children/adolescents with osteoporosis (2 strategies)?
bone marrow trasnplant - also g-IFN + calcitriol have shown some benefit
what is paget's disease like, and what are the treatments (2)?
large, deformed bones - treated with 1) alendronate; 2) calcitonin
what are other clinical applications of note for calcitriol (2)?
1) psoriasis; 2) cancer (can induce leukemic cell differentiation)
what interleuken released by T cells was said to be an important stimulator of differentiation and proliferation of T and B cells, and what T cells release it?
IL-2, released by CD4+ T cells
what leads to the stimulation of calcineurin, and what is calcineurin?
T-cell receptor activation elevates intracellular Ca++ which stimulates the Ca++ calmodulin dependent phosphatace, calcineurin
what else does this increase in Ca++ stimulate (2 pathways)?
MAP kinase and NFkB signaling
what does calcineurin activate, and what is the result?
activates NFAT which helps induce expression of cytokines, like IL-2, TNF-alpha, and INF-gamma
what drug and drug type targets antigen recognition?
antibody therapy - Muromonab
what types of drugs (2) and examples target cytokine induction?
calcineurin inhibitors (cyclosporine, tacromilus) and corticosteroids (prednisone, prednisolone)
what type of drug and two examples target IL-2 receptor activation on T and B cells?
antibody therapy - daclizumab and basiliximab
what drug types (2) and drug examples targets lymphocyte proliferation?
antiproliferatives (sirolimus) and cytotoxic drugs (azathioprene and mycophenylate), and possibly steroids
how do these work, generally (2 categories of effects)?
1) interfere with T cell activation at multiple levels - reduce lymphocyte levels, inhibit cytokine gene expression and bind to glucocorticoid response elements; 2) anti-inflammatory effects
for allograft rejection what are they given in combination with?
cyclosporine or tacrolimus - permits lower dose of cyclosporine
what regimens are given if acute rejection is likely (either/or)?
1) methylprednisone IV pulses; 2) high dose oral prednisone
what are the most commonly used cytotoxic drugs for immunosuppression (4)?
1) azathioprine; 2) mycophenolate mofetil; 3) cyclophosphamide; 4) methotrexate
how does azathioprine work and what does it inhibit (complete MA)?
metabolized to 6-mercaptopurine, which inhibits de novo purine synthesis, but also inhibits the salvage pathway, and produces Thio-GMP which is incorporated into DNA backbone and damages DNA - these effects ultimately inhibit gene translation and prevent cell proliferation
how is it given and what is the regimen for organ transplant?
injected at time of transplant, then given orally with decreasing dose
what else was azathioprine said to be used for?
rheumatoid arthritis
what is the most limiting adverse reaction to azathiprine, and how many people get it?
leukopenia - 50% of renal transplant patients - often from bone marrow suppression
what patients should not receive azathioprine and why?
pregnant/nursing patients, due to teratogenic effects
what is the MOA of mycophenolate mofetil (complete)?
it is metabolized to MPA (mycophenolic acid) which is a potent, selective, uncompetitive, and reversible inhibitor of inosine monophosphate dehydrogenase, which is critical for de novo synthesis of purines
how does this differ from azathiprine?
lymphocytes almost exclusively use the de novo synthesis pathway rather than the salvage pathway, and as such leucopenia is not nearly as big of a problem
wha action does MPA dramatically inhibit?
B cell proliferation
what should be remembered about the pharmacokinetics of MPA (2)?
1) highly protein bound (95%); 2) high bioavailability (94%)
what is mycophenolate mofetil used for, andwhat is it given with?
prophylaxis for rejection of renal and hepatic transplants - almost always given with cyclosporine or tacromilus and/or corticosteroids - has helped make possible discontinuation/lowering of steroids
what drug interactions must we know for MPA (3 drugs/problems)?
1) antacids with magnesium/aluminum hydroxides reduce absorption; 2) acyclovir/MPA can increase each other's levels; 3) cholestyramine reduces MPA levels by binding to MPA glucuronide in the intestine preventing its excretion
who should not be given mycophenolate mofetil?
pregnant/nursing patients, due to teratogenic effects
what is the MOA of cyclophosphamide?
alkylating agent - alkylates DNA in proliferating cells
what part of the immune response is it most effective against?
B cells / humoral immunity
what is cyclophosphamide used for (2 categories)?
1) patients receiving bone marrow transplants; 2) autoimmune disorders (RA, SLE, WG, ITP)
what are adverse reactions of cyclophosphamide (3)?
1) hemorrhagic cystitis; 2) cardiotoxicity; 3) severe pancytopenia
what other immunosuppressant is typically used for RA and psoriasis that are intractable to corticosteroids/other immunosuppressant therapies?
what can chronic use of low doses of methotrexate result in?
liver damage, exacerbated by alcohol
what are the calcineurin inhibitors we must know (3)?
1) cyclosporine; 2) tacromilus; 3) pimecrolimus
what other drug is a "classic immunosuppressant" but does not inhibit calcineurin?
where do classic immunosuppressants come from (origin) and what are they like chemically?
highly lipophilic, from microorganisms
what part of the MOA is shared by all of these drugs?
they cross the cell membrane unmetabolized and bind endogenous ligands called immunophilins - binding to immunophilins is a MUST for calcineurin inhibition
what immunophilins are bound by which drugs?
cyclosporine binds cyclophilin A while the rest bind FKBPs (FK-506 binding proteins)
what type of activity does calcineurin have that these drugs (except sirolimus) inhibit?
protein phosphatase activity - blocks the activation/nuclear translocation of NFAT, which in turn blocks the induction of numerous cytokines, especially IL-2
how can cyclosporine and tacromilus and pimecrolimus share a mechanism, but have different binding targets?
each immunophilin/immunosuppressant complex shares the same binding site on calcineurin catalytic subunit
what should be remembered about the disposition/pharmacokinetics of calcineurin inhibitors?
1) absorbed slowly and incompletely - 6-56% bioavailability; 2) distribute widely outside blood; 3) eliminated/metabolized in liver (earlier drugs in lecture eliminated renally, but metabolized hepatically)
in what organ transplants are calcineurin inhibitors used, and what are they given with?
almost all solid organ transplants - often with corticosteroids, also sometimes with cycotoxic drugs as well
when is IV administration performed and what can result?
when there are GI complications - IV administration may be accompanied by anaphylactic reactions
what have recent studies shown is the most effective of these drugs in improving graft survival and preventing rejection?
tacrolimus - used in 50% of all new renal transplants
what is its potency compared to cyclosporine?
100x as potent
what are emerging as first line treatments for atopic dermatitis, especially in children (2)?
ointment forms of tacrolimus and pimecrolimus
what are advantages of calcineurin inhibitors over steroids?
1) do not impair function/viability of Langerhans and dendritic cells, which are critical to development of mature immune responses in children; 2) topical calcineurin inhibitors are not absorbed into the bloodstream as steroids are (steroids cause problems such as alteration of HP axis this way); 3) lack of absorption into the bloodstream results in very little systemic immunosuppression, resulting in fewer AEs compared to orally administered counterparts
what are the differences in treatment efficacy like between calcineurin inhibitors and steroids?
which drug is generally recommended for mild to moderate atopic dermatitis, and which is recommended for moderate to severe cases?
pimecrolimus for mild-moderate, tacrolimus for moderate-severe
which of these drugs is absorbed into the blood the very least, and thus causes the least systemic immunosuppression?
what are calcineurin inhibitors 2nd or 3rd line for (3)?
1) RA; 2) Crohn's; 3) Behcet's syndrome
what are main AEs for calcineurin inhibitors (4 besides increased susceptibility to infections)?
1) lymphoproliferative disease (leading to immunodeficiency); 2) nephrotoxicity (can occur in 75% of patients); 3) hypertension; 4) neurotoxicity; 5) GI; 6) hirsutism; 7) hypoglycemia
what are the two forms of renal dysfunction, and what is each?
1) functional - improves when drug is withdrawn; 2) chronic dysfunction - irreversible, with histologic abnormalities and mild proteinuria - seen at 6-12 months post-op
what is typically the first sign that renal function may be impaired?
halt in decline of levels of BUN, creatinine (these are generally higher post-operatively, but then return toward baseline)
what is the leading reason for conversion to tacrolimus therapy?
failure of reduction in cyclosporine dose to cause response in BUN/creatinine levels
what should it be noted that renal dysfunction and hypertension can result in?
negative impact on allograft survival
how common is hypertension in transplant patients who use calcineurin inhibitors, and what are effects/course like?
occur in 50% of transplant patients - effects are mild to moderate, and generally improve with time and therapy
what problem can certain antihypertensives cause in these patients?
can decrease the metabolism of calcineurin inhibitors
why shouldn't potassium sparing diuretics be used for hypertension caused by calcineurin inhibitors?
calcineurin inhibitors can cause hyperkalemia
what can tacrolimus cause in the heart?
hypertrophy - effects subside when dosing lowered
what neurotoxic effects occur (3)?
1) tremor; 2) headache; 3) convulsions (infrequent)
what GI effects occur (2) besides N/V and diarrhea?
1) gum hyperplasia; 2) hepatotoxicity
what drug is most likely to cause hirsutism, and what race is most likely to get it?
cyclosporine - commin in dark skinned caucasians
what drug is most likely to cause hyperglycemia, and what % of liver transplant patients get it with this drug?
tacrolimus - 33 to 47%
what % of patients with kidney transplant get post-transplant diabetes melltus?
what races are most likely to get PTDM?
black, hispanic
what treatment does PTDM often require, and what effect does it have?
insulin - reverses 15% in one year, 50% by two years
what adverse reactions can be caused by topical calcineurin inhibitors (4)?
1) itching; 2) burning; 3) melanoma; 4) lymphoproliferative disease
what drugs increase levels of cyclosporine (4 classes)?
1) CCB's (dilatiazem, nicardipine, verapimil); 2) antibiotics (erythromycin, gentamicin, tobramicin, vancomycin); 3) antifungals (amphotericin B, azoles); 4) grapefruit juice
what drugs reduce immunosuppressive potency (3)?
1) anticonvulsants (phenytoin); 2) antibiotics (rifampin); 3) St. John's wort - reduction in drug levels can cause rejection
what classes of drugs exacerbate toxicity (5)?
1) other immunosuppressants; 2) certain antibiotics; 3) antifungals; 4) certain antiinflammatory; 5) GI agents; 6) azathioprine
what can azathioprine cause when combined with cyclosporine?
what anti-inflammatory drugs exacerbate toxicity (2)?
1) azapropazon; 2) naproxen
what GI agents exacerbate toxicity (2)?
1) ranitidine; 2) cimetidine
people with what diseases should not be given topical calcineurin inhibitors?
chicken pox, measles
what drug in particular should be avoided in diabetics?
what is the most important precaution/contraindication for these drugs?
what is it absolutely imperative that the physician should do after transplant?
monitor plasma cyclosporine levels due to all of the adverse effects and drug interactions, as well as the variable absorbance of orally administered calcineurin inhibitors
what does sirolimus do once it binds to the FKBP?
binds to and inhibits the protein kinase mTOR (target of rapamycin - rapamycin is the other name of sirolimus) that is part of a larger protein complex
what is the result of inhibition of mTOR?
induces G1 phase and prevents cellular proliferation of T and B cells
how is sirolimus absorbed/eliminated/metabolized?
well absorbed, biliary elimination, metabolized by CYP3A4 into many metabolites
what dramatically slows absorption?
administration with fatty food
how do gender and age affect pharmacokinetics of sirolimus?
cleared more rapidly by women, absorbed more slowly by children (avoid under 13 years of age)
what drug, when co-administered with sirolimus, causes increase in sirolimus levels?
what is sirolimus mainlu used for, and how is dosing given?
used for organ transplant - given ASAP post op, with loading dose of triple maintenance dose
what is the most important reason for considering co-administration of sirolimus with cyclosporine/corticosteroid therapy?
permits the discontinuation of cyclosporine after only a couple months
what adverse effect must we know for sirolimus?
hypercholesterolemia (can be treated by lipid-lowering agents) - take precautions with those with history of hypercholesterolemia/heart disease/obesity
what drug interactions must we know for sirolimus (2)?
P450, also cyclosporine (increases renal risks/myelosuppression/lipemia)
what is Rh0D immune globulin (rhogam) derived from, what is it directed aganst/used for?
derived from human plasma and against Rh(D) antigen on RBC - prevents sensitization of mothers to Rh(D) antigen - prevents hemolytic disease of newborn
how are monoclonal antibodies produced?
immunize mouse with an antigen, and take mature dendritic cells from the mouse and fuse them with immortal cells, creating hybridoma cells that can be maintained in culture and will continue producing a certain antibody
what monoclonal antibody must we know?
what is it used for (2)?
1) prophylaxis of organ rejection in kidney tranplants; 2) to deplete T cells from donor bone marrow prior to transplants
what does it bind to, and what is the result?
binds to CD3 glycoprotein, resulting in preventing antigen from binding to antigen recognition complex on T cell surface, and also causes clearance of CD3 T cells - these actions inhibit T cell immunity
what is it usually co-administered with?
cyclosporine/tacrolimus and/or cortocisteroids
how is it administered?
IV bolus
what are the three main adverse effects with muromonab-CD3?
1) CRS (cytokine release syndrome) where binding causes activation of T cells and a release of cytokines; 2) increased risk of infection compared to corticosteroids; 3) neoplasia
what is CRS like and what precaution should be taken?
can be flu-like ranging to shock - patients should be monitored in a facility equipped and staffed for CPR
what may help prevent CRS?
pretreatment with steroids before muromonab delivery
what else limits muromonab use?
what does cyclooxygenase produce, and from what?
arachadonic acid --> PGH2 (which can be converted to other prostaglandins)
what does arachadonic acid come from?
clel membrane phospholipids
what do prostaglandins made by COX do in the stomach (2)?
1) decrease cAMP and decrease K/H ATPase in parietal cells; 2) stimulate secretion of mucous HCO3- from epithelial cells
what therapy relates to thromboxane A2 and how does it work?
aspirin blocks thromboxane A2 and prevents platelet aggregation
will nonspecific COX inhibitors be effective in treating asthma, and why?
no, because PGF and PGD constrict / PGEs relax bronchial/tracheal muscles
what do PGs do to the CV system?
increase cardiac output, vasodilate (hypotensive)), PGD2 vasoconstricts
what type of pain are salicylates (aspirin, salicylic acid, methyl salicylate) good for?
integument, not visceral
what are salicylates contraindicated in (4)?
1) hemophilia; 2) vit K deficiency; 3) hepatic damage; 4) hypoprothrombinemia (congenital or acquired disorder where factor II (prothrombin) is deficient - this can result from vitamin K deficiency
what are the metabolic effects of salicylate?
hyperglycemia, glycosuria, increase O2 consumption, CO2 production, and metabolic rate, reduce serum triglycerides, increase fat burning, decrease lipogenesis
what are endocrine effects of salicylates (2)?
increae glucocorticoid secretion, decrease thyroid function
what are the effects of salicylates on pregnancy?
decrease birth weight, increase perinatal mortality, anema, and postpartum hemorrhage
what cancer is aspirin helpful with?
what are additional contraindications of aspirin?
1) viral infections like flu, chickenpox (Reye's syndrome); 2) peptic ulcers
what effects do very low (1mg/kg), low (10mg/kg); and high (100mg/kg) doses of aspirin have?
very low - antiplatelet; low - analgesic/antipyretic; high - anti-inflammatory
what are three AEs of aspirin?
tinnitus, vertigo, deafness
what happens in aspirin overdose (2) and what results from each?
1) hyperventilation --> respiratory alkalosis; 2) salicylate --> fever, dehydration, and metabolic acidosis
how does aspirin overdose culminate?
shock, coma, organ system failure, death
what is the treatment for aspirin overdose?
1) induce vomiting/lavage; 2) give fluids and electrolytes to support renal function; 3) administer sodium bicarbonate to counter metabolic acidosis and increase urinary clearance
why is acetaminophen not an NSAID?
no antiinflammatory activity
what does it do, and when is it used?
functions only centrally - antipyretic / analgesic (no alteration on bleeding time, uric acid, acid/base)
what can acetaminophen OD cause?
fatal hepatic necrosis
what NSAID is useful for gout, and what class is it a part of?
indomethacin - an acetic acid
what is another acetic acid with limited toxicity and selectivity for COX2?
what are fenamates and why are they not used much?
no advantage in anti-inflammatory activity, but cause diarrhea - mefanamic acid, meclofenamic acid
what NSAID was said to have little difference in therapeutic efficacy compared to aspirin, but is better tolerated?
what drug is an effective analgesic, but a poor anti-inflammatory, that can be administered many ways (IM, IV, oral, and also topically for conjunctivitis) and is limited to short term use?
what NSAID is approved for long term treatment of RA, osteoarthritis, and ankylosing spondylitis?
what class of drugs are all anti-inflammatory, analgesic, and antipyretic, and are better tolerated than aspirin and indomethacin?
propionic acids (ibuprofen, naproxen, fenoprofen, ketoprofin, flurbiprofen)
in what case is ibuprofen used, and what is it effective for?
in patients with history of GI intolerance to other NSAIDs - effective analgesic and anti-inflammatory
what what type of toxicity does naproxen have, similar frequency to indomethacin?
GI, CNS (but naproxen better tolerated, generally)
what drug is an effective antiinflammatory agent, but poorly inhibits COX in seminal vesicles, where COX1 is the only type?
what problem occurs with vioxx?
HA, stroke
what additional program (besides HA, stroke, DVT) occurs with bextra?
severe skin reactions
what NSAID suppresed breast tumors in human breast cancer cells, and why?
piroxicam, since human cancer cells expres high levels of COX-2
what drugs reduce the size/number of colorectal polyps in animal models?
aspirin, COX-2 inhibitors
what is the MOA of aspirin?
suicide inhibitor of COX-1 (thromboxane A2)
what drug closes the ductus arteriosus in premature neonates?
what drug is a first generation selective COX 2 inhibitor that is used for RA and osteoarthritis?
celecoxib (celebrex)
what things was it said ibuprofen is useful for (3)?
1) RA; 2) dysmenorrhea; 3) gout; 4) ankylosing spnodylitis
what toxicity does it have, and how well tolerated is it?
gastrix toxicity, but is tolerated as well as any nonselective COX inhibitor
what is achieved at lower doses with ibuprofen - inflammatory or analgesic effects?
analgesic effects achieved at lower doses
what is an early COX inhibitor used for rheumatoid and osteoarthritis?
what is a second generation COX inhibitor that is used for osteo and rheumatoid arthritis, migraine, and fever, with gastric complications and pediatric use?
what are the CNS actions of morphine (5)?
analgesia, respiratory depression, miosis, antitussive, nausea
what are the peripheral actions of morphine?
analgesia, anti-diarrheal, increased smooth muscle tone
what is meant by the term potency?
relative amount of drug needed to achieve half of maximum effect
what are the effects of opiods at the cellular level (3)?
1) decrease cAMP by inhibiting adenylate cyclase; 2) increase K current; 3) decrease Ca++ influx; last two effects decrease cell excitability
where are all types of opioid receptors found?
peripheral nervous system, GI, cortex, striatum, hippocampus, dorsal horn
where are only delta receptors found?
where are only mu and kappa receptors found?
periaqueductal grey
which endogenous opioid agonists are co-released with ACTH in the pituitary, and tie in with HPA stress axis?
what endogenous opioids are present in inhibitory circuits, and found in brain/spinal cord, and what receptors do they prefer?
enkephalins - prefer deltareceptor
which endogenous opioids are found in pitiuitary, hypothalamus, midbrain, and striatum?
what receptors do dynorphins prefer, and what action are they involved in?
brain region-dependent precursor processing - prefer kappa receptor
what is an opioid antagonist that is used to counteract opioid overdose, and what does it do in normal healthy adults vs. post-surgery?
naloxone - raises LH and FSH in normal adults, does not alter pain threshold in normal adults, but is hyperalgesic in post-surgery patients
what are the three opioid drug classes?
phenanthrene, phenylpiperidine, phenylheptanone
which class only has two drugs in it, and what are they?
phenylhepatone (methadone, propoxyphene)
what class are morphine, codeine, hydrocodone, hydromorphone, hydrocodeine, oxycodone, dihydrocodeine, diacethylmorphine in?
what drugs are phenylpiperidine?
meperadine, fentanyl, alfentanil, sufentanil, femifentanil
what type of pain is morphine best against?
continuous, dull pain
what effect of morphine occurs at sub-algesic/respiratory depressing doses?
antitussive (anti-cough)
what can morphine cause that can interfere with ventilation in surgery?
truncal rigidity
what effects of morphine do tolerance not develop for?
miosis, diarrhea
in what ways does morphine depress respiration?
1) depress CO2 blood tension sensitivity in BS; 2) depress medullary/pontine centers that regulate frequency
what is the effect of prolonged exposure to morphine on N/V?
nearly completely prevents stimulation of CTZ and blocks emesis via other agents (but early exposure to opiates stimulates CTZ)
what are GI effects of morphine?
increased SM tone, muscle spasms can increase pain, decreases secretions, decreased motility - antidiarrheal/constipating effect
what does morphine do to SM tone at therapeutic doses?
insignificant increase in tone at therapeutic doses - but at higher doses, increases tone, aggravating asthma, causing urinary retention, and prolonging labor
what does morphine do to the CV system at therapeutic doses?
minimal effects - decreased BP, stimulate histamine release, orthostatic hypotension
what is morphine effective in treating due to these CV effects?
pulmonary edema
why are morphine and similar opiates good for pain asociated with inflammation?
opioid receptors are upregulated at nociceptors due to local inflammation/injury - exogenously applied opioid takes advantage of increased receptor #
why is oral morphine not as effective as IV?
first pass effect (1/3 to 1/6 as potent)
how is morphine excreted, and how fast?
almost all gone in 24h in urine
what is the triad of symptoms that should make one highly suspicious of opioid toxicity?
miosis, decreased respiration, and coma
why must naloxene be monitored/readministered?
shorter t1/2 than toxicant
what is morphine metabolized to in the first pass?
morphine-6-glucuronide and morphine-3-glucuronide, which are active metabolites, one excitotoxic, and one analgesic - these build up in blood over long term
what induces morphine dependence?
only withdrawal of drug
what is the active analgesic when codeine is administered, and how is it metabolized to this?
10% metabolized by CYP2D6 to morphine
what should be used to treat severe pain with an inflammatory sourec?
both an opioid and an anti-inflammatory
what are three semi-synthetic modified versions of molecules found in the opium poppy, that are used as with codeine (3)?
1) dihydrocodeine (in synalgos); 2) oxycodone (in percocet); 3) hydrocodone (in vicodin)
what drugs are completely synthetic and structurally dissimilar than morphine that we must know, but have similar actions and side effects (3)?
1) meperidine (demerol); 2) methadone; 3) fentanyl (and family)
what is the DOC for outpatient anesthesia, and why?
alfentanil - fentanyl family - repeated doses do not accumulate, and recovery is rapid
which of these synthetics was said to have high abuse potential?
meperidine (demerol) - as hard to kick as heroin -
what is potency of meperidine like compared to morphine, and what is it used in?
used in labor and delivery - 1/10 morphine's potency
what AE's are reduced with meperidine compared to morphine?
retains atropine-like functions - reduced biliary spasm and miosis
what is the AE of meperidine we must know?
CNS excitation/tremors/convulsions
what is the potency of methadone compared to morphine, and how does it differ in pharmacokinetics?
equipotent with morphine, high bioavailability - repeated dosage causes longer-lasting effects - can use orally for once daily dosing - functions as pure agonist, and does not block opioid actions
what group of people is methadone used for?
heroin addicts
what is fentanyl like in potency and pharmacokinetics?
100x as potent as morphine, short duration, lipophilic (lollipop preparations for addult breakthrough pain)
in what situation is fentanyl (and family) used in anesthesia, besdies outpatient anesthesia, and for what reasons?
used as IV analgesic in balanced anesthesia (especially cardiac surgery) because of improved cardiac stability (post-surgical reaction)
what function does it lack when used in surgery, and what should be used concomitantly?
lacks anesthetic activity - people open eyes, dilate pupils, move during surgery - should use concomitant muscle relaxers for truncal rigidity
what opioid antagonists must we know, what is the duration of each, and which is available orally?
naloxone and naltrexone, naloxone has 1-4 hour duration and is NOT available orally, naltrexone has 48-72 hour duration and is available orally
what drug is used as an antitussive, why is it used, and what is it like chemically?
dextromethorphan - D-isomer of codeine analog methorphan - no analgesic/addictive properties - D-isomer of codeine analog methorphan
what is the MOA of dextromethorphan?
acts via non-opioid receptors, centrally, to elevate coughing threshold - not reversed by naloxone
what is the brand name for OTC dextromethorphan and how can it be abused?
cough syrup - robitussin - "roboing" is when it antagonizes NMDA receptors at high doses, for hallucination
what type of side effects are caused by increased dosage in long-term use of mixed agents?
dysphoric side effects
will addiction develop after long term use?
no evidence of addiction per se developing, but physical dependence will
what is the most likely cause of flushed feeling and itchiness when opioids are given?
morphine triggers histamine release
what can help itching and N/V from morphine?
concomitant antihistamine
in addition to normal pain medication, what should cancer patients always be given?
a rapid onset drug for reakthrough pain
when should opioids be used for chronic non-malignant pain?
only after other analgesics have been tried and failed
how does cortisol increase fight or flight response (2)?
1) increase epinephrine synthesis; 2) increase sensitivity of tissues to catecholamines
what four problems will sustained increase in glucocorticoids cause?
1) diabetes (from counter-regulation of glucose); 2) CV effects; 3) osteoporosis; 4) (increased bone resorption, decreased Ca++ absorption)
what is a synthetic CRH, and what is it used for clinically?
cosyntropin, a synthetic CRH, is used to diagnose Cushing's disease
in what pattern is GC synthesis secreted?
what enzymes mediate the direct genomic effects of GC action (3)?
1) tyrosine aminotransferase (AA degradation); 2) phosphoenolpyruvate carboxykinase; 3) G-6-Phosphatase - last two involved in gluconeogenesis - dysregulation leads to diabetes
how do indirect genomic effects work?
GR binds to DNA binding proteins like NFkB and inhibits their ability to upregulate genes
what type of genes are downregulated?
those that stimulate inflammatory response - cytokines like IL-8, 12, and TNF-a
what are indirect genomic effects initiated by, and what are they important for?
interactions with membrane bound or cytoplasmic GRs, or interactions with cell membrane - important for eliciting changes in vascular tone
what actions occur first, genomic or nongenomic?
nongenomic - they occur very fast
what is the treatment for glucocorticoids increasing bone loss through interference with Ca++ uptake and vitamin D actions, in adults?
administration of oral bisphosphonate, Ca++, vitamin D
what hormones do GCs inhibit production of, that relate to growth and development?
sex steroids
what do excessive amounts of GCs or MCs do to muscle/skeleton?
can impair muscle, and cause skeletal wasting
why can large GC doses lead to ulcers?
suppress immune response against H. pylori
what is normal treatment for glucocorticoid insufficiency?
what is added if it is Addison's (both inner and outer zone destroyed)?
hydrocortisone + fludrocortisone
what drugs (3) can pharmacologically reduce cortisol synthesis (3)?
1) ketoconazole; 2) aminogluthemide; 3) metapyrone
how do glucocorticoids affect cell trafficking and adhesion molecules in innate immune response?
alter bone marrow release and infiltration and clearance of leukocytes, decrease expression of adhesion molecules, decrease chemokine release at inflammation site
in what disease do glucocorticoids prevent inflammatory response from overshooting?
what cells do they promote survival and proliferation of, and what cells do they induce apoptosis of (innate IR)?
promote survival of neutrophils, induce apoptosis of eosinophils
in what case are glucocorticoids used to prevent inflammatory response from overshooting, and how does this work on phagocytes?
enhance clearance of foreign antigens, toxins, microbes, enhance opsonization, stimulate macrophages to phagocytose
how does this affect cytokines?
increase antiinflammatory, decrease proinflammatory
how do glucocorticoids affect biochemical mediators of inflammation?
block release of arachadonic acid and thus formation of prostaglandins, thromboxanes, and leukotrienes, decrease NO release, decrease formation of free radicals
formation of what particular cell is blocked that may lead to cellular immunodeficiency?
Th1 helper T cell
how are dendritic cells affected?
can't present antigens as well or mature as well
formation of what cell is increased by glucocorticoids, and what is the result?
Th2 helper cell - stimulates humoral immune response and increased antibody formation
what may be the underlying mechanism of steroid resistant asthma and ulcerative colitis?
administration of GCs will increase IgE levels
what do glucocorticoids do to B cells and why is this useful?
inhibit proliferation and development, useful for leukemia
how else do glucocorticoids relate to IgE secretion?
prevent the release of IgE-R mediated release of inflammatory mediators, and also deplete tissue mucosal mast cells
what AE can glucocorticoids cause in the eye?
what is a recently developed drug in glucocorticoid therapy, how does it function, what is it used for, and what are its advantages?
ZK 216348 - binds GR with high affinity, represses inflammatory response, and does not appear to induce side effects such as thinning of skin and increased glucose
how is dose usually determined in glucocorticoid treatment?
trial and error
what can happen after abrupt cessation after long term use?
adrenal insufficiency (may be fatal)
what is alternate dose therapy and when is it used?
GC may suppress allergic phenomena when given every 48 hours, whereas pituitary suppression is shorter lived
what iGC is used for asthma and why?
flucitasone, because it is highly metabolized
what is an example of a GC given intravenously?
hydrocortisone Na++ succinate
what is a long acting type of GC?
intraarticular injection of crystalline, insoluble GC
what are the features of pulmonary and dermal administration both (2)?
high potency, limited systemic effect
what drug regimen with GCs is most effective for asthma?
inhaled GC coadministered with inhaled beta-2 agonists
what were said not to be considered significant risks for children (4)?
decreased growth, decreased bone mineral density, suppressed adrenal glands, cataracts (but height of children should be monitored)
what drugs must we know are sued for asthma (2)?
1) beclomethasone; 2) flucitasone
what drugs are used for allergic rhinitis (2), how are they given, and which has higher potency?
given as nasal spray - 1) beclomethasone (high potency); 2) triamcinolone (medium potency)
what are pros and cons of treating allergic rhinitis with GCs?
broad relief of symptoms, low systemic absorption, but adverse effects
what drugs are typically given topically for eczema and psoriasis (2)?
1) hydrocortisone; 2) betamethasone
what drug is given as an intralesional injection?
triamcinolone acetonide
what is done for acute eczematous reaction such as poison oak?
systemic therapy with prednisone, tapered over 21 days
what is the goal of GC therapy for MS?
ameliorate suffering during attacks (6 weeks)
what GC drugs are given for MS and how is each administered (2)?
1) prednisone oral tapering course; 2) methylprednisone IV for 3-5 days
what drugs are given for allograft rejection (2)?
prednisone, methylprednisone
what drug is typically given for rheumatic diseases, and what other drugs are used with it (non GC - 2)?
prednisolone - also NSAID and disease modifying drug
what happens to the GC, eventually, and over how long?
weaning, over as much as two years
what type of therapy is often given for RA with methylprednisone?
pulse therapy IV ofer 3-7 days
what GC drug is given as a joint injection for RA?
triamcinolone acetonide
what are GCs able to do for RA?
decrease pain/disability/inflammation in first year but not sure about long term efficacy, does not alter structural damage
what are side effects of treating RA with GCs (2)?
1) osteoporosis; 2) ulcers
in what case are GCs used in Crohn's disease, what drug is used, and why?
in patients who do not respond to conservative management - oral budesonide is used because it is better tolerated and more effective than prednisolone
what should be remembered about pharmacokinetics of oral budesonide?
11% bioavailability because it dissolves in ileum and ascending colon due to pH
what malignancy are GCs particularly used for (to induce apoptosis), and what GCs are used (3)?
lymphoid malignancies, namely ALL - drugs used: 1) prednisone; 2) methylprednisone; 3) dexamethasone
how else is it useful in cancer (2)?
potentiates effeccts of other cytotoxic agents (prednisone/vincristine/doxorubicin/cyclophosphamide for non-Hodgkin's), also treats complications associated with cancer (cerebral edema, pain)
what GC drug regimen is used in tuberculous meningitis?
prednisone for first month
what drug is a mineralocorticoid receptor antagonist, and what does it do?
spironolactone - reduces the expression of gene controlling synthesis of Na/K ATPase
what drug is an antagonist of glucocorticoid receptors, and what is it used for (2)?
RU 486 (Mifepristone) - used in: 1) Cushing's; 2) abortion
what drug inhibits the initial and rate-limiting step in the biosynthesis of all physiological steroids?
what is it used for (in conjunction with other drugs)?
to treat steroid producing adrenocortical tumor
what drug inhibits the terminal step in GC synthesis (11-B hydroxylase) and what is this drug used for?
metyrapone - used in diagnostic test of adrenal function
what drug can block all teroidogenesis and can be used for hirsutism, adrenal carcinomas, and breast cancer?
in what diseases is glucocorticoid resistance the most problematic (2)?
asthma, ALL (5% of patients have no response to 7 day therapy with prednisone)
what are three new therapeutic develpments with GCs?
1) develop drugs with transrepression >> transactivation (flucitasone pripionate, RU486, other RU's); 2) develop drugs that specifically inhibit NFkB or TNF (i.e. infliximab for RA); 3) develop retinoic acid derivatives (synergistic actions between RXR and GR)
what genes are directly regulated by aldosterone (2)?
1) CHIF - challen inducing factor; 2) epithelial sodium channel subunits
what were said to directly regulate the Na/K ATPase genes?
glucocorticoids such as dexamethasone
how strongly does aldosterone activate the MR compared to cortisol?
equal affinity
how do MR and GR compare as far as their ability to activate gene transcription via hormone response element?
stimulate it equvalently
how is specificity gained?
by location of MR and GR
where is the GR located, and where is the MR (5)?
GR - all cells; MR - kidney, gut, sweat glands, brain, and vascular smooth muscle
how else do they differ?
differential transcriptional activation
what key enzyme is expressed only in some mineralocorticoid responsive tissues?
11B-hydroxysteroid dehydrogenase type 2 (11B-HSD)
what are the two main strategies for treating mineralocorticoid excess, and what drug(s) is used for each?
1) antagonize mineralocorticoid receptor (spironolactone); 2) antagonize Na+ exchange in distal nephrone (amiloride, triamterene)
what happens when there is high concentrations of spironolactone?
inhibits androgen receptor
what other problems may spironolactone cuase (2)?
1) hyperchloremic acidosis; 2) hypokalemia
how is mineralocorticoid deficiency treated, and what is the affinity of this drug for MR and GR?
flucortisone - 10x affinity for MR compared to GR
what are side effects of flucortisone, and what should be monitored?
hypertension, hypokalemia - monitor BP and renin activity
what is the treatment for CAH (21-hydroxylase or 17-hydroxyprogesterone deficiency) (2)?
1) fludrocortisone; 2) hydrocortisone (GC)
what is the treatment for primary aldosteronism?
unilateral adrenalectomy
what is the treatment for pseudohypoaldosteronism (a rare form of mineralocorticoid resistance that presents as neonatal renal salt wasting, caused by mutations in mineralocorticoid receptor)?
sodium supplementation
what is the treatment for apparent mineralocorticoid excess (3)?
1) amiloride and/or spironolactone; 2) antihypertensive; 3) KCl supplements
what mutation can cause pregnancy induced hypertension, and why?
missense mutation (L810) in ligand binding domain of MR allows a number of steroids to act as MR agonists
what else can act as an agonist, and what does it cause?
spironolactone can act as an agonist, and allow constitutive activity of MR
what MR antagonist is more preferred than spironolactone, and why?
eplenerone - it is more selective (but has lower affinity for MR)
what are the three high potency GC agonists?
1) beclomethasone; 2) betamethasone; 3) dexamethasone
what are the three mid potency GC agonists?
1) methylprednisone; 2) prednisolone; 3) prednisone
what are three inhibitors of cortisol synthesis?
1) metyrapone; 2) ketoconazole; 3) aminoglutethimide
what MR agonist must we know?
what MR antagonists must we know (2)?
1) spironolactone; 2) eplenerone
what cells do FSH, and LH, respectively, stimulate in the testis?
FSH --> sertoli cells; LH --> leydig cells
what cells release testosterone in the testes?
leydig cells
what genetic element initiates sexual differentiation in males?
TDF on Y chromosome
what if there is no TDF?
baby will be female (have ovaries)
in early fetal development, what is necessary for internal male genitalia to form, and where does it come from?
mullerian inhibiting hormone - comes from sertoli cells
what if there is no mullerian inhibiting hormone?
female internal genitalia
what is necessary for external male genitalia?
what is necessary for external female genitalia?
lack of testosterone
what needs to happen for there to be DHT?
conversion of testosterone to DHT by 5-alpha-reductase
where is type 1, and type 2 5-alpha-reductase found?
type 1 - liver and skin; type 2 - urogenital tract and liver
what can deficiencies of type 2 5-alpha-reductase result in?
ambiguous gender idnetification at birth, usually female
what can be done about this?
dramatic reversal at puberty, as testosterone is converted by type 1 5-alpha-reductase, resulting in male gender assignment
hyperplasia/carcinoma of the prostate is treated by inhibiting what androgen(s)?
acne is treated by inhibiting what androgen(s)?
male pattern baldness is treated by inhibiting what androgen(s)?
precocious puberty in boys is treated by inhibiting what androgen(s)?
sex drive in sex offenders is treated by inhibiting what androgen(s)?
what is the Kd for the androgen receptor with DHT compared to T?
DHT 1000> T
what feature of AR gene increases sensitivity to androgens?
lesser amount of glutamine repeats (12-32 normal - if over 40, spinal/bulbar muscular atrophy)
what are the indications for giving testosterone (2) and how is it given?
given as skin cream for: 1) congenital or acquired hypogonadalism in men; 2) breast carcinoma in posmenopausal women
what drug must we know that is used for prostate cancer, precocious puberty, uterine leiomyoma, and endometriosis?
what type of drug is it, and what is its MOA?
GnRH agonist - continued exposure disrupts pulsatility of gonadotrophs, inhibiting FSH and LH secretion
what are its adverse effects (4)?
1) short term rise in serum testosterone; 2) decreased libido; 3) negative effects on mood; 4) osteoporosis
what is a non-FDA approved use for ketoconazole?
prostate cancer
what are its adverse effects (4)?
1) short term rise in serum testosterone; 2) decreased libido; 3) negative effects on mood; 4) osteoporosis - same as leuprolide
what drug is used for metastatic prostate cancer and BPH, and what type of drug is it?
flutamide - nonsteroidal anti-androgen - directly blocks androgen receptor
what are its adverse effects (4)?
1) short term rise in serum testosterone; 2) decreased libido; 3) negative effects on mood; 4) osteoporosis - same as leuprolide
what is flutamide most effective in combination with?
what drug is used for prostate cancer, BPH, and alopecia, and what is its class/MOA?
finasteride - 4-aza analog of T that acts as competitive, specific inhibitor of type II 5-alpha-reductase
what does finasteride block, and not block?
blocks actions of DHT but not T in prostate, seminal vesicles, hair follicles, epididymis
what are the adverse effects of finasteride like?
generally better tolerated than flutamide
what is a non-FDA approved use of testosterone?
to improve libido in both women and men
what decreases local pH in gouty attacks, and what leads to that?
increased lactate production, from inflammatory response
what exacerbates inflammatory response?
increased synovial phagocytosis of crystallized uric acid
why is there more crystallized uric acid?
drop in local pH (all of these create a vicious cycle)
what are treatment goals of gout (3)?
1) relieving gouty attacks; 2) preventing recurring gouty episodes; 3) preventing urate lythiasis
what drug is a diagnostic indicator of gout, and what type of drug is it?
colchicine - a plant alkaloid - diagnostic because it is only effective against gout - dramatically relieves pain and inflammation of gouty arthritis in 12-24 hours
what is the MOA of colchicine?
inhibits tubulin polymerization, leading to inhibition of leukocyte and phagocyte migration and phagocytosis of crystals in joints
why are NSAIDS often used?
decreased side effects
what is colchicine indicated for?
prophylaxis of recurrent episodes of gouty arthritis
what are adverse effects of colchicine?
diarrhea, N/V, abdominal pain, hair loss, bone marrow suppression, peripheral neuritis, myopathy
what is the normal dosing of colchicine for an acute attack, and what should be avoided?
2mg is given as a single dose IV - not to exceed 4 mg, not to be repeated within 7 days
how much is lethal?
8mg/24 hours
what NSAID is used in gout, and how does it help besides being anti-inflammatory?
indomethacin - inhibits urate crystal phagocytosis
what NSAID is better than others at lowering serum uric acid, and what is the problem?
oxaprozin may be better at this, but its use, like other uricosuric agents, is not recommendeed in patients with uric acid stones
what drug is effective for treatment of primary uricemia caused by antineoplastic therapy, and what is its MOA?
allopurinol - competitive inhibitor of xanthine oxidase - inhibits urate synthesis
what is the main use of allopurinol?
effective for treatment of primary hyperuricemia and that secondary to antineoplastic therapy
what are other indications for allopurinol?
reserved for more severe forms of gout - high urinary urate (600-700), gouty nephropathy, recurrent renal sotnes, elevated serum urate
allopurinol is used in situations when what two drugs are contraindiicated?
sulfinpyrazone, probenecid
why is probenecid contraindicated with allopurinol?
allopurinol increases the half life of probenecid, which itself increases clearance of oxypurinol (an active allopurinol metabolite)
what problem may allopurinol induce in the short term, and how?
gouty arthritis - as serum levels of uric acid fall, crystal previously phagocytosed by synovocytes will be released, initiating gouty attack
what may be required during initial treatment?
coadministration of colchicine, sulfinpyrazone, or probenecid
what are other adverse effects of allopurinol (5)?
1) depression of bone marrow; 2) hepatic toxicity; 3) interstitial nephritis; 4) allergic skin reactions; 5) cataracts
what is the name of agents used to increase the rate of uric acid excretion, and what two must we know?
uricosuric agents - used to increase rate of uric acid secretion - 1) probenecid; 2) sulfapyrazone
what treatment course does probenecid have?
should begin with goal of lifelong treatment (like allopurinol)
what is probenecid mainly used for?
to decrease the bodies pool of urate in patients with increasingly frequent gouty attacks
what is probenecid not effective in doing?
relieving acute gouty attack (may exacerbate)
what is the MOA of probenecid and where does it act?
potent inhibitor of uric acid reabsorption at renal tubules
what drugs inhibit the actions of probenecid and sylfinpyrazone?
what happens when probenecid and sulfinpyrazone are used together?
their effects are additive
what AE is associated with probenecid, and who should it not be used in?
uric acid stones - avoid in patients with nephrolithiasis, and with caution in patients with high serum urate levels
what is the primary complication of probenecid?
precipitation of acute gouty attack
what is the toxicity of sulfinpyrazone?
gastric distress/peptic ulcers
what drug interaction was mentioned for sulfinpyrazone?
can increase hepatic toxicity of acetaminophen
what are the primary agents for managing acute gouty attacks?
NSAIDs, colchicine, and other anti-inflammatory agents (allopurinol and uricosuric agents do not alter course, and actually increase gouty attacks)
what drug is used to reduce frequency of gouty attack during early chronic treatment?
what NSAIDS are DOC for acute gouty attacks (2)?
indomethacin, naproxen
how do salicylates affect gout?
they elevate serum urate concentration and antagonize probenecid and sulfinpyrazone
what things minimize intrarenal deposition of uric acid (2), why, and when is this essential?
since pKa is 5.6, and solubility of undissociated form is low, maintaining plasma volume, alkaline urine minimizes its intrarenal deposition - this is important in first few weeks of therapy
what are the adverse effects of allopurinol in the chart (4)?
1) skin rash; 2) N/V; 3) kidney abnormalities; 4) diarrhea
what are the main adverse effects of colchicine (2)?
1) GI distress; 2) bone marrow depression
what are the side effects/toxicity of probenecid?
1) increase risk of stones; 2) may cause attacks during early treatment
what are often the first line drugs in gout, and what are they used in conjunction with?
NSAIDS - used in conjunction with uricosurics
what types of headache (migraine, tension, and sinus) are aggravated by activity?
migraine, sinus
what is migraine duration and tension duration?
3hr-3days for migraine, up to 7 days for rebounders with tension
what non-drug treatment often alleviates migraine?
how many attacks are needed to diagnose migraine?
5 without aura or 2 with aura
2 of what 4 features are needed to diagnose migraine?
1) unilateral; 2) pulsating; 3) moderate to severe pain; 4) aggravated by physical activity
at least 1 of what 4 additional features is needed?
1) nausea; 2) vomiting; 3) photophobia; 4) phonophobia
what three simple questions, if two are right, have 93% diagnostic accuracy for migraine?
1) do headaches limit daily activit/cause disabilities?; 2) do you have N/V with headahce?; 3) does light bother you during headache?
what are the three hypothesis for migraine pathophysiology?
1) vascular (vasoconstriction leads to aura, then responsive vasodilation leads to pain); 2) cortical spreading depression (ineuronal hypoactivity spreads from a focus across the brain - vascular changes follow) 3) sterile neurogenic inflammation (abnormal hyperexcitability drives trigeminovascular system to release substance P, CGRP and other noxious signals stimulate nociceptors, sensitizing them to feel circulatory turbulence as pain)
what are the two major drug classes we must know to treat moderate to severe acute migraine?
1) triptans; 2) ergot derivatives
what drug classes are used to treat mild to moderate acute migraine (3)?
1) NSAIDS; 2) barbiturates; 3) analgesics (aspirin/acetaminophen)
what other drug classes are used for acute rescue treatment (2)?
1) antiemetics; 2) opioids
what is the MOA of triptans?
similar to serotonin, they are selective agonists of 5HT(1B/D) receptor, and vasoconstrictors - they presynaptically inhibit trigeminal nerve activity
what AE must we know for triptans?
chest pressure/tightness (3-5 in trial, 26% retrospectively)
what are strong, and weak (2), contraindications to triptans?
strong - chest pressure/tightness; weak - MAOI, SSRI interactoins
what is the prototype triptan?
what triptan has a long half life (26 hours, while others are 2-6)?
what is the mechanism of ergot derivatives?
non-selective 5HT agonists/p-agonists/antagonists, also agonize the dopaminergic system
what is the ergot prototype, and what other one must we know?
prototype - dihydroergotamine mesylate; also must know ergotamine
what should we know about pharmacokinetics of dihydroergotamine mesylate?
poorly/erratically absorbed in different people at different times
what is the single most important contraindication for dihydroergotamine mesylate?
potent abortifacient
what are the other side effects of dihydroergotamine mesylate (4)?
1) cramps; 2) parasthesias; 3) edema; 4) peripheral ischemia
why can it cause peripheral ischemia?
causes acute vasospasm
what causes rebound headache?
overuse of medication, especially combination drugs (acetaminophen/aspirin/caffeine/butalbital combinations)
what adverse effect can occur with SSRIs when mixed with triptans or MAOIs, and what must we know happens?
serotonin syndrome - shivering occurs - should discontinue offending agents
when is rescue strategy used for migraine, alone?
<2 headaches/week
what parenteral drugs can be used in rescue strategy?
parenteral: sumatriptan, dihydroergotamine, prochlorperazine, chlorpromazine, morphine, metaclopramide, rescue opioids
when should prophylactic therapy be considered?
>1 headache/week
what are the adverse effects of beta blockers (3) and who are they contraindicated in (3)?
fatigue, orthostatic hypotension, impotence are adverse effects - contraindicaed in diabetics, asthmatics, and patients with AV block
what tricyclic antidepressant is used for migraine, and what are two contraindications?
amitriptyline - contraindicated in bipolar, and within 2 weeks of MAOI therapy
what are adverse effects of amatriptyline?
can build dependence, should be withdrawn slowly, anti-muscarinic effects (dry mouth, constipation, dizziness, fuzzy thinking)
what antiepileptic drugs are used for migraine prophylaxis (2)?
1) valproic acid (depakote); 2) topiramate (topamax)
what adverse reactions occur with valproic acid (2)?
1) nausea/vomiting/diarrhea; 2) fatal hepatic dysfunction in babies
what is the mechanism of topiramate (topamax)?
unique antagonism of glutamate (kainate) receptors, allosteric enhancement of GABA channel, state-dependent Na+ channel block
what are lifestyle changes to stop migraine?
avoid triggers, establish regular sleeping hours, eat healthy foods, exercise, avoid analgesics (use only for rescue), use acute treatments less than 2x/week
what therapeutic strategy should be used with acute therapy?
high dose range - dose back if side effects not tolerated - try three triptans before others
what should be used for nausea?
non-oral anti-emetic
what is the dosing strategy for prophylactic therapy (TCA, AED, beta blocker)?
start low, go slow
what is the only non-peptide factor released by the hypothalamus?
what is its function?
inhibiting prolactn release
what type of growth does GH promote?
what does secretion of GH induce release of, and what do these affect?
induces release of somatomedins (insulin-like growth factors) which affect carbohydrate and lipid metabolism
how does GH receptor work?
GH binds to it, and it dimerizes, which activates a cascade producing IGF-1
what happens if there is GH receptor defect?
Laron syndrome
what causes "dwarfism", and what is the treatment (2)?
GH deficiency in children (hyposecretion), usually hypothalamic - treated by somatotropin or sermorelin
what are somatotropin and sermorelin?
somatotropin - recombinant human growth hormone; sermorelin - synthetic GHRH
which treatment is more effective?
somatotropin is more effective
what other GH can be used, and what is it?
somatrem - a derivative of GH that has an additional methionine
what are the side effects of hormone replacements, sermorelin/somatotropin?
headache, vomiting, intracranial hypertension, scoliosis, arthralgia, myalgia, edema, carpal tunnel syndrome
what are the symptoms of GH deficiency in adults?
changes in fat distribution, decreased muscle mass and exercise capacity, impaired psychosocial function
what is the treatment for adult GH deficiency?
somatotropin - cannot use sermorelin
what is the treatment for Laron syndrome?
how is GH deficiency diagnosed?
random sampling of GH won't work - induce hypoglycemia with insulin, then check GH levels (hypoglycemia should stimulate release) - if they are low, patient has GH deficiency
how do you check where the defect is in adult GH deficiency?
give GHRH (selmorelin), look at serum GH levels - if GH goes up, there is a hypothalamic defect, if GH levels don’t go up, there is a pituitary defect
what drugs are used to treat GH excess syndromes (2), and what type of drug is each?
1) octreotide - a synthetic somatostatin analog (with a long half life); 2) pegvisomant - a GH antagonist
how does octreotide work and what are the effects?
it binds to surface of tumors via somatostatin receptors expressed on the surface - tumor that express receptors that bind octreotide with high affinity respond well - treatment decreases GH secretion and tumor size
how does pegvisomant work and what is its advantage?
pegvisomant binds the GH receptor, but does not induce dimerization - the action of pegvisomant is independent of tumor characteristics, and works on virtually all patients with acromegaly - it inhibits the action of GH
what else should we remember about its effect on hormone levels and tumors (2)?
does not decrease tumor size, inreases GH levels
what are the side effects of pegvisomant?
abnormal/reversible liver function
what are anabolic steroids?
chemically modified analogs of testosterone
what is the effect of hGH, if used on athletes?
increases body mass, but has not been shown to increase strength or performance
what are other uses of GH (4)?
1) Turner's (short stature); 2) AIDS-associated wasting; 3) maladsorption associated with short bowel syndrome; 4) intrauterine growth retardation
how are prolactin levels controlled?
by TRH and dopamine - no feedback control
what can cause hyperprolactinemia (3)?
1) pituitary or hypothalamic excess; 2) renal failure; 3) chest trauma
what are the symptoms in non-pregnant women (3)?
infertility, amennorrhea, milk secretion
what are the symptoms in men (4)?
infertility, loss of libido, impotence, breast enlargement
besides surgery and radiation, what type of drug is used to treat hyperprolactinemia, and what are two examples?
dopamine receptor agonists (bromocriptine, pergolide)
what are the effects of these drugs?
decrease PRL levels and induce tumor regression - tumors recur following cessation of treatment
what are the side effects of bromocriptine and pergolide?
N/V, insomnia
what is the function of FSH in men, and in women?
stimulates spermatogenesis in men, stimulates follicle development in women
what is the function of LH in men, and in women?
increases testosterone secretion in men, causes maturation of follicle to corpus luteum in women, and is required for rupture of follicle/ovulation
what is CG, and what is its function?
chorionic gonadotropin - released from placenta - acts like LH during pregnancy to sustain corpus luteum
what hormones control gonadotropin secretion (2), and how?
1) GnRH from hypothalamus causes secretion of gonadotropins if pulsatile - sustained release inhibits gonadotropin release; 2) prolactin inhibits gonadotropin; 3) inhibin, produced in ovaries and testes, acts to inhibit FSH production
what is it called when there is a hypothalamic/pituitary defect that causes decreased gonadotropin production?
hypogonadotropic hypogonadism
what happens due to lack of FSH in women (3)?
amenorrhea, infertility, absent breast development
what happens due to lack of FSH in men (2)?
decreased testis size, oligospermia
what happens due to lack of LH in women (3)?
amenorrhea, infertility, cystic ovaries
what happens due to lack of LH in men (3)?
infertility, lack of spontaneous puberty
what is used to treat lack of LH?
chorionic gonadotropin - mimics LH
what is used to treat lack of both FSH and LH, and what are they?
menotropins - from urine of postmenopausal women
what things can be used to treat lack of FSH (2)?
1) recombinant FSH; 2) urofollitropin (purified FSH)
what are side effects of these treatments (2)?
1) multiple births; 2) ovarian hyperstimulation syndrome (characterized by rapid accumulation of fluid in peritoneal cavity, pericardium, and thorax - symptoms include pain, distension, N/V, ovarian enlargement, and respiratory distress)
who gets increased gonadotropin production, what is the cause, and what are the symptoms (2)?
primarily males, with constitutively active mutation of LH receptor, with testicular tumors and precocious puberty
what is the treatment?
inhibitors of steroid synthesis
what are other uses of gonadotropins (2) and which hormones are used for each?
1) cryptorchidism (failure of testes descent) - CG; 2) IVF - FSH, CG
what si the treatment for hypogonadism, and what is this drug?
gonadorelin acetate - synthetic GNRH
what receptors does ADH bind to and what is the function of each?
V1 - mediates contraction of smooth muscle; V2 - mediates renal conservation of water
what is the treatment for diabetes insipidus and how is it given?
desmopressin (vasopressin analog) by oral or nasal spray
what are the adverse effects of desmopressin, from the V1 and V2 receptor?
V1 - excessive water retention, intestinal cramping, vasoconstriction; V2 - water intoxication, which causes seizures, vomiting, dizziness (due to brain swelling), and increases risik for angina, hypertension and heart failure
what are the contraindications for desmopressin (2)?
1) CAD (causes coronary insufficiency; 2) patients with renal failure
what disease is caused by a defective response to ADH (can be familial mutation in ADH V2 receptor, aquaporin mutation, or caused by drugs)?
nephrogenic diabetes insipidus
what drugs can cause NDI (2)?
1) foscarnet; 2) lithium
what is the treatment, and why?
thiazide diuretics, because desmopressin has no effect (receptors insensitive)
why would thiazide diuretics be used for a disease with increased urinary output?
they reduce urine output by a paradoxical, uknown mechanism
what is SIADH and what can cause it?
syndrome of inappropriate ADH secretion - caused by cerebellar disease, pulmonary disease, malignancy, head trauma, drugs (vincristine, vinblastine, haloperadol, clonidine)
what is the treatment, besides saline/fluid restriction, for SIADH, where ios this drug active, and what does this drug do?
demeclocycline - inhibits the response to ADH in the collecting duct
what drug must we know stimulates response to ADH?
what is the MOA of modification of ADH response by drugs?
direct effects on CNS structures that regulate ADH secretion
what is the drug form of oxytocin, and what is it used for (2)?
pitocin - used to: 1) induce labor; 2) induce lactation (nasal spray)
what are the adverse effects of pitocin?
excessive uterine contractions, uterine rupture, fetal hypoxia, high doses cause vasodilation, hypotension, tachycardia
what drug is used to suppress preterm labor, and what is it?
atosiban - oxytocin antagonist
what is the name of T3 and T4?
triiodothyronine (T3) and thyroxine (T4)
what is thyroid colloid made of?
the protein thyroglobulin
how does iodide get transported into the thyroid?
active transport, membrane bound protein = sudoium-iodide symporter
what drugs inhibit transport of iodide (2), and in what way?
the anions thiocyanate and perchlorate inhibit transport of iodide competitively
what else inhibits iodine transport?
high concentration of serum iodide
what increases iodine transport (2)?
1) TSH; 2) decreased stores
how is iodide synthesized, and what enzyme is involved?
oxidized, then tyrosyl residues are iodinated, and then coupled - this is catalyzed by thyroid peroxidase
how are thyroid hormones released?
T3 and T4 are stored within thyroglobulin, which is endocytosed from colloid into the epithelial cells, then undergoes proteolysis via lysosomal enzymes - TSH enhances this degradation by increasing enzymatic activity
what is propylthiouracil, and how does it work?
it is an anti-thyroid drug which inhibits 5' deiodinases, which convert T4 to more potent T3 in peripheral tissues
what is a transport protein that binds T4 only?
transthyretin - thyroxine binding prealbumin
what drugs increase binding of thyroid hormones to plasma proteins (3)?
estrogens, tamoxifen, 5-FU
what drugs decrease binding of thryroid hormones to plasma proteins (4)?
glucocorticoids, salicylates, androgens, anti-seizure medications
what was said about the effect of T4 on transcription?
has no effect on transcription and thus may only act as a prohormone
what synthetic thyroid hormones are used to treat thyroid deficiency, and what is a mixture fo the two called?
1) thyroxine (levothyroxine sodium - Synthroid - prolonged duration); 2) T3 - liothyronine sodium; mixture of the two is called liotrix
when is T3 used?
when a quick onset is needed (used occasionally)
in what patients should lower doses be used, and why?
lower doses should be used in the elderly because they are more susceptible to cardiotoxicity
what are three classes of antithyroid drugs?
1) thyioureylenes; 2) ions (not used); 3) aniline derivatives (PAS/sulfonamides - not used)
what are the thiourylenes (2)?
propylthiouracil, methimazole
what is the MOA of these drugs?
inhibit the formation of thyroid hormones by inhibiting two steps catalyzed by thyroid preoxidase - oxidation of iodide / iodination of tyrosyl residues, and coupling of iodotyrosines - they inhibit thyroid peroxidase by binding and inactivating the enzyme
which one of these drugs has an additional effect, and what is it?
propylthiouracil also inhibits T4 --> T3 conversion by inhibiting the D1 5' deiodinase
what are the side effects of thioureylenes (propylthiouracil, methimazole) (4)?
1) agranulocytosis; 2) bone marrow suppression; 3) rash; 4) liver damage
when are anti-thyroid drugs generally used, and with what?
used in conjunction with 131-iodine to hasten recovery while awaiting radiation effects, and also to control the disorder prior to surgical thyroid
what anions diminish iodide accumulation and thyroid function?
tiocyanate, nitrate, perchlorate - not currently used due to toxicity (fatal aplastic anemia)
how else can people get thiocyanate in their bodies?
cigarette smoke cabbage
what drug is used to treat symptoms of hyperthyroidism?
what other drug is used to inhibit iodine transport and inhibit synthesis of thyroid hormones?
KI (potassium iodide)
when is this useful, and why?
effect of iodide is very rapid, and is good in treatments where an immediate effect is needed, such as severe thyrotoxicosis - reduces vascularity of gland and it becomes firmer and the cells smaller
what are severe side effects of iodide?
bswelling of larynx, suffering, pulmonary edema
what are other side effects of iodide?
burning of mouth, throat, headache, cough, gastric irritation, cutaneous hemorrhage, enlargement of lymph nodes
what happens to the beneficial effects of iodide over time?
they disappear
what substance can be helpful in evaluating thyroid nodules?
radioactive iodine uptake/scan, which measures utilization - hot nodules are hypermetabolic, and cold nodules are hypometabolic (may indicate carcinoma)
how are benign thyroid nodules treated, if TSH levels are normal (and what is the rationale)?
levothyroxine - this will decrease TSH levels and stimulation of the tumor to grow - if nodule continues to grow, should surgically remove, followed by iodine-131 and hormone replacement therapy
when is liotrix, the T4/T3 mixture used?
when patients remain symptomatic on synthroid
what drug is used for myxedema coma?
liothyronine sodium - fast working ,higher cost
what is the DOC for thyroid hormone replacement?
levothyroxine sodium
what cofactor does the enzyme histidine decarboxylase require to function, and what is it derived from?
PLP - a derivative of vitamin B6
where is the H1 receptor found, and what is H1 signaling mediated by?
nonvascular smooth muscle, including intestine and bronchi, brain, and vascular endothelial cells - H1 signaling is mediated by IP3/DAG3 and cAMP
what does activation of H1 receptor cause?
increased vascular permeability, vasodilation, and constriction of non-vascular smooth muscle
where are H2 receptors found, and what is their action mediated by?
found in gastric parietal cells, vascular smooth muscle cells, cardiac myocytes, and in the CNS - action is mediated by cAMP at target cells
where are H3 receptors found, and what do H3 agonists cause?
found in CNS, H3 agonists promote sleep
what is the H4 receptor's function, and where are they expressed?
like H3 receptors, but expressed on immune cells like eosinophils and neutrophils, where they regulate recruitment
what may the new H4-specific antagonist (JNJ77771208400483314) have potential in doing?
treating allergic and immune responses
what are the two main cardiovascular effects, and which histamine receptor is responsible for each?
1) vasodilation of terminal arterioles, capillaries, and postcapillary venules (H1); 2) hypotension (H2) - although hsitamine constricts larger vessels and can cause hypertension
what do other actions on terminal vessels lead to?
widening of endothelial gaps
what are the respiratory effects and what histamine receptor is responsible?
H1 - mediates bronchoconstriction
what are the GI effects of histamine (2) and what receptor is involved with each?
H1 - mediates intestinal smooth muscle contraction; H2 - promotes gastric secretion
what does histamine do in the CNS (2), and what receptosr are respnsible?
increases wakefulness and inhibits appetite through H1 receptor
what are symptoms of histamine release?
hyptension, flushing, headache, difficulty breathing, nausea, vomiting, diarrhea visual disturbances - massive doses can lead to shock, circulatory collapse, and death
how do all antihistamines discussed in this lecture function?
reversible, competitive inhibitors of the H1 receptor
how are these drugs metabolized?
P450 in the liver
what do these H1 antagonists normally have a strong effect on, and weak effect on?
strong effect on capillary permeability, but little effect on bronchoconstriction and hypotension
what is the prototype first generation histamine, and what does it do, and not do?
diphenhydramine (benadryl) is the prototype, and it is a competitive H1R antagonist but not an inhibitor of histamine release
what is its adverse effect, and why does it have this effect?
1) sedation via CNS depression; 2) antimuscarinic properties (dry mouth, tachycardia, blurred vision, constipation [GI effects minimal]) - crosses the BBB
when is it best to administer diphenhydramine?
prior to histamine release
what is a 1st generation H1 blocker that is commonly used in combination with cold products, in the relief of motion sickness, and for nausea/vomiting?
what is the main side effect of promethazine?
sedative (also has antiemetic and central anticholinergic effects)
what H1 antagonist is not like the others, and why is it different?
doxepin is different, because it is used primarily as an antidepressant - it is much better tolerated by depressed patients
what are the side effects of doxepin?
drowsiness and anticholinergic effects
what second generation H1 blockers were said to have the longest half lives (2)?
loratidine (claritin) - >24 hours, cetirizine (zyrtec) 12-24 hours
what other second generation H1 blocker must we know?
fexofenadine (allegra) -duration 1-12 hours
which 2nd generation H1 antagonist was said to have poor penetration of the BBB, and what are its side effects?
cetirizine (zyrtec) - but it is still more prone to cause drowsiness than other second generation antihistamines
what else should we know about loratidine?
desloratidine (clarinex) is the active metabolite, and has same activity, duration of action, and lack of side effects
how are first generation antihistamines metabolized and excreted?
metabolized in liver, excreted in urine in a modified form
how are second generation antihistamines metabolized and excreted?
mexcreted in liver in unmetabolized form
what is the implication of generation two antihistamines metabolism?
there should not be P450 interactions
what are drug interactions with antihistamines?
1) sedating antihistamines / depressants such as barbiturtates; 2) alcohol in combination with sedating antihistamines can lead to excessive sedation (applies to ALL antihistamines in this lecture)
what H1 blocker is effective in treating motion sickness, N/V, and as an adjuvant to Parkinson's disease and why?
promethazine, because of antimuscarinic properties (but better drugs are available for Parkinson's than G1 H1 antagonists)
how effective are H1 antagonists in treating anaphylaxis?
ineffective, due to the participation of other autacoids (leukotrienes, PAF) - initial treatment should be with epinephrine - antihistamines and corticosteroids are typically administered after the patient stabilizes, and may reduce late phase responses
what else were first-generation antihistamines said not to be useful for?
how useful are antihistamines in treating colds/flu?
not useful - may do more harm than good
who is benadryl (diphenhydramine) contraindicated in?
nursing mothers, neonates, and premature infants
what are side effects of promethazine, and how does it compare in action to 2nd generation drugs?
causes BP effects, skin rash, and drowsiness - rapid onset - less selectivity than 2nd generation drugs