Pharm 3

Front 3

ESTROGENS/PROGESTINS

Front 5

what is the natural hormone we refer to as "estrogen"?

Back 5

17-B-estradiol - other natrual estrogens are are estrone, estriol

Front 6

what is premarin and what is its use?

Back 6

equilin sulfate and estrone sulfate, from pregnant mare urine, used in HRT

Front 7

what chemically modified natural progestin must we know, and what is it used for?

Back 7

medroxyprogesterone - most common for HRT, also depot contraception

Front 8

what is the most common therapeutic regimen for contraception (specific estrogen, and type of progestin)?

Back 8

a synthetic estrogen, ethinyl estradiol (EE), and one of the five synthetic progestins

Front 9

what are the five synthetic progestins we must know, and what generation is each?

Back 9

1st generation: norethinedrone (NE); 2nd generation: levonorgestrel (LNG); 3rd generation norgestimate (NGM) and desogestrel (DSG); 4th generation drosperinone

Front 10

what is the most common therapeutic regimen for HRT?

Back 10

premarin (two equine estrogens) plus medroxyprogesterone - together called prempro

Front 11

what is the rate limiting step in biosynthesis of E and P?

Back 11

conversion of cholesterol to pregneolone

Front 12

what is the function of aromatase (2 conversions)?

Back 12

androstenedione --> estradiol; testosterone --> 17-B-estradiol

Front 13

what is the source of estrogens in men and postmenopausal women, and what estrogen do they have?

Back 13

adipose tissue takes DHEA from adrenals and converts it to estrone

Front 14

what hormonal change causes ovulation?

Back 14

E peaking adt midcycle, causing surge in LH and FSH

Front 15

what happens to hormone levels after this?

Back 15

E levels decline, but P levels rise

Front 16

how do oral contraceptives inhibit ovulation?

Back 16

by creating an environment which inhibits the FSH and LH surge

Front 17

what concentrations suppress the LH and FSH release?

Back 17

high concentrations of E and P

Front 18

what are the relative concentrations of E to P in luteal phase?

Back 18

P >>> E - P is measured in mg, while E is measured in ug

Front 19

how does estrogen level affect transport of E in blood?

Back 19

it increases the level of the binding globulin SHBG

Front 20

which hormone, E or P, binds with high affinity and specificity to its receptors?

Back 20

estrogen

Front 21

besides P receptors, what else does B bind to and agonize (3)?

Back 21

1) PR; 2) GR; 3) ER

Front 22

what are the two estrogen receptors, and which does E bind with more affinity?

Back 22

ER-alpha and ER-beta, E binds with same affinity

Front 23

what hormone(s) prefer alpha and what hormone(s) prefer beta?

Back 23

estrone prefers alpha, estriol and genstein prefer beta

Front 24

where does beta receptor predominate?

Back 24

prostate, GIT

Front 25

where does alpha receptor predominate (3)?

Back 25

breast, endometrium, liver

Front 26

which hormone, E or P, modulates many metabolic processes?

Back 26

estrogen

Front 27

what are other functions of estrogen (3)?

Back 27

development of female secondary sex characteristics, control of ovulatory cycle control of pregnancy

Front 28

what are effects of progesterone (list)?

Back 28

mammary development, prepare uterus for implantation, increases bosal body temp, sloughing of endometrium, maintains pregnancy, inhibits uterine contractility

Front 29

how does estrogen affect coagulation?

Back 29

increases clotting factors and decreases coagulation factors

Front 30

how does estrogen affect lipid profile/

Back 30

increases HDL, increases TG, decreases LDL

Front 31

what other metabolic effects does estrogen have (2)?

Back 31

increases Na+ retention, stimulates cell proliferation

Front 32

how do types of estrogens rank in potency, and which are used in oral contraceptives?

Back 32

synthetic > conjugated > equine > natural - synthetic (ethinyl estradiol) used in oral contraceptives

Front 33

what should be known about pharmacokinetics of natural vs. conjugated and synthetic estrogens?

Back 33

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)

Front 34

what pharmacokinetic properties cause prolonged effects of estrogen in body?

Back 34

enterohepatic effects - metabolized to E-glucuronide in liver, then cleaved in intestine by bacteria, and reabsorbed

Front 35

what is the primary metabolite of progestins and how are they metabolized/excreted?

Back 35

primary metabolite is pregnanediol - progestins are glucuronidated, and excreted by kidney

Front 36

how do the potency of progenstins rank?

Back 36

levonorgestrel, desogestrel, norgestamate, norethindrone

Front 37

what is the benefit if triphasic oral contraceptives?

Back 37

less exposure to progestin component minimizes possible progestin-related side effects

Front 38

when are monophasics better (2)?

Back 38

1) when woman has signs of progestin deficiency (late cycle bleeding); 2) if woman experiences mood swings on triphasic

Front 39

how long is "backup" required when there is a Sunday start for oral contraceptives?

Back 39

one week

Front 40

what should patient be told about taking pills, and missing one pill?

Back 40

take same time every day, and if you miss a pill take two on day remembered

Front 41

what if two pills are missed in week one or two?

Back 41

tmust take 2 on day remembered and 2 on day after, and use backup for one week

Front 42

what if two pills are missed in a row in week three?

Back 42

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

Front 43

what is the mini pill, and what is in it?

Back 43

progestin only pill (POP)

Front 44

what forms of progesterone might be in the mini-pill?

Back 44

norethindrone or norgestrel

Front 45

how should it be taken, and what is the most common use?

Back 45

taken at same time every day, with no pill-free interval - most commonly used in lactating women

Front 46

what are two forms of extended progestin-only contraception (what is each and how is it given) and how long does contraception last?

Back 46

1) depo-provera - three months - IM injections of medroxyprogesterone acetate; 2) norplant - subdermal tubes of levonorgestrel - provides contraception up to 5 years

Front 47

what are adverse effects of oral progestin only contaception (3)?

Back 47

1) irregular bleeding (50% amenorrhea after one year); 2) acne; 3) depression

Front 48

when should depo-provera be used, and why (3)?

Back 48

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

Front 49

what are the mechanisms of action and effects of oral contraceptives (both COCs and progestin only) (3)?

Back 49

1) inhibit ovulation (by suppresing FSH and LH release); 2) thicken cervical mucosa (sperm barrier); 3) altered endometrial lining blocks implantation

Front 50

what increases risk of pregnancy when POPs are missed?

Back 50

>3 hr delay in taking pill (need to miss 2 doses with COCs)

Front 51

what cancers do COCs decrease risk of (2)?

Back 51

endometrial, ovarian

Front 52

what diseases do COCs decrease risk of (3)?

Back 52

1) fibrocystic disease; 2) fibroadenomas; 3) PID

Front 53

what other benefits do COCs provide (2)?

Back 53

greater cycle regularity, lower blood loss during menses

Front 54

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?

Back 54

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)

Front 55

what is the single greatest risk factor for breast cancer?

Back 55

lifetime exposure to estrogen

Front 56

who is this more of a risk in?

Back 56

long term users

Front 57

what type of use showed the most seroius increased risk in breast cancer?

Back 57

4 or more years before first full-term pregnancy

Front 58

besides increased breast cancer and thrombosis, what other increased risks are associated with estrogen (5)?

Back 58

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)

Front 59

what specific hormone form is most associated with stroke and CVD?

Back 59

levonorgestrel (most potent progestin)

Front 60

what are risks associated with progesterone (3)?

Back 60

1) unfavorable lipid profile; 2) impaired glucose tolerance; 3) thrombosis

Front 61

what progesterone decreases the HDL:LDL ratio the most?

Back 61

levonorgestrel is the worst

Front 62

which progesterones have other effects on lipid profiles, and what effects does each have?

Back 62

noregestimate or desogestrel increase HDL, desogestrel also lowers LDL (positive)

Front 63

how do progestins affect glucose tolerance?

Back 63

decrease insulin receptors

Front 64

what is the worst progestin in causing IGT?

Back 64

levonorgestrel

Front 65

what progestins were said to have no effect on IGT?

Back 65

norgestimate or desogestrel

Front 66

what progestins are associated with higher risk for DVT?

Back 66

newer 3rd generation progestins (desogestrel)

Front 67

what are mild/moderate effects associated with estrogen?

Back 67

N/V, cramping, fluid retention, dizziness, headache, breast discomfort, changes in quality of tears, corneal edema

Front 68

what are mild/moderate effects associated with progesterone?

Back 68

spotting and breakthrough bleeding, weight gain, acne, hirsutism

Front 69

what progestins have an effect on glucose tolerance (2) and what is the effect of each?

Back 69

levonorgestrel - exacerbates; norgestimate - slight improvement

Front 70

what progesterone has a lot of androgenic effects, and what has moderate?

Back 70

levonorgestrel - most androgenic effects, norethindrone - minimal/moderate, rest minimal

Front 71

what progesterone has no effect on lipid profile?

Back 71

norethindrone

Front 72

which progesterones have positive effects on lipid profiles?

Back 72

desogestrel (increase LDL, lower LDL), norgestimate (increases HDL)

Front 73

what are contraindications for COCs (list)?

Back 73

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

Front 74

what types of women should get progestin only pills?

Back 74

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

Front 75

what new progestin reduces problems with Na+ and water retention, and what drug does it resemble?

Back 75

drospirenone - resembbles spironolactone

Front 76

what problems may it cause and who is it contraindicated in (3)?

Back 76

may elevate potassium, contraindicated in those with liver, kidney, and adrenal problems

Front 77

what free hormone do all OC's lower?

Back 77

free testosterone

Front 79

LOCAL ANESTHETICS

Front 81

what are five characteristics of an ideal local anesthetic?

Back 81

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

Front 82

what are local anesthetics like chemically?

Back 82

weak bases that exist in both ionized and unionized form at physiologic pH

Front 83

what are two major classes of local anesthetics distinguished by?

Back 83

either an ester or an amide group linking aromatic and amine portions of molecule

Front 84

what form of local anesthetics can cross limpid membranes?

Back 84

only base form (unionized)

Front 85

what is the prototype amide anesthetic, and how does acidic pH affect its action?

Back 85

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

Front 86

what three things affect the onset of local anesthetic action?

Back 86

1) tissue pH, 2) pKa of drug; 3) nerve fiber type

Front 87

what is the order of sensations lost (what is first, next, etc…five things)?

Back 87

pain, cold, warmth, touch, pressure (B and C fibers most sensitive, A alpha and A beta the least, A gamma and A delta intermediate)

Front 88

where is the site of action for local anesthetic drugs?

Back 88

deep within sodium channels

Front 89

what forms of the sodium channel have higher affinity for local anesthetics?

Back 89

open or inactive channels (closed have lower affinity) - so frequency of nerve stimulation enhances access of ionized local anesthetics to their receptor

Front 90

what form of local anesthetics can only access the receptor under certain conditions, and what are those conditions (2)?

Back 90

the ionized form can only access the receptor from inside the nerve, and only when the channel is briefly open

Front 91

what are the actions of local anesthetics on the CNS?

Back 91

initial excitaiton (tremors, restlessness, possible convulsions) followed by CNS depression, respiratory failure, and death

Front 92

how should convulsions/CNS toxicity be treated?

Back 92

convulsions treated with diazepam, also administer oxygen

Front 93

what do local anesthetics do to the cardiovascular system?

Back 93

decreased excitability of myocardium, decreased conduction rate, decreased contractility, possible ventricular fibrillation

Front 94

what are the effects of local anesthetics on ganglia and NMJ, and why?

Back 94

decreased transmission due to actions of local anesthetics at nicotine receptors

Front 95

what type of local anesthetics can cause allergic reaction, and how common is it?

Back 95

very rare, only ester anesthetics

Front 96

what is metabolism of ester type and amide type like?

Back 96

ester type hydrolyzed rapidly by plasma esterases, amide type more slowly degraded by liver enzymes

Front 97

what metabolic problem can occur, and with what type of anesthetics?

Back 97

ester type anesthetics - some patients who metabolize ester anesthetics poorly due to a rare mgenetic defect in plasma cholinesterase

Front 98

how do local anesthetics cause death by overdose?

Back 98

due to ventricular fibrillation and cardiac arrest, or by CNS depression with respiratory failure

Front 99

how can lidocaine be administered?

Back 99

oral, parenteral, surface application

Front 100

what is a potent, long-acting amide local anesthetic, frequently used epidurally or spinally (for partirution, lower limb orthopedics)?

Back 100

bupivacaine

Front 101

what is an amide anesthetic similar to bupivicaine, but with a supposed advantage, and what is that advantage?

Back 101

ropivicaine, similar but supposedly less cardiotoxic

Front 102

what is a prototype ester anesthetic, and how does its action compare to lidocaine?

Back 102

procaine (novocain) - less potent and shorter acting than lidocaine

Front 103

how is it administered, and by what method is it not active?

Back 103

rapidly absorbed after parenteral injection, but not effective topically

Front 104

what is the duration of action of lidocaine?

Back 104

40-90 minutes

Front 105

what is the duration of action of bupivicane?

Back 105

120-240 minutes

Front 106

duration of procaine?

Back 106

20-60 minutes

Front 107

what is an ester that is more active and more toxic than procaine, and how else does it differ?

Back 107

tetracaine - 10x as active and more toxic, but slower onset and longer duration

Front 108

what ester is useful as a topical anesthetic, and what else should we know about this?

Back 108

benzocaine - useful as topical anesthetic, has no ionizable amine group, so exists only in an unionized state

Front 109

besides local anesthetic activity what does cocaine do?

Back 109

inhibit reuptake of catecholamines / potentiation of indirect-acting sympathomimetics

Front 110

what do moderate doses of cocaine cause in the CNS?

Back 110

emesis, tremors, and possibly convulsions

Front 111

what do high doses cause in CNS?

Back 111

CNS stimulation followed by CNS and respiratory depression

Front 112

what is cocaine's effect on the hypothalamus?

Back 112

pyrexia

Front 113

what does cocaine do to the heart at high doses?

Back 113

tachycardia/vasoconstriction

Front 114

what should cocaine not be coadministered with?

Back 114

other vasoconstrictors

Front 115

what amide anesthetic can be used topically?

Back 115

lidocaine

Front 116

what is the AE of bupivicaine?

Back 116

can cause significantly greater CV toxicity compared to lidocaine

Front 117

where is lidocaine metabolized (and other amides)?

Back 117

liver

Front 118

how does potency/duration of ropivicane compare to other amides?

Back 118

longer lasting and more potent than lidocaine, but less potent and shorter acting than bupiviciane

Front 119

what anesthetic is most likely to cause allergies?

Back 119

procaine (novocain) - short duration of action

Front 120

what anesthetic lacks amine group, and only exists unionized?

Back 120

benzocaine

Front 121

how is benzocaine administered?

Back 121

topical only

Front 123

GENERAL AND IV ANESTHETICS

Front 125

what are four factors affecting the actions of general anesthetics (4)?

Back 125

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

Front 126

what is used to define the amount of anesthetic gas?

Back 126

partial pressure

Front 127

what is the partition coefficient?

Back 127

relative solubility in blood vs. gas phase

Front 128

what is the main method of elimination of anesthetic gases?

Back 128

expiration

Front 129

if a patient has achieved equilibrium with a gas at high partial pressure, what can sudden discontinuation of gas delivery cause?

Back 129

rapid exchange of gas into alveolar air - can cause diffusional anoxia if remaining air contains insufficient oxygen, such as breathing room air

Front 130

what is therapeutic index/dose repsonse curve like in general anesthetics?

Back 130

very low therapeutic index, steep dose response curve (99% of patients anesthetized at 1.3 MAC - MAC is concentraiton at which 50% are unconscious)

Front 131

what can reduce MAC (3)?

Back 131

reduced by presence of other CNS depressants, in the elderly, and in pregnant women

Front 132

when is MAC increased?

Back 132

infants and children

Front 133

how does anesthetic potency to lipid:gas particion foefficent rule relate to mechanism of anesthetic action?

Back 133

does not seem to relate to it

Front 134

how does structure of gas relate to activity?

Back 134

does not - even inert gases like xenon have anesthetic effects

Front 135

what is the postulated mechanism?

Back 135

action at specific membrane proteins

Front 136

what is the prototype inhaled anesthetic?

Back 136

halothane

Front 137

what is its potency and speed of induction/recovery like?

Back 137

high potency (MAC <1%) - moderately prompt induction and recovery

Front 138

what is the metabolism of halothane?

Back 138

mostly eliminated in air, but undergoes significant liver metabolism (20%)

Front 139

what is the most important cardiovascular effect of halothane (bold) and other CV effects?

Back 139

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

Front 140

what are the respiratory effects of halothane?

Back 140

if not adequately ventilated patient can get hypoxia (rapid, shalow breathing, reduced response to CO2, impaired oxygen exchange)

Front 141

what is the CNs effect besides anesthesia?

Back 141

1) dose dependent depression of autonomics; 2) increases secrebral blood flow; 3) increases intracranial pressure; 4) decreases oxygen consumption in brain

Front 142

what are rare instances of severe adverse effects with halothane (2)?

Back 142

1) malignant hyperthermia; 2) halothane hepatitis (50% mortality)

Front 143

how is malignant hyperthermia treated?

Back 143

with the calcium channel blocker, dantrolene

Front 144

what inhaled anesthetic has a very high MAC, and what is its MAC?

Back 144

nitrous oxide - MAC 105.00

Front 145

what other drug has very rapid onset and recovery like nitrous oxide, but is much more potent?

Back 145

desflurane

Front 146

what anesthetic has similar CV, CNS, and respiratory effects to desflurane?

Back 146

isoflurane

Front 147

how does isoflurane compare to halothane in induction and recovery speed, and potency?

Back 147

faster induction and more rapid recovery, but slightly lower potency

Front 148

what is isoflurane a DOC for and why?

Back 148

DOC for neuroanesthesia, because it does not increase intracranial pressure

Front 149

what else does halothane do that isoflurane was said not to do (2)?

Back 149

1) sensitize heart to catecholamien-induced arrhythmias; 2) still get dose-dependent hypotension (but still get dose-dependent hypotension)

Front 150

what are two other advantages of isoflurane over halothane?

Back 150

1) no reported hepatotoxicity; 2) better muscle relaxation (no convulsive activity)

Front 151

what drug has rapid onset and recovery, but is not irritating to the airways and does not cause tachycardia?

Back 151

sevoflurane

Front 152

what else should be remembered about sevoflurane?

Back 152

hepatic metabolism 100x greater than desflurane, with some release of fluoride ion

Front 153

so, what drugs have significant hepatic metabolism (2)?

Back 153

halothane, sevoflurane

Front 154

how is nitrous oxide useful for anesthesia?

Back 154

only in combination with other inhalational or IV anesthetics

Front 155

how is it metabolized?

Back 155

not metabolized

Front 156

how effective is nitrous oxide in muscle relaxation?

Back 156

no significant relaxation

Front 157

what property does it have that other inhalation anesthetics do not, and what is the mechanism behind this effect?

Back 157

analgesic effect at less than 1.0 MAC - caused by release of endogenous opioids

Front 158

what adverse effects can nitrous oxide cause (2 major, other)?

Back 158

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)

Front 159

what IV anesthetic is an ultrashort acting barbiturate, and what is it good for?

Back 159

thiopental - causes loss of consciousness 10-20 seconds after IV injection

Front 160

how quickly does consciousness return with thiopental, and why?

Back 160

returns slowly due to redistribution from brain to other tissues (fat)

Front 161

where is thiopental metabolized?

Back 161

in the liver

Front 162

what is the MOA of thiopental?

Back 162

allosteric regulation of GABA-a coupled chloride channels (increase opening time, allowing more influx of Cl- and nerve hyperpolarization

Front 163

what is this the most frequently used drug for?

Back 163

rapid sequence induction of anesthesia

Front 164

what problem can thiopental cause, and how can it be avoided?

Back 164

can cause painful tissue necrosis at injection site when used in concentrations >2.5% (use in lower concentrations)

Front 165

what is an ultrashort acting, nonbarbiturate sedative and anisthetic agent, which can cause unconsciousness (5 minutes worth) in a single IV injection?

Back 165

etomidate

Front 166

what problem can etomidate cause?

Back 166

1) muscle spasm (treat with diazepam); 2) dose-dependent decrease in plasma cortisol levels

Front 167

who should etomidate be avoided in?

Back 167

prolonged sedation of critically ill patients

Front 168

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?

Back 168

propofol

Front 169

what else is propofol used for?

Back 169

IV sedative for regional anesthesia

Front 170

what side effects does it cause (2)?

Back 170

1) hypotension (30%); 2) slows respiration / decreases response to CO2

Front 171

what is propofol's effect on hepatic/renal function and intracranial pressure?

Back 171

no impairment of hepatic or renal function, and generaly decreases intracranial pressure

Front 172

what adverse effect of propofol occurs, but with low incidence?

Back 172

PONV (post-operative nausea and vomiting) possibly to intrinsic antiemetic actions

Front 173

what IV anesthetic causes dissociative anesthesia?

Back 173

ketamine

Front 174

what other effects does ketamine have?

Back 174

analgesia, amnesia (and others like hallucination, delirium)

Front 175

what was it said not to affect (2)?

Back 175

laryngeal reflexes, respiratory responses

Front 176

what are the cardiovascular effects of ketamine (must know)?

Back 176

increases CO, BP, and HR, possibly due to increased sympathetic outflow

Front 177

what is the site of action of ketamine, and what does it do there?

Back 177

cortex, limbic system - blocks glutamate (NMDA) receptors - also has high affinity for opioid sigma receptors

Front 178

what is ketamine useful for (3)?

Back 178

1) trauma/emergency surgeries; 2) radiological procedures in children; 3) cardiac surgeries

Front 179

what general anesthetic is used for very short procedures (<10 min)?

Back 179

etomidate

Front 180

what IV anesthetic is useful for induction of anesthesia?

Back 180

thiopental - causes loss of consciousness 10-20 seconds after IV injection

Front 182

VITAMIN D AND PARATHYROID

Front 184

what drugs reduce Ca++ absorption (2)?

Back 184

anticonvulsants, glucocorticoids - other factors are intestinal disease, phytates and oxalates, and age

Front 185

what is used to treat calcium deficiency that causes rickets/osteomalacia?

Back 185

100 U vitamin D/day

Front 186

what is used to treat hypocalcemic tetany?

Back 186

calcium chloride, IV

Front 187

what is used to treat hypocalcemia related to hypoparathyroidism, what is it, and why is it used?

Back 187

DHT (dihydrotachysterol) - a vitamin D2 analog - shorter duration of action and greater effect on bone mobilization than D2 or D3

Front 188

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)?

Back 188

DHT (dihydrotachysterol) + calcium supplementation

Front 189

what is used to treat vitamin D-dependent rickets (type I rickets - defective conversion of 25-OHD to calcitriol)?

Back 189

physiologic doses of calcitriol

Front 190

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)?

Back 190

phosphate binders, Ca supplementation

Front 191

what about in late stages when there is dialysis?

Back 191

calcitriol

Front 192

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?

Back 192

treatment is long-term parenteral administration of calcium

Front 193

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)?

Back 193

oral PO4, calcitriol, but not always effective

Front 194

how is vitamin D effective in osteoporosis treatment?

Back 194

yes, 400-800 U/day improves intestinal Ca absorption

Front 195

what strategy is used to delay osteoporosis?

Back 195

vitamin D, dietary Ca++ supplementation

Front 196

what drug is used to slow bone resorption, what class is it, and how does it work?

Back 196

alendronate (fosamax) - a bisphosphonate - binds to hydroxyapatite, and blocks ability of osteoclast to resorb bone - used in osteoporosis

Front 197

what are the side effects of fosamaxx (list) and how common are they?

Back 197

rare - abdominal, musculoskeletal pain, nausea, heartburn, irritation of esophagus (minimized by remaining upright)

Front 198

what may be a long term problem caused by fosamax?

Back 198

might induce osteomalacia by inhibiting mineralization

Front 199

what other drugs can be used for osteoporosis (4) and what class is each?

Back 199

1) raloxifene (SERM); 2) teriparatide (synthetic PTH); 3) calcitonin; 4) estrogens (17-B estradiol)

Front 200

what is the function of 17-B-estradiol in osteoporosis?

Back 200

decreases osteoblast production of IL-6, a chemoattractant for osteoclast precursors

Front 201

what is raloxifine (a SERM) protective against, and what advantage does it have over 17B-estradiol?

Back 201

protective against spine fractures (but not hip) - avoids most undesirable effects of 17B (but has some hot flashes, thrombophlebitis)

Front 202

how is teriparatide given, and what is its effect?

Back 202

appears to stimulate Ca++ conservation, when administered in low, intermittent doses

Front 203

how does it stimulate Ca++ conservation (2)?

Back 203

1) minimize bone resorption; 2) via intestinal absorption (calcitriol dependent)

Front 204

where does teriparatide induce bone growth?

Back 204

both spine and hip, but so far only demonstrated efficacy against spine fractures

Front 205

what is the MOA of calcitonin, and what is the problem?

Back 205

it is a powerful inhibitor of bone resorption, but there is little net bone growth

Front 206

how can calcitonin be administered (2), and what side effects occur with each mode of administration?

Back 206

1) nasal spray (runny nose); 2) parenteral - N/V, flushing of face, frequent urination

Front 207

what may have benefit in children/adolescents with osteoporosis (2 strategies)?

Back 207

bone marrow trasnplant - also g-IFN + calcitriol have shown some benefit

Front 208

what is paget's disease like, and what are the treatments (2)?

Back 208

large, deformed bones - treated with 1) alendronate; 2) calcitonin

Front 209

what are other clinical applications of note for calcitriol (2)?

Back 209

1) psoriasis; 2) cancer (can induce leukemic cell differentiation)

Front 210

IMMUNOSUPPRESSANTS

Front 212

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?

Back 212

IL-2, released by CD4+ T cells

Front 213

what leads to the stimulation of calcineurin, and what is calcineurin?

Back 213

T-cell receptor activation elevates intracellular Ca++ which stimulates the Ca++ calmodulin dependent phosphatace, calcineurin

Front 214

what else does this increase in Ca++ stimulate (2 pathways)?

Back 214

MAP kinase and NFkB signaling

Front 215

what does calcineurin activate, and what is the result?

Back 215

activates NFAT which helps induce expression of cytokines, like IL-2, TNF-alpha, and INF-gamma

Front 216

what drug and drug type targets antigen recognition?

Back 216

antibody therapy - Muromonab

Front 217

what types of drugs (2) and examples target cytokine induction?

Back 217

calcineurin inhibitors (cyclosporine, tacromilus) and corticosteroids (prednisone, prednisolone)

Front 218

what type of drug and two examples target IL-2 receptor activation on T and B cells?

Back 218

antibody therapy - daclizumab and basiliximab

Front 219

what drug types (2) and drug examples targets lymphocyte proliferation?

Back 219

antiproliferatives (sirolimus) and cytotoxic drugs (azathioprene and mycophenylate), and possibly steroids

Front 221

CORTICOSTEROIDS

Front 223

how do these work, generally (2 categories of effects)?

Back 223

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

Front 224

for allograft rejection what are they given in combination with?

Back 224

cyclosporine or tacrolimus - permits lower dose of cyclosporine

Front 225

what regimens are given if acute rejection is likely (either/or)?

Back 225

1) methylprednisone IV pulses; 2) high dose oral prednisone

Front 227

CYTOTOXIC DRUGS

Front 229

what are the most commonly used cytotoxic drugs for immunosuppression (4)?

Back 229

1) azathioprine; 2) mycophenolate mofetil; 3) cyclophosphamide; 4) methotrexate

Front 230

how does azathioprine work and what does it inhibit (complete MA)?

Back 230

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

Front 231

how is it given and what is the regimen for organ transplant?

Back 231

injected at time of transplant, then given orally with decreasing dose

Front 232

what else was azathioprine said to be used for?

Back 232

rheumatoid arthritis

Front 233

what is the most limiting adverse reaction to azathiprine, and how many people get it?

Back 233

leukopenia - 50% of renal transplant patients - often from bone marrow suppression

Front 234

what patients should not receive azathioprine and why?

Back 234

pregnant/nursing patients, due to teratogenic effects

Front 235

what is the MOA of mycophenolate mofetil (complete)?

Back 235

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

Front 236

how does this differ from azathiprine?

Back 236

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

Front 237

wha action does MPA dramatically inhibit?

Back 237

B cell proliferation

Front 238

what should be remembered about the pharmacokinetics of MPA (2)?

Back 238

1) highly protein bound (95%); 2) high bioavailability (94%)

Front 239

what is mycophenolate mofetil used for, andwhat is it given with?

Back 239

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

Front 240

what drug interactions must we know for MPA (3 drugs/problems)?

Back 240

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

Front 241

who should not be given mycophenolate mofetil?

Back 241

pregnant/nursing patients, due to teratogenic effects

Front 242

what is the MOA of cyclophosphamide?

Back 242

alkylating agent - alkylates DNA in proliferating cells

Front 243

what part of the immune response is it most effective against?

Back 243

B cells / humoral immunity

Front 244

what is cyclophosphamide used for (2 categories)?

Back 244

1) patients receiving bone marrow transplants; 2) autoimmune disorders (RA, SLE, WG, ITP)

Front 245

what are adverse reactions of cyclophosphamide (3)?

Back 245

1) hemorrhagic cystitis; 2) cardiotoxicity; 3) severe pancytopenia

Front 246

what other immunosuppressant is typically used for RA and psoriasis that are intractable to corticosteroids/other immunosuppressant therapies?

Back 246

methotrexate

Front 247

what can chronic use of low doses of methotrexate result in?

Back 247

liver damage, exacerbated by alcohol

Front 249

CLASSIC IMMUNOSUPPRESSANTS

Front 251

what are the calcineurin inhibitors we must know (3)?

Back 251

1) cyclosporine; 2) tacromilus; 3) pimecrolimus

Front 252

what other drug is a "classic immunosuppressant" but does not inhibit calcineurin?

Back 252

sirolimus

Front 253

where do classic immunosuppressants come from (origin) and what are they like chemically?

Back 253

highly lipophilic, from microorganisms

Front 254

what part of the MOA is shared by all of these drugs?

Back 254

they cross the cell membrane unmetabolized and bind endogenous ligands called immunophilins - binding to immunophilins is a MUST for calcineurin inhibition

Front 255

what immunophilins are bound by which drugs?

Back 255

cyclosporine binds cyclophilin A while the rest bind FKBPs (FK-506 binding proteins)

Front 256

what type of activity does calcineurin have that these drugs (except sirolimus) inhibit?

Back 256

protein phosphatase activity - blocks the activation/nuclear translocation of NFAT, which in turn blocks the induction of numerous cytokines, especially IL-2

Front 257

how can cyclosporine and tacromilus and pimecrolimus share a mechanism, but have different binding targets?

Back 257

each immunophilin/immunosuppressant complex shares the same binding site on calcineurin catalytic subunit

Front 258

what should be remembered about the disposition/pharmacokinetics of calcineurin inhibitors?

Back 258

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)

Front 259

in what organ transplants are calcineurin inhibitors used, and what are they given with?

Back 259

almost all solid organ transplants - often with corticosteroids, also sometimes with cycotoxic drugs as well

Front 260

when is IV administration performed and what can result?

Back 260

when there are GI complications - IV administration may be accompanied by anaphylactic reactions

Front 261

what have recent studies shown is the most effective of these drugs in improving graft survival and preventing rejection?

Back 261

tacrolimus - used in 50% of all new renal transplants

Front 262

what is its potency compared to cyclosporine?

Back 262

100x as potent

Front 263

what are emerging as first line treatments for atopic dermatitis, especially in children (2)?

Back 263

ointment forms of tacrolimus and pimecrolimus

Front 264

what are advantages of calcineurin inhibitors over steroids?

Back 264

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

Front 265

what are the differences in treatment efficacy like between calcineurin inhibitors and steroids?

Back 265

negligibile

Front 266

which drug is generally recommended for mild to moderate atopic dermatitis, and which is recommended for moderate to severe cases?

Back 266

pimecrolimus for mild-moderate, tacrolimus for moderate-severe

Front 267

which of these drugs is absorbed into the blood the very least, and thus causes the least systemic immunosuppression?

Back 267

pimecrolimus

Front 268

what are calcineurin inhibitors 2nd or 3rd line for (3)?

Back 268

1) RA; 2) Crohn's; 3) Behcet's syndrome

Front 269

what are main AEs for calcineurin inhibitors (4 besides increased susceptibility to infections)?

Back 269

1) lymphoproliferative disease (leading to immunodeficiency); 2) nephrotoxicity (can occur in 75% of patients); 3) hypertension; 4) neurotoxicity; 5) GI; 6) hirsutism; 7) hypoglycemia

Front 270

what are the two forms of renal dysfunction, and what is each?

Back 270

1) functional - improves when drug is withdrawn; 2) chronic dysfunction - irreversible, with histologic abnormalities and mild proteinuria - seen at 6-12 months post-op

Front 271

what is typically the first sign that renal function may be impaired?

Back 271

halt in decline of levels of BUN, creatinine (these are generally higher post-operatively, but then return toward baseline)

Front 272

what is the leading reason for conversion to tacrolimus therapy?

Back 272

failure of reduction in cyclosporine dose to cause response in BUN/creatinine levels

Front 273

what should it be noted that renal dysfunction and hypertension can result in?

Back 273

negative impact on allograft survival

Front 274

how common is hypertension in transplant patients who use calcineurin inhibitors, and what are effects/course like?

Back 274

occur in 50% of transplant patients - effects are mild to moderate, and generally improve with time and therapy

Front 275

what problem can certain antihypertensives cause in these patients?

Back 275

can decrease the metabolism of calcineurin inhibitors

Front 276

why shouldn't potassium sparing diuretics be used for hypertension caused by calcineurin inhibitors?

Back 276

calcineurin inhibitors can cause hyperkalemia

Front 277

what can tacrolimus cause in the heart?

Back 277

hypertrophy - effects subside when dosing lowered

Front 278

what neurotoxic effects occur (3)?

Back 278

1) tremor; 2) headache; 3) convulsions (infrequent)

Front 279

what GI effects occur (2) besides N/V and diarrhea?

Back 279

1) gum hyperplasia; 2) hepatotoxicity

Front 280

what drug is most likely to cause hirsutism, and what race is most likely to get it?

Back 280

cyclosporine - commin in dark skinned caucasians

Front 281

what drug is most likely to cause hyperglycemia, and what % of liver transplant patients get it with this drug?

Back 281

tacrolimus - 33 to 47%

Front 282

what % of patients with kidney transplant get post-transplant diabetes melltus?

Back 282

20%

Front 283

what races are most likely to get PTDM?

Back 283

black, hispanic

Front 284

what treatment does PTDM often require, and what effect does it have?

Back 284

insulin - reverses 15% in one year, 50% by two years

Front 285

what adverse reactions can be caused by topical calcineurin inhibitors (4)?

Back 285

1) itching; 2) burning; 3) melanoma; 4) lymphoproliferative disease

Front 286

what drugs increase levels of cyclosporine (4 classes)?

Back 286

1) CCB's (dilatiazem, nicardipine, verapimil); 2) antibiotics (erythromycin, gentamicin, tobramicin, vancomycin); 3) antifungals (amphotericin B, azoles); 4) grapefruit juice

Front 287

what drugs reduce immunosuppressive potency (3)?

Back 287

1) anticonvulsants (phenytoin); 2) antibiotics (rifampin); 3) St. John's wort - reduction in drug levels can cause rejection

Front 288

what classes of drugs exacerbate toxicity (5)?

Back 288

1) other immunosuppressants; 2) certain antibiotics; 3) antifungals; 4) certain antiinflammatory; 5) GI agents; 6) azathioprine

Front 289

what can azathioprine cause when combined with cyclosporine?

Back 289

leukopenia

Front 290

what anti-inflammatory drugs exacerbate toxicity (2)?

Back 290

1) azapropazon; 2) naproxen

Front 291

what GI agents exacerbate toxicity (2)?

Back 291

1) ranitidine; 2) cimetidine

Front 292

people with what diseases should not be given topical calcineurin inhibitors?

Back 292

chicken pox, measles

Front 293

what drug in particular should be avoided in diabetics?

Back 293

tacrolimus

Front 294

what is the most important precaution/contraindication for these drugs?

Back 294

pregnancy

Front 295

what is it absolutely imperative that the physician should do after transplant?

Back 295

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

Front 296

what does sirolimus do once it binds to the FKBP?

Back 296

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

Front 297

what is the result of inhibition of mTOR?

Back 297

induces G1 phase and prevents cellular proliferation of T and B cells

Front 298

how is sirolimus absorbed/eliminated/metabolized?

Back 298

well absorbed, biliary elimination, metabolized by CYP3A4 into many metabolites

Front 299

what dramatically slows absorption?

Back 299

administration with fatty food

Front 300

how do gender and age affect pharmacokinetics of sirolimus?

Back 300

cleared more rapidly by women, absorbed more slowly by children (avoid under 13 years of age)

Front 301

what drug, when co-administered with sirolimus, causes increase in sirolimus levels?

Back 301

cyclosporine

Front 302

what is sirolimus mainlu used for, and how is dosing given?

Back 302

used for organ transplant - given ASAP post op, with loading dose of triple maintenance dose

Front 303

what is the most important reason for considering co-administration of sirolimus with cyclosporine/corticosteroid therapy?

Back 303

permits the discontinuation of cyclosporine after only a couple months

Front 304

what adverse effect must we know for sirolimus?

Back 304

hypercholesterolemia (can be treated by lipid-lowering agents) - take precautions with those with history of hypercholesterolemia/heart disease/obesity

Front 305

what drug interactions must we know for sirolimus (2)?

Back 305

P450, also cyclosporine (increases renal risks/myelosuppression/lipemia)

Front 307

ANTIBODY REAGENTS

Front 309

what is Rh0D immune globulin (rhogam) derived from, what is it directed aganst/used for?

Back 309

derived from human plasma and against Rh(D) antigen on RBC - prevents sensitization of mothers to Rh(D) antigen - prevents hemolytic disease of newborn

Front 310

how are monoclonal antibodies produced?

Back 310

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

Front 311

what monoclonal antibody must we know?

Back 311

muromonab-CD3

Front 312

what is it used for (2)?

Back 312

1) prophylaxis of organ rejection in kidney tranplants; 2) to deplete T cells from donor bone marrow prior to transplants

Front 313

what does it bind to, and what is the result?

Back 313

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

Front 314

what is it usually co-administered with?

Back 314

cyclosporine/tacrolimus and/or cortocisteroids

Front 315

how is it administered?

Back 315

IV bolus

Front 316

what are the three main adverse effects with muromonab-CD3?

Back 316

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

Front 317

what is CRS like and what precaution should be taken?

Back 317

can be flu-like ranging to shock - patients should be monitored in a facility equipped and staffed for CPR

Front 318

what may help prevent CRS?

Back 318

pretreatment with steroids before muromonab delivery

Front 319

what else limits muromonab use?

Back 319

expensive

Front 321

NSAIDS

Front 323

what does cyclooxygenase produce, and from what?

Back 323

arachadonic acid --> PGH2 (which can be converted to other prostaglandins)

Front 324

what does arachadonic acid come from?

Back 324

clel membrane phospholipids

Front 325

what do prostaglandins made by COX do in the stomach (2)?

Back 325

1) decrease cAMP and decrease K/H ATPase in parietal cells; 2) stimulate secretion of mucous HCO3- from epithelial cells

Front 326

what therapy relates to thromboxane A2 and how does it work?

Back 326

aspirin blocks thromboxane A2 and prevents platelet aggregation

Front 327

will nonspecific COX inhibitors be effective in treating asthma, and why?

Back 327

no, because PGF and PGD constrict / PGEs relax bronchial/tracheal muscles

Front 328

what do PGs do to the CV system?

Back 328

increase cardiac output, vasodilate (hypotensive)), PGD2 vasoconstricts

Front 329

what type of pain are salicylates (aspirin, salicylic acid, methyl salicylate) good for?

Back 329

integument, not visceral

Front 330

what are salicylates contraindicated in (4)?

Back 330

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

Front 331

what are the metabolic effects of salicylate?

Back 331

hyperglycemia, glycosuria, increase O2 consumption, CO2 production, and metabolic rate, reduce serum triglycerides, increase fat burning, decrease lipogenesis

Front 332

what are endocrine effects of salicylates (2)?

Back 332

increae glucocorticoid secretion, decrease thyroid function

Front 333

what are the effects of salicylates on pregnancy?

Back 333

decrease birth weight, increase perinatal mortality, anema, and postpartum hemorrhage

Front 334

what cancer is aspirin helpful with?

Back 334

colorectal

Front 335

what are additional contraindications of aspirin?

Back 335

1) viral infections like flu, chickenpox (Reye's syndrome); 2) peptic ulcers

Front 336

what effects do very low (1mg/kg), low (10mg/kg); and high (100mg/kg) doses of aspirin have?

Back 336

very low - antiplatelet; low - analgesic/antipyretic; high - anti-inflammatory

Front 337

what are three AEs of aspirin?

Back 337

tinnitus, vertigo, deafness

Front 338

what happens in aspirin overdose (2) and what results from each?

Back 338

1) hyperventilation --> respiratory alkalosis; 2) salicylate --> fever, dehydration, and metabolic acidosis

Front 339

how does aspirin overdose culminate?

Back 339

shock, coma, organ system failure, death

Front 340

what is the treatment for aspirin overdose?

Back 340

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

Front 341

why is acetaminophen not an NSAID?

Back 341

no antiinflammatory activity

Front 342

what does it do, and when is it used?

Back 342

functions only centrally - antipyretic / analgesic (no alteration on bleeding time, uric acid, acid/base)

Front 343

what can acetaminophen OD cause?

Back 343

fatal hepatic necrosis

Front 344

what NSAID is useful for gout, and what class is it a part of?

Back 344

indomethacin - an acetic acid

Front 345

what is another acetic acid with limited toxicity and selectivity for COX2?

Back 345

etodolac

Front 346

what are fenamates and why are they not used much?

Back 346

no advantage in anti-inflammatory activity, but cause diarrhea - mefanamic acid, meclofenamic acid

Front 347

what NSAID was said to have little difference in therapeutic efficacy compared to aspirin, but is better tolerated?

Back 347

tolmetin

Front 348

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?

Back 348

ketorolac

Front 349

what NSAID is approved for long term treatment of RA, osteoarthritis, and ankylosing spondylitis?

Back 349

diclofenac

Front 350

what class of drugs are all anti-inflammatory, analgesic, and antipyretic, and are better tolerated than aspirin and indomethacin?

Back 350

propionic acids (ibuprofen, naproxen, fenoprofen, ketoprofin, flurbiprofen)

Front 351

in what case is ibuprofen used, and what is it effective for?

Back 351

in patients with history of GI intolerance to other NSAIDs - effective analgesic and anti-inflammatory

Front 352

what what type of toxicity does naproxen have, similar frequency to indomethacin?

Back 352

GI, CNS (but naproxen better tolerated, generally)

Front 353

what drug is an effective antiinflammatory agent, but poorly inhibits COX in seminal vesicles, where COX1 is the only type?

Back 353

nimesulide

Front 354

what problem occurs with vioxx?

Back 354

HA, stroke

Front 355

what additional program (besides HA, stroke, DVT) occurs with bextra?

Back 355

severe skin reactions

Front 356

what NSAID suppresed breast tumors in human breast cancer cells, and why?

Back 356

piroxicam, since human cancer cells expres high levels of COX-2

Front 357

what drugs reduce the size/number of colorectal polyps in animal models?

Back 357

aspirin, COX-2 inhibitors

Front 358

what is the MOA of aspirin?

Back 358

suicide inhibitor of COX-1 (thromboxane A2)

Front 359

what drug closes the ductus arteriosus in premature neonates?

Back 359

indomethacin

Front 360

what drug is a first generation selective COX 2 inhibitor that is used for RA and osteoarthritis?

Back 360

celecoxib (celebrex)

Front 361

what things was it said ibuprofen is useful for (3)?

Back 361

1) RA; 2) dysmenorrhea; 3) gout; 4) ankylosing spnodylitis

Front 362

what toxicity does it have, and how well tolerated is it?

Back 362

gastrix toxicity, but is tolerated as well as any nonselective COX inhibitor

Front 363

what is achieved at lower doses with ibuprofen - inflammatory or analgesic effects?

Back 363

analgesic effects achieved at lower doses

Front 364

what is an early COX inhibitor used for rheumatoid and osteoarthritis?

Back 364

indomethacin

Front 365

what is a second generation COX inhibitor that is used for osteo and rheumatoid arthritis, migraine, and fever, with gastric complications and pediatric use?

Back 365

naproxen

Front 367

OPIOIDS

Front 369

what are the CNS actions of morphine (5)?

Back 369

analgesia, respiratory depression, miosis, antitussive, nausea

Front 370

what are the peripheral actions of morphine?

Back 370

analgesia, anti-diarrheal, increased smooth muscle tone

Front 371

what is meant by the term potency?

Back 371

relative amount of drug needed to achieve half of maximum effect

Front 372

what are the effects of opiods at the cellular level (3)?

Back 372

1) decrease cAMP by inhibiting adenylate cyclase; 2) increase K current; 3) decrease Ca++ influx; last two effects decrease cell excitability

Front 373

where are all types of opioid receptors found?

Back 373

peripheral nervous system, GI, cortex, striatum, hippocampus, dorsal horn

Front 374

where are only delta receptors found?

Back 374

amygdala

Front 375

where are only mu and kappa receptors found?

Back 375

periaqueductal grey

Front 376

which endogenous opioid agonists are co-released with ACTH in the pituitary, and tie in with HPA stress axis?

Back 376

endorphins

Front 377

what endogenous opioids are present in inhibitory circuits, and found in brain/spinal cord, and what receptors do they prefer?

Back 377

enkephalins - prefer deltareceptor

Front 378

which endogenous opioids are found in pitiuitary, hypothalamus, midbrain, and striatum?

Back 378

dynorphins

Front 379

what receptors do dynorphins prefer, and what action are they involved in?

Back 379

brain region-dependent precursor processing - prefer kappa receptor

Front 380

what is an opioid antagonist that is used to counteract opioid overdose, and what does it do in normal healthy adults vs. post-surgery?

Back 380

naloxone - raises LH and FSH in normal adults, does not alter pain threshold in normal adults, but is hyperalgesic in post-surgery patients

Front 381

what are the three opioid drug classes?

Back 381

phenanthrene, phenylpiperidine, phenylheptanone

Front 382

which class only has two drugs in it, and what are they?

Back 382

phenylhepatone (methadone, propoxyphene)

Front 383

what class are morphine, codeine, hydrocodone, hydromorphone, hydrocodeine, oxycodone, dihydrocodeine, diacethylmorphine in?

Back 383

phenanthrene

Front 384

what drugs are phenylpiperidine?

Back 384

meperadine, fentanyl, alfentanil, sufentanil, femifentanil

Front 385

what type of pain is morphine best against?

Back 385

continuous, dull pain

Front 386

what effect of morphine occurs at sub-algesic/respiratory depressing doses?

Back 386

antitussive (anti-cough)

Front 387

what can morphine cause that can interfere with ventilation in surgery?

Back 387

truncal rigidity

Front 388

what effects of morphine do tolerance not develop for?

Back 388

miosis, diarrhea

Front 389

in what ways does morphine depress respiration?

Back 389

1) depress CO2 blood tension sensitivity in BS; 2) depress medullary/pontine centers that regulate frequency

Front 390

what is the effect of prolonged exposure to morphine on N/V?

Back 390

nearly completely prevents stimulation of CTZ and blocks emesis via other agents (but early exposure to opiates stimulates CTZ)

Front 391

what are GI effects of morphine?

Back 391

increased SM tone, muscle spasms can increase pain, decreases secretions, decreased motility - antidiarrheal/constipating effect

Front 392

what does morphine do to SM tone at therapeutic doses?

Back 392

insignificant increase in tone at therapeutic doses - but at higher doses, increases tone, aggravating asthma, causing urinary retention, and prolonging labor

Front 393

what does morphine do to the CV system at therapeutic doses?

Back 393

minimal effects - decreased BP, stimulate histamine release, orthostatic hypotension

Front 394

what is morphine effective in treating due to these CV effects?

Back 394

pulmonary edema

Front 395

why are morphine and similar opiates good for pain asociated with inflammation?

Back 395

opioid receptors are upregulated at nociceptors due to local inflammation/injury - exogenously applied opioid takes advantage of increased receptor #

Front 396

why is oral morphine not as effective as IV?

Back 396

first pass effect (1/3 to 1/6 as potent)

Front 397

how is morphine excreted, and how fast?

Back 397

almost all gone in 24h in urine

Front 398

what is the triad of symptoms that should make one highly suspicious of opioid toxicity?

Back 398

miosis, decreased respiration, and coma

Front 399

why must naloxene be monitored/readministered?

Back 399

shorter t1/2 than toxicant

Front 400

what is morphine metabolized to in the first pass?

Back 400

morphine-6-glucuronide and morphine-3-glucuronide, which are active metabolites, one excitotoxic, and one analgesic - these build up in blood over long term

Front 401

what induces morphine dependence?

Back 401

only withdrawal of drug

Front 402

what is the active analgesic when codeine is administered, and how is it metabolized to this?

Back 402

10% metabolized by CYP2D6 to morphine

Front 403

what should be used to treat severe pain with an inflammatory sourec?

Back 403

both an opioid and an anti-inflammatory

Front 404

what are three semi-synthetic modified versions of molecules found in the opium poppy, that are used as with codeine (3)?

Back 404

1) dihydrocodeine (in synalgos); 2) oxycodone (in percocet); 3) hydrocodone (in vicodin)

Front 405

what drugs are completely synthetic and structurally dissimilar than morphine that we must know, but have similar actions and side effects (3)?

Back 405

1) meperidine (demerol); 2) methadone; 3) fentanyl (and family)

Front 406

what is the DOC for outpatient anesthesia, and why?

Back 406

alfentanil - fentanyl family - repeated doses do not accumulate, and recovery is rapid

Front 407

which of these synthetics was said to have high abuse potential?

Back 407

meperidine (demerol) - as hard to kick as heroin -

Front 408

what is potency of meperidine like compared to morphine, and what is it used in?

Back 408

used in labor and delivery - 1/10 morphine's potency

Front 409

what AE's are reduced with meperidine compared to morphine?

Back 409

retains atropine-like functions - reduced biliary spasm and miosis

Front 410

what is the AE of meperidine we must know?

Back 410

CNS excitation/tremors/convulsions

Front 411

what is the potency of methadone compared to morphine, and how does it differ in pharmacokinetics?

Back 411

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

Front 412

what group of people is methadone used for?

Back 412

heroin addicts

Front 413

what is fentanyl like in potency and pharmacokinetics?

Back 413

100x as potent as morphine, short duration, lipophilic (lollipop preparations for addult breakthrough pain)

Front 414

in what situation is fentanyl (and family) used in anesthesia, besdies outpatient anesthesia, and for what reasons?

Back 414

used as IV analgesic in balanced anesthesia (especially cardiac surgery) because of improved cardiac stability (post-surgical reaction)

Front 415

what function does it lack when used in surgery, and what should be used concomitantly?

Back 415

lacks anesthetic activity - people open eyes, dilate pupils, move during surgery - should use concomitant muscle relaxers for truncal rigidity

Front 416

what opioid antagonists must we know, what is the duration of each, and which is available orally?

Back 416

naloxone and naltrexone, naloxone has 1-4 hour duration and is NOT available orally, naltrexone has 48-72 hour duration and is available orally

Front 417

what drug is used as an antitussive, why is it used, and what is it like chemically?

Back 417

dextromethorphan - D-isomer of codeine analog methorphan - no analgesic/addictive properties - D-isomer of codeine analog methorphan

Front 418

what is the MOA of dextromethorphan?

Back 418

acts via non-opioid receptors, centrally, to elevate coughing threshold - not reversed by naloxone

Front 419

what is the brand name for OTC dextromethorphan and how can it be abused?

Back 419

cough syrup - robitussin - "roboing" is when it antagonizes NMDA receptors at high doses, for hallucination

Front 420

what type of side effects are caused by increased dosage in long-term use of mixed agents?

Back 420

dysphoric side effects

Front 421

will addiction develop after long term use?

Back 421

no evidence of addiction per se developing, but physical dependence will

Front 422

what is the most likely cause of flushed feeling and itchiness when opioids are given?

Back 422

morphine triggers histamine release

Front 423

what can help itching and N/V from morphine?

Back 423

concomitant antihistamine

Front 424

in addition to normal pain medication, what should cancer patients always be given?

Back 424

a rapid onset drug for reakthrough pain

Front 425

when should opioids be used for chronic non-malignant pain?

Back 425

only after other analgesics have been tried and failed

Front 427

GLUCOCORTICOIDS

Front 429

how does cortisol increase fight or flight response (2)?

Back 429

1) increase epinephrine synthesis; 2) increase sensitivity of tissues to catecholamines

Front 430

what four problems will sustained increase in glucocorticoids cause?

Back 430

1) diabetes (from counter-regulation of glucose); 2) CV effects; 3) osteoporosis; 4) (increased bone resorption, decreased Ca++ absorption)

Front 431

what is a synthetic CRH, and what is it used for clinically?

Back 431

cosyntropin, a synthetic CRH, is used to diagnose Cushing's disease

Front 432

in what pattern is GC synthesis secreted?

Back 432

diurnal

Front 433

what enzymes mediate the direct genomic effects of GC action (3)?

Back 433

1) tyrosine aminotransferase (AA degradation); 2) phosphoenolpyruvate carboxykinase; 3) G-6-Phosphatase - last two involved in gluconeogenesis - dysregulation leads to diabetes

Front 434

how do indirect genomic effects work?

Back 434

GR binds to DNA binding proteins like NFkB and inhibits their ability to upregulate genes

Front 435

what type of genes are downregulated?

Back 435

those that stimulate inflammatory response - cytokines like IL-8, 12, and TNF-a

Front 436

what are indirect genomic effects initiated by, and what are they important for?

Back 436

interactions with membrane bound or cytoplasmic GRs, or interactions with cell membrane - important for eliciting changes in vascular tone

Front 437

what actions occur first, genomic or nongenomic?

Back 437

nongenomic - they occur very fast

Front 438

what is the treatment for glucocorticoids increasing bone loss through interference with Ca++ uptake and vitamin D actions, in adults?

Back 438

administration of oral bisphosphonate, Ca++, vitamin D

Front 439

what hormones do GCs inhibit production of, that relate to growth and development?

Back 439

sex steroids

Front 440

what do excessive amounts of GCs or MCs do to muscle/skeleton?

Back 440

can impair muscle, and cause skeletal wasting

Front 441

why can large GC doses lead to ulcers?

Back 441

suppress immune response against H. pylori

Front 442

what is normal treatment for glucocorticoid insufficiency?

Back 442

hydrocortisone

Front 443

what is added if it is Addison's (both inner and outer zone destroyed)?

Back 443

hydrocortisone + fludrocortisone

Front 444

what drugs (3) can pharmacologically reduce cortisol synthesis (3)?

Back 444

1) ketoconazole; 2) aminogluthemide; 3) metapyrone

Front 446

GLUCOCORTICOIDS AND INNATE IMMUNE RESPONSE

Front 448

how do glucocorticoids affect cell trafficking and adhesion molecules in innate immune response?

Back 448

alter bone marrow release and infiltration and clearance of leukocytes, decrease expression of adhesion molecules, decrease chemokine release at inflammation site

Front 449

in what disease do glucocorticoids prevent inflammatory response from overshooting?

Back 449

meningitis

Front 450

what cells do they promote survival and proliferation of, and what cells do they induce apoptosis of (innate IR)?

Back 450

promote survival of neutrophils, induce apoptosis of eosinophils

Front 451

in what case are glucocorticoids used to prevent inflammatory response from overshooting, and how does this work on phagocytes?

Back 451

enhance clearance of foreign antigens, toxins, microbes, enhance opsonization, stimulate macrophages to phagocytose

Front 452

how does this affect cytokines?

Back 452

increase antiinflammatory, decrease proinflammatory

Front 453

how do glucocorticoids affect biochemical mediators of inflammation?

Back 453

block release of arachadonic acid and thus formation of prostaglandins, thromboxanes, and leukotrienes, decrease NO release, decrease formation of free radicals

Front 455

ADAPTIVE/CELLULAR/HUMORAL IMMUNE RESPONSE

Front 457

formation of what particular cell is blocked that may lead to cellular immunodeficiency?

Back 457

Th1 helper T cell

Front 458

how are dendritic cells affected?

Back 458

can't present antigens as well or mature as well

Front 459

formation of what cell is increased by glucocorticoids, and what is the result?

Back 459

Th2 helper cell - stimulates humoral immune response and increased antibody formation

Front 460

what may be the underlying mechanism of steroid resistant asthma and ulcerative colitis?

Back 460

administration of GCs will increase IgE levels

Front 461

what do glucocorticoids do to B cells and why is this useful?

Back 461

inhibit proliferation and development, useful for leukemia

Front 462

how else do glucocorticoids relate to IgE secretion?

Back 462

prevent the release of IgE-R mediated release of inflammatory mediators, and also deplete tissue mucosal mast cells

Front 463

what AE can glucocorticoids cause in the eye?

Back 463

cataracts

Front 464

what is a recently developed drug in glucocorticoid therapy, how does it function, what is it used for, and what are its advantages?

Back 464

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

Front 466

GLUCOCORTICOID DRUGS AND TREATMENTS

Front 468

how is dose usually determined in glucocorticoid treatment?

Back 468

trial and error

Front 469

what can happen after abrupt cessation after long term use?

Back 469

adrenal insufficiency (may be fatal)

Front 470

what is alternate dose therapy and when is it used?

Back 470

GC may suppress allergic phenomena when given every 48 hours, whereas pituitary suppression is shorter lived

Front 471

what iGC is used for asthma and why?

Back 471

flucitasone, because it is highly metabolized

Front 472

what is an example of a GC given intravenously?

Back 472

hydrocortisone Na++ succinate

Front 473

what is a long acting type of GC?

Back 473

intraarticular injection of crystalline, insoluble GC

Front 474

what are the features of pulmonary and dermal administration both (2)?

Back 474

high potency, limited systemic effect

Front 475

what drug regimen with GCs is most effective for asthma?

Back 475

inhaled GC coadministered with inhaled beta-2 agonists

Front 476

what were said not to be considered significant risks for children (4)?

Back 476

decreased growth, decreased bone mineral density, suppressed adrenal glands, cataracts (but height of children should be monitored)

Front 477

what drugs must we know are sued for asthma (2)?

Back 477

1) beclomethasone; 2) flucitasone

Front 478

what drugs are used for allergic rhinitis (2), how are they given, and which has higher potency?

Back 478

given as nasal spray - 1) beclomethasone (high potency); 2) triamcinolone (medium potency)

Front 479

what are pros and cons of treating allergic rhinitis with GCs?

Back 479

broad relief of symptoms, low systemic absorption, but adverse effects

Front 480

what drugs are typically given topically for eczema and psoriasis (2)?

Back 480

1) hydrocortisone; 2) betamethasone

Front 481

what drug is given as an intralesional injection?

Back 481

triamcinolone acetonide

Front 482

what is done for acute eczematous reaction such as poison oak?

Back 482

systemic therapy with prednisone, tapered over 21 days

Front 483

what is the goal of GC therapy for MS?

Back 483

ameliorate suffering during attacks (6 weeks)

Front 484

what GC drugs are given for MS and how is each administered (2)?

Back 484

1) prednisone oral tapering course; 2) methylprednisone IV for 3-5 days

Front 485

what drugs are given for allograft rejection (2)?

Back 485

prednisone, methylprednisone

Front 486

what drug is typically given for rheumatic diseases, and what other drugs are used with it (non GC - 2)?

Back 486

prednisolone - also NSAID and disease modifying drug

Front 487

what happens to the GC, eventually, and over how long?

Back 487

weaning, over as much as two years

Front 488

what type of therapy is often given for RA with methylprednisone?

Back 488

pulse therapy IV ofer 3-7 days

Front 489

what GC drug is given as a joint injection for RA?

Back 489

triamcinolone acetonide

Front 490

what are GCs able to do for RA?

Back 490

decrease pain/disability/inflammation in first year but not sure about long term efficacy, does not alter structural damage

Front 491

what are side effects of treating RA with GCs (2)?

Back 491

1) osteoporosis; 2) ulcers

Front 492

in what case are GCs used in Crohn's disease, what drug is used, and why?

Back 492

in patients who do not respond to conservative management - oral budesonide is used because it is better tolerated and more effective than prednisolone

Front 493

what should be remembered about pharmacokinetics of oral budesonide?

Back 493

11% bioavailability because it dissolves in ileum and ascending colon due to pH

Front 494

what malignancy are GCs particularly used for (to induce apoptosis), and what GCs are used (3)?

Back 494

lymphoid malignancies, namely ALL - drugs used: 1) prednisone; 2) methylprednisone; 3) dexamethasone

Front 495

how else is it useful in cancer (2)?

Back 495

potentiates effeccts of other cytotoxic agents (prednisone/vincristine/doxorubicin/cyclophosphamide for non-Hodgkin's), also treats complications associated with cancer (cerebral edema, pain)

Front 496

what GC drug regimen is used in tuberculous meningitis?

Back 496

prednisone for first month

Front 497

what drug is a mineralocorticoid receptor antagonist, and what does it do?

Back 497

spironolactone - reduces the expression of gene controlling synthesis of Na/K ATPase

Front 498

what drug is an antagonist of glucocorticoid receptors, and what is it used for (2)?

Back 498

RU 486 (Mifepristone) - used in: 1) Cushing's; 2) abortion

Front 499

what drug inhibits the initial and rate-limiting step in the biosynthesis of all physiological steroids?

Back 499

aminogluthemide

Front 500

what is it used for (in conjunction with other drugs)?

Back 500

to treat steroid producing adrenocortical tumor

Front 501

what drug inhibits the terminal step in GC synthesis (11-B hydroxylase) and what is this drug used for?

Back 501

metyrapone - used in diagnostic test of adrenal function

Front 502

what drug can block all teroidogenesis and can be used for hirsutism, adrenal carcinomas, and breast cancer?

Back 502

ketoconazole

Front 503

in what diseases is glucocorticoid resistance the most problematic (2)?

Back 503

asthma, ALL (5% of patients have no response to 7 day therapy with prednisone)

Front 504

what are three new therapeutic develpments with GCs?

Back 504

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)

Front 506

MINERALOCORTICOIDS

Front 508

what genes are directly regulated by aldosterone (2)?

Back 508

1) CHIF - challen inducing factor; 2) epithelial sodium channel subunits

Front 509

what were said to directly regulate the Na/K ATPase genes?

Back 509

glucocorticoids such as dexamethasone

Front 510

how strongly does aldosterone activate the MR compared to cortisol?

Back 510

equal affinity

Front 511

how do MR and GR compare as far as their ability to activate gene transcription via hormone response element?

Back 511

stimulate it equvalently

Front 512

how is specificity gained?

Back 512

by location of MR and GR

Front 513

where is the GR located, and where is the MR (5)?

Back 513

GR - all cells; MR - kidney, gut, sweat glands, brain, and vascular smooth muscle

Front 514

how else do they differ?

Back 514

differential transcriptional activation

Front 515

what key enzyme is expressed only in some mineralocorticoid responsive tissues?

Back 515

11B-hydroxysteroid dehydrogenase type 2 (11B-HSD)

Front 516

what are the two main strategies for treating mineralocorticoid excess, and what drug(s) is used for each?

Back 516

1) antagonize mineralocorticoid receptor (spironolactone); 2) antagonize Na+ exchange in distal nephrone (amiloride, triamterene)

Front 517

what happens when there is high concentrations of spironolactone?

Back 517

inhibits androgen receptor

Front 518

what other problems may spironolactone cuase (2)?

Back 518

1) hyperchloremic acidosis; 2) hypokalemia

Front 519

how is mineralocorticoid deficiency treated, and what is the affinity of this drug for MR and GR?

Back 519

flucortisone - 10x affinity for MR compared to GR

Front 520

what are side effects of flucortisone, and what should be monitored?

Back 520

hypertension, hypokalemia - monitor BP and renin activity

Front 521

what is the treatment for CAH (21-hydroxylase or 17-hydroxyprogesterone deficiency) (2)?

Back 521

1) fludrocortisone; 2) hydrocortisone (GC)

Front 522

what is the treatment for primary aldosteronism?

Back 522

unilateral adrenalectomy

Front 523

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)?

Back 523

sodium supplementation

Front 524

what is the treatment for apparent mineralocorticoid excess (3)?

Back 524

1) amiloride and/or spironolactone; 2) antihypertensive; 3) KCl supplements

Front 525

what mutation can cause pregnancy induced hypertension, and why?

Back 525

missense mutation (L810) in ligand binding domain of MR allows a number of steroids to act as MR agonists

Front 526

what else can act as an agonist, and what does it cause?

Back 526

spironolactone can act as an agonist, and allow constitutive activity of MR

Front 527

what MR antagonist is more preferred than spironolactone, and why?

Back 527

eplenerone - it is more selective (but has lower affinity for MR)

Front 528

what are the three high potency GC agonists?

Back 528

1) beclomethasone; 2) betamethasone; 3) dexamethasone

Front 529

what are the three mid potency GC agonists?

Back 529

1) methylprednisone; 2) prednisolone; 3) prednisone

Front 530

what are three inhibitors of cortisol synthesis?

Back 530

1) metyrapone; 2) ketoconazole; 3) aminoglutethimide

Front 531

what MR agonist must we know?

Back 531

fludrocortisone

Front 532

what MR antagonists must we know (2)?

Back 532

1) spironolactone; 2) eplenerone

Front 534

ANDROGENS

Front 536

what cells do FSH, and LH, respectively, stimulate in the testis?

Back 536

FSH --> sertoli cells; LH --> leydig cells

Front 537

what cells release testosterone in the testes?

Back 537

leydig cells

Front 538

what genetic element initiates sexual differentiation in males?

Back 538

TDF on Y chromosome

Front 539

what if there is no TDF?

Back 539

baby will be female (have ovaries)

Front 540

in early fetal development, what is necessary for internal male genitalia to form, and where does it come from?

Back 540

mullerian inhibiting hormone - comes from sertoli cells

Front 541

what if there is no mullerian inhibiting hormone?

Back 541

female internal genitalia

Front 542

what is necessary for external male genitalia?

Back 542

DHT

Front 543

what is necessary for external female genitalia?

Back 543

lack of testosterone

Front 544

what needs to happen for there to be DHT?

Back 544

conversion of testosterone to DHT by 5-alpha-reductase

Front 545

where is type 1, and type 2 5-alpha-reductase found?

Back 545

type 1 - liver and skin; type 2 - urogenital tract and liver

Front 546

what can deficiencies of type 2 5-alpha-reductase result in?

Back 546

ambiguous gender idnetification at birth, usually female

Front 547

what can be done about this?

Back 547

dramatic reversal at puberty, as testosterone is converted by type 1 5-alpha-reductase, resulting in male gender assignment

Front 548

hyperplasia/carcinoma of the prostate is treated by inhibiting what androgen(s)?

Back 548

DHT

Front 549

acne is treated by inhibiting what androgen(s)?

Back 549

T

Front 550

male pattern baldness is treated by inhibiting what androgen(s)?

Back 550

T, DHT

Front 551

precocious puberty in boys is treated by inhibiting what androgen(s)?

Back 551

T

Front 552

sex drive in sex offenders is treated by inhibiting what androgen(s)?

Back 552

T

Front 553

what is the Kd for the androgen receptor with DHT compared to T?

Back 553

DHT 1000> T

Front 554

what feature of AR gene increases sensitivity to androgens?

Back 554

lesser amount of glutamine repeats (12-32 normal - if over 40, spinal/bulbar muscular atrophy)

Front 555

what are the indications for giving testosterone (2) and how is it given?

Back 555

given as skin cream for: 1) congenital or acquired hypogonadalism in men; 2) breast carcinoma in posmenopausal women

Front 556

what drug must we know that is used for prostate cancer, precocious puberty, uterine leiomyoma, and endometriosis?

Back 556

leuprolide

Front 557

what type of drug is it, and what is its MOA?

Back 557

GnRH agonist - continued exposure disrupts pulsatility of gonadotrophs, inhibiting FSH and LH secretion

Front 558

what are its adverse effects (4)?

Back 558

1) short term rise in serum testosterone; 2) decreased libido; 3) negative effects on mood; 4) osteoporosis

Front 559

what is a non-FDA approved use for ketoconazole?

Back 559

prostate cancer

Front 560

what are its adverse effects (4)?

Back 560

1) short term rise in serum testosterone; 2) decreased libido; 3) negative effects on mood; 4) osteoporosis - same as leuprolide

Front 561

what drug is used for metastatic prostate cancer and BPH, and what type of drug is it?

Back 561

flutamide - nonsteroidal anti-androgen - directly blocks androgen receptor

Front 562

what are its adverse effects (4)?

Back 562

1) short term rise in serum testosterone; 2) decreased libido; 3) negative effects on mood; 4) osteoporosis - same as leuprolide

Front 563

what is flutamide most effective in combination with?

Back 563

leuprolide

Front 564

what drug is used for prostate cancer, BPH, and alopecia, and what is its class/MOA?

Back 564

finasteride - 4-aza analog of T that acts as competitive, specific inhibitor of type II 5-alpha-reductase

Front 565

what does finasteride block, and not block?

Back 565

blocks actions of DHT but not T in prostate, seminal vesicles, hair follicles, epididymis

Front 566

what are the adverse effects of finasteride like?

Back 566

generally better tolerated than flutamide

Front 567

what is a non-FDA approved use of testosterone?

Back 567

to improve libido in both women and men

Front 569

GOUT

Front 571

what decreases local pH in gouty attacks, and what leads to that?

Back 571

increased lactate production, from inflammatory response

Front 572

what exacerbates inflammatory response?

Back 572

increased synovial phagocytosis of crystallized uric acid

Front 573

why is there more crystallized uric acid?

Back 573

drop in local pH (all of these create a vicious cycle)

Front 574

what are treatment goals of gout (3)?

Back 574

1) relieving gouty attacks; 2) preventing recurring gouty episodes; 3) preventing urate lythiasis

Front 575

what drug is a diagnostic indicator of gout, and what type of drug is it?

Back 575

colchicine - a plant alkaloid - diagnostic because it is only effective against gout - dramatically relieves pain and inflammation of gouty arthritis in 12-24 hours

Front 576

what is the MOA of colchicine?

Back 576

inhibits tubulin polymerization, leading to inhibition of leukocyte and phagocyte migration and phagocytosis of crystals in joints

Front 577

why are NSAIDS often used?

Back 577

decreased side effects

Front 578

what is colchicine indicated for?

Back 578

prophylaxis of recurrent episodes of gouty arthritis

Front 579

what are adverse effects of colchicine?

Back 579

diarrhea, N/V, abdominal pain, hair loss, bone marrow suppression, peripheral neuritis, myopathy

Front 580

what is the normal dosing of colchicine for an acute attack, and what should be avoided?

Back 580

2mg is given as a single dose IV - not to exceed 4 mg, not to be repeated within 7 days

Front 581

how much is lethal?

Back 581

8mg/24 hours

Front 582

what NSAID is used in gout, and how does it help besides being anti-inflammatory?

Back 582

indomethacin - inhibits urate crystal phagocytosis

Front 583

what NSAID is better than others at lowering serum uric acid, and what is the problem?

Back 583

oxaprozin may be better at this, but its use, like other uricosuric agents, is not recommendeed in patients with uric acid stones

Front 584

what drug is effective for treatment of primary uricemia caused by antineoplastic therapy, and what is its MOA?

Back 584

allopurinol - competitive inhibitor of xanthine oxidase - inhibits urate synthesis

Front 585

what is the main use of allopurinol?

Back 585

effective for treatment of primary hyperuricemia and that secondary to antineoplastic therapy

Front 586

what are other indications for allopurinol?

Back 586

reserved for more severe forms of gout - high urinary urate (600-700), gouty nephropathy, recurrent renal sotnes, elevated serum urate

Front 587

allopurinol is used in situations when what two drugs are contraindiicated?

Back 587

sulfinpyrazone, probenecid

Front 588

why is probenecid contraindicated with allopurinol?

Back 588

allopurinol increases the half life of probenecid, which itself increases clearance of oxypurinol (an active allopurinol metabolite)

Front 589

what problem may allopurinol induce in the short term, and how?

Back 589

gouty arthritis - as serum levels of uric acid fall, crystal previously phagocytosed by synovocytes will be released, initiating gouty attack

Front 590

what may be required during initial treatment?

Back 590

coadministration of colchicine, sulfinpyrazone, or probenecid

Front 591

what are other adverse effects of allopurinol (5)?

Back 591

1) depression of bone marrow; 2) hepatic toxicity; 3) interstitial nephritis; 4) allergic skin reactions; 5) cataracts

Front 592

what is the name of agents used to increase the rate of uric acid excretion, and what two must we know?

Back 592

uricosuric agents - used to increase rate of uric acid secretion - 1) probenecid; 2) sulfapyrazone

Front 593

what treatment course does probenecid have?

Back 593

should begin with goal of lifelong treatment (like allopurinol)

Front 594

what is probenecid mainly used for?

Back 594

to decrease the bodies pool of urate in patients with increasingly frequent gouty attacks

Front 595

what is probenecid not effective in doing?

Back 595

relieving acute gouty attack (may exacerbate)

Front 596

what is the MOA of probenecid and where does it act?

Back 596

potent inhibitor of uric acid reabsorption at renal tubules

Front 597

what drugs inhibit the actions of probenecid and sylfinpyrazone?

Back 597

salicylates

Front 598

what happens when probenecid and sulfinpyrazone are used together?

Back 598

their effects are additive

Front 599

what AE is associated with probenecid, and who should it not be used in?

Back 599

uric acid stones - avoid in patients with nephrolithiasis, and with caution in patients with high serum urate levels

Front 600

what is the primary complication of probenecid?

Back 600

precipitation of acute gouty attack

Front 601

what is the toxicity of sulfinpyrazone?

Back 601

gastric distress/peptic ulcers

Front 602

what drug interaction was mentioned for sulfinpyrazone?

Back 602

can increase hepatic toxicity of acetaminophen

Front 603

what are the primary agents for managing acute gouty attacks?

Back 603

NSAIDs, colchicine, and other anti-inflammatory agents (allopurinol and uricosuric agents do not alter course, and actually increase gouty attacks)

Front 604

what drug is used to reduce frequency of gouty attack during early chronic treatment?

Back 604

colchicine

Front 605

what NSAIDS are DOC for acute gouty attacks (2)?

Back 605

indomethacin, naproxen

Front 606

how do salicylates affect gout?

Back 606

they elevate serum urate concentration and antagonize probenecid and sulfinpyrazone

Front 607

what things minimize intrarenal deposition of uric acid (2), why, and when is this essential?

Back 607

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

Front 608

what are the adverse effects of allopurinol in the chart (4)?

Back 608

1) skin rash; 2) N/V; 3) kidney abnormalities; 4) diarrhea

Front 609

what are the main adverse effects of colchicine (2)?

Back 609

1) GI distress; 2) bone marrow depression

Front 610

what are the side effects/toxicity of probenecid?

Back 610

1) increase risk of stones; 2) may cause attacks during early treatment

Front 611

what are often the first line drugs in gout, and what are they used in conjunction with?

Back 611

NSAIDS - used in conjunction with uricosurics

Front 613

MIGRAINE

Front 615

what types of headache (migraine, tension, and sinus) are aggravated by activity?

Back 615

migraine, sinus

Front 616

what is migraine duration and tension duration?

Back 616

3hr-3days for migraine, up to 7 days for rebounders with tension

Front 617

what non-drug treatment often alleviates migraine?

Back 617

sleep

Front 618

how many attacks are needed to diagnose migraine?

Back 618

5 without aura or 2 with aura

Front 619

2 of what 4 features are needed to diagnose migraine?

Back 619

1) unilateral; 2) pulsating; 3) moderate to severe pain; 4) aggravated by physical activity

Front 620

at least 1 of what 4 additional features is needed?

Back 620

1) nausea; 2) vomiting; 3) photophobia; 4) phonophobia

Front 621

what three simple questions, if two are right, have 93% diagnostic accuracy for migraine?

Back 621

1) do headaches limit daily activit/cause disabilities?; 2) do you have N/V with headahce?; 3) does light bother you during headache?

Front 622

what are the three hypothesis for migraine pathophysiology?

Back 622

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)

Front 623

what are the two major drug classes we must know to treat moderate to severe acute migraine?

Back 623

1) triptans; 2) ergot derivatives

Front 624

what drug classes are used to treat mild to moderate acute migraine (3)?

Back 624

1) NSAIDS; 2) barbiturates; 3) analgesics (aspirin/acetaminophen)

Front 625

what other drug classes are used for acute rescue treatment (2)?

Back 625

1) antiemetics; 2) opioids

Front 626

what is the MOA of triptans?

Back 626

similar to serotonin, they are selective agonists of 5HT(1B/D) receptor, and vasoconstrictors - they presynaptically inhibit trigeminal nerve activity

Front 627

what AE must we know for triptans?

Back 627

chest pressure/tightness (3-5 in trial, 26% retrospectively)

Front 628

what are strong, and weak (2), contraindications to triptans?

Back 628

strong - chest pressure/tightness; weak - MAOI, SSRI interactoins

Front 629

what is the prototype triptan?

Back 629

sumatriptan

Front 630

what triptan has a long half life (26 hours, while others are 2-6)?

Back 630

frovatriptan

Front 631

what is the mechanism of ergot derivatives?

Back 631

non-selective 5HT agonists/p-agonists/antagonists, also agonize the dopaminergic system

Front 632

what is the ergot prototype, and what other one must we know?

Back 632

prototype - dihydroergotamine mesylate; also must know ergotamine

Front 633

what should we know about pharmacokinetics of dihydroergotamine mesylate?

Back 633

poorly/erratically absorbed in different people at different times

Front 634

what is the single most important contraindication for dihydroergotamine mesylate?

Back 634

potent abortifacient

Front 635

what are the other side effects of dihydroergotamine mesylate (4)?

Back 635

1) cramps; 2) parasthesias; 3) edema; 4) peripheral ischemia

Front 636

why can it cause peripheral ischemia?

Back 636

causes acute vasospasm

Front 637

what causes rebound headache?

Back 637

overuse of medication, especially combination drugs (acetaminophen/aspirin/caffeine/butalbital combinations)

Front 638

what adverse effect can occur with SSRIs when mixed with triptans or MAOIs, and what must we know happens?

Back 638

serotonin syndrome - shivering occurs - should discontinue offending agents

Front 639

when is rescue strategy used for migraine, alone?

Back 639

<2 headaches/week

Front 640

what parenteral drugs can be used in rescue strategy?

Back 640

parenteral: sumatriptan, dihydroergotamine, prochlorperazine, chlorpromazine, morphine, metaclopramide, rescue opioids

Front 641

when should prophylactic therapy be considered?

Back 641

>1 headache/week

Front 642

what are the adverse effects of beta blockers (3) and who are they contraindicated in (3)?

Back 642

fatigue, orthostatic hypotension, impotence are adverse effects - contraindicaed in diabetics, asthmatics, and patients with AV block

Front 643

what tricyclic antidepressant is used for migraine, and what are two contraindications?

Back 643

amitriptyline - contraindicated in bipolar, and within 2 weeks of MAOI therapy

Front 644

what are adverse effects of amatriptyline?

Back 644

can build dependence, should be withdrawn slowly, anti-muscarinic effects (dry mouth, constipation, dizziness, fuzzy thinking)

Front 645

what antiepileptic drugs are used for migraine prophylaxis (2)?

Back 645

1) valproic acid (depakote); 2) topiramate (topamax)

Front 646

what adverse reactions occur with valproic acid (2)?

Back 646

1) nausea/vomiting/diarrhea; 2) fatal hepatic dysfunction in babies

Front 647

what is the mechanism of topiramate (topamax)?

Back 647

unique antagonism of glutamate (kainate) receptors, allosteric enhancement of GABA channel, state-dependent Na+ channel block

Front 648

what are lifestyle changes to stop migraine?

Back 648

avoid triggers, establish regular sleeping hours, eat healthy foods, exercise, avoid analgesics (use only for rescue), use acute treatments less than 2x/week

Front 649

what therapeutic strategy should be used with acute therapy?

Back 649

high dose range - dose back if side effects not tolerated - try three triptans before others

Front 650

what should be used for nausea?

Back 650

non-oral anti-emetic

Front 651

what is the dosing strategy for prophylactic therapy (TCA, AED, beta blocker)?

Back 651

start low, go slow

Front 653

PITUITARY HORMONES

Front 655

what is the only non-peptide factor released by the hypothalamus?

Back 655

dopamine

Front 656

what is its function?

Back 656

inhibiting prolactn release

Front 657

what type of growth does GH promote?

Back 657

linear

Front 658

what does secretion of GH induce release of, and what do these affect?

Back 658

induces release of somatomedins (insulin-like growth factors) which affect carbohydrate and lipid metabolism

Front 659

how does GH receptor work?

Back 659

GH binds to it, and it dimerizes, which activates a cascade producing IGF-1

Front 660

what happens if there is GH receptor defect?

Back 660

Laron syndrome

Front 661

what causes "dwarfism", and what is the treatment (2)?

Back 661

GH deficiency in children (hyposecretion), usually hypothalamic - treated by somatotropin or sermorelin

Front 662

what are somatotropin and sermorelin?

Back 662

somatotropin - recombinant human growth hormone; sermorelin - synthetic GHRH

Front 663

which treatment is more effective?

Back 663

somatotropin is more effective

Front 664

what other GH can be used, and what is it?

Back 664

somatrem - a derivative of GH that has an additional methionine

Front 665

what are the side effects of hormone replacements, sermorelin/somatotropin?

Back 665

headache, vomiting, intracranial hypertension, scoliosis, arthralgia, myalgia, edema, carpal tunnel syndrome

Front 666

what are the symptoms of GH deficiency in adults?

Back 666

changes in fat distribution, decreased muscle mass and exercise capacity, impaired psychosocial function

Front 667

what is the treatment for adult GH deficiency?

Back 667

somatotropin - cannot use sermorelin

Front 668

what is the treatment for Laron syndrome?

Back 668

IGF-1

Front 669

how is GH deficiency diagnosed?

Back 669

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

Front 670

how do you check where the defect is in adult GH deficiency?

Back 670

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

Front 671

what drugs are used to treat GH excess syndromes (2), and what type of drug is each?

Back 671

1) octreotide - a synthetic somatostatin analog (with a long half life); 2) pegvisomant - a GH antagonist

Front 672

how does octreotide work and what are the effects?

Back 672

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

Front 673

how does pegvisomant work and what is its advantage?

Back 673

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

Front 674

what else should we remember about its effect on hormone levels and tumors (2)?

Back 674

does not decrease tumor size, inreases GH levels

Front 675

what are the side effects of pegvisomant?

Back 675

abnormal/reversible liver function

Front 676

what are anabolic steroids?

Back 676

chemically modified analogs of testosterone

Front 677

what is the effect of hGH, if used on athletes?

Back 677

increases body mass, but has not been shown to increase strength or performance

Front 678

what are other uses of GH (4)?

Back 678

1) Turner's (short stature); 2) AIDS-associated wasting; 3) maladsorption associated with short bowel syndrome; 4) intrauterine growth retardation

Front 679

how are prolactin levels controlled?

Back 679

by TRH and dopamine - no feedback control

Front 680

what can cause hyperprolactinemia (3)?

Back 680

1) pituitary or hypothalamic excess; 2) renal failure; 3) chest trauma

Front 681

what are the symptoms in non-pregnant women (3)?

Back 681

infertility, amennorrhea, milk secretion

Front 682

what are the symptoms in men (4)?

Back 682

infertility, loss of libido, impotence, breast enlargement

Front 683

besides surgery and radiation, what type of drug is used to treat hyperprolactinemia, and what are two examples?

Back 683

dopamine receptor agonists (bromocriptine, pergolide)

Front 684

what are the effects of these drugs?

Back 684

decrease PRL levels and induce tumor regression - tumors recur following cessation of treatment

Front 685

what are the side effects of bromocriptine and pergolide?

Back 685

N/V, insomnia

Front 686

what is the function of FSH in men, and in women?

Back 686

stimulates spermatogenesis in men, stimulates follicle development in women

Front 687

what is the function of LH in men, and in women?

Back 687

increases testosterone secretion in men, causes maturation of follicle to corpus luteum in women, and is required for rupture of follicle/ovulation

Front 688

what is CG, and what is its function?

Back 688

chorionic gonadotropin - released from placenta - acts like LH during pregnancy to sustain corpus luteum

Front 689

what hormones control gonadotropin secretion (2), and how?

Back 689

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

Front 690

what is it called when there is a hypothalamic/pituitary defect that causes decreased gonadotropin production?

Back 690

hypogonadotropic hypogonadism

Front 691

what happens due to lack of FSH in women (3)?

Back 691

amenorrhea, infertility, absent breast development

Front 692

what happens due to lack of FSH in men (2)?

Back 692

decreased testis size, oligospermia

Front 693

what happens due to lack of LH in women (3)?

Back 693

amenorrhea, infertility, cystic ovaries

Front 694

what happens due to lack of LH in men (3)?

Back 694

infertility, lack of spontaneous puberty

Front 695

what is used to treat lack of LH?

Back 695

chorionic gonadotropin - mimics LH

Front 696

what is used to treat lack of both FSH and LH, and what are they?

Back 696

menotropins - from urine of postmenopausal women

Front 697

what things can be used to treat lack of FSH (2)?

Back 697

1) recombinant FSH; 2) urofollitropin (purified FSH)

Front 698

what are side effects of these treatments (2)?

Back 698

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)

Front 699

who gets increased gonadotropin production, what is the cause, and what are the symptoms (2)?

Back 699

primarily males, with constitutively active mutation of LH receptor, with testicular tumors and precocious puberty

Front 700

what is the treatment?

Back 700

inhibitors of steroid synthesis

Front 701

what are other uses of gonadotropins (2) and which hormones are used for each?

Back 701

1) cryptorchidism (failure of testes descent) - CG; 2) IVF - FSH, CG

Front 702

what si the treatment for hypogonadism, and what is this drug?

Back 702

gonadorelin acetate - synthetic GNRH

Front 703

what receptors does ADH bind to and what is the function of each?

Back 703

V1 - mediates contraction of smooth muscle; V2 - mediates renal conservation of water

Front 704

what is the treatment for diabetes insipidus and how is it given?

Back 704

desmopressin (vasopressin analog) by oral or nasal spray

Front 705

what are the adverse effects of desmopressin, from the V1 and V2 receptor?

Back 705

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

Front 706

what are the contraindications for desmopressin (2)?

Back 706

1) CAD (causes coronary insufficiency; 2) patients with renal failure

Front 707

what disease is caused by a defective response to ADH (can be familial mutation in ADH V2 receptor, aquaporin mutation, or caused by drugs)?

Back 707

nephrogenic diabetes insipidus

Front 708

what drugs can cause NDI (2)?

Back 708

1) foscarnet; 2) lithium

Front 709

what is the treatment, and why?

Back 709

thiazide diuretics, because desmopressin has no effect (receptors insensitive)

Front 710

why would thiazide diuretics be used for a disease with increased urinary output?

Back 710

they reduce urine output by a paradoxical, uknown mechanism

Front 711

what is SIADH and what can cause it?

Back 711

syndrome of inappropriate ADH secretion - caused by cerebellar disease, pulmonary disease, malignancy, head trauma, drugs (vincristine, vinblastine, haloperadol, clonidine)

Front 712

what is the treatment, besides saline/fluid restriction, for SIADH, where ios this drug active, and what does this drug do?

Back 712

demeclocycline - inhibits the response to ADH in the collecting duct

Front 713

what drug must we know stimulates response to ADH?

Back 713

NSAIDs

Front 714

what is the MOA of modification of ADH response by drugs?

Back 714

direct effects on CNS structures that regulate ADH secretion

Front 715

what is the drug form of oxytocin, and what is it used for (2)?

Back 715

pitocin - used to: 1) induce labor; 2) induce lactation (nasal spray)

Front 716

what are the adverse effects of pitocin?

Back 716

excessive uterine contractions, uterine rupture, fetal hypoxia, high doses cause vasodilation, hypotension, tachycardia

Front 717

what drug is used to suppress preterm labor, and what is it?

Back 717

atosiban - oxytocin antagonist

Front 719

THYROID HORMONES

Front 721

what is the name of T3 and T4?

Back 721

triiodothyronine (T3) and thyroxine (T4)

Front 722

what is thyroid colloid made of?

Back 722

the protein thyroglobulin

Front 723

how does iodide get transported into the thyroid?

Back 723

active transport, membrane bound protein = sudoium-iodide symporter

Front 724

what drugs inhibit transport of iodide (2), and in what way?

Back 724

the anions thiocyanate and perchlorate inhibit transport of iodide competitively

Front 725

what else inhibits iodine transport?

Back 725

high concentration of serum iodide

Front 726

what increases iodine transport (2)?

Back 726

1) TSH; 2) decreased stores

Front 727

how is iodide synthesized, and what enzyme is involved?

Back 727

oxidized, then tyrosyl residues are iodinated, and then coupled - this is catalyzed by thyroid peroxidase

Front 728

how are thyroid hormones released?

Back 728

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

Front 729

what is propylthiouracil, and how does it work?

Back 729

it is an anti-thyroid drug which inhibits 5' deiodinases, which convert T4 to more potent T3 in peripheral tissues

Front 730

what is a transport protein that binds T4 only?

Back 730

transthyretin - thyroxine binding prealbumin

Front 731

what drugs increase binding of thyroid hormones to plasma proteins (3)?

Back 731

estrogens, tamoxifen, 5-FU

Front 732

what drugs decrease binding of thryroid hormones to plasma proteins (4)?

Back 732

glucocorticoids, salicylates, androgens, anti-seizure medications

Front 733

what was said about the effect of T4 on transcription?

Back 733

has no effect on transcription and thus may only act as a prohormone

Front 734

what synthetic thyroid hormones are used to treat thyroid deficiency, and what is a mixture fo the two called?

Back 734

1) thyroxine (levothyroxine sodium - Synthroid - prolonged duration); 2) T3 - liothyronine sodium; mixture of the two is called liotrix

Front 735

when is T3 used?

Back 735

when a quick onset is needed (used occasionally)

Front 736

in what patients should lower doses be used, and why?

Back 736

lower doses should be used in the elderly because they are more susceptible to cardiotoxicity

Front 737

what are three classes of antithyroid drugs?

Back 737

1) thyioureylenes; 2) ions (not used); 3) aniline derivatives (PAS/sulfonamides - not used)

Front 738

what are the thiourylenes (2)?

Back 738

propylthiouracil, methimazole

Front 739

what is the MOA of these drugs?

Back 739

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

Front 740

which one of these drugs has an additional effect, and what is it?

Back 740

propylthiouracil also inhibits T4 --> T3 conversion by inhibiting the D1 5' deiodinase

Front 741

what are the side effects of thioureylenes (propylthiouracil, methimazole) (4)?

Back 741

1) agranulocytosis; 2) bone marrow suppression; 3) rash; 4) liver damage

Front 742

when are anti-thyroid drugs generally used, and with what?

Back 742

used in conjunction with 131-iodine to hasten recovery while awaiting radiation effects, and also to control the disorder prior to surgical thyroid

Front 743

what anions diminish iodide accumulation and thyroid function?

Back 743

tiocyanate, nitrate, perchlorate - not currently used due to toxicity (fatal aplastic anemia)

Front 744

how else can people get thiocyanate in their bodies?

Back 744

cigarette smoke cabbage

Front 745

what drug is used to treat symptoms of hyperthyroidism?

Back 745

propranolol

Front 746

what other drug is used to inhibit iodine transport and inhibit synthesis of thyroid hormones?

Back 746

KI (potassium iodide)

Front 747

when is this useful, and why?

Back 747

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

Front 748

what are severe side effects of iodide?

Back 748

bswelling of larynx, suffering, pulmonary edema

Front 749

what are other side effects of iodide?

Back 749

burning of mouth, throat, headache, cough, gastric irritation, cutaneous hemorrhage, enlargement of lymph nodes

Front 750

what happens to the beneficial effects of iodide over time?

Back 750

they disappear

Front 751

what substance can be helpful in evaluating thyroid nodules?

Back 751

radioactive iodine uptake/scan, which measures utilization - hot nodules are hypermetabolic, and cold nodules are hypometabolic (may indicate carcinoma)

Front 752

how are benign thyroid nodules treated, if TSH levels are normal (and what is the rationale)?

Back 752

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

Front 753

when is liotrix, the T4/T3 mixture used?

Back 753

when patients remain symptomatic on synthroid

Front 754

what drug is used for myxedema coma?

Back 754

liothyronine sodium - fast working ,higher cost

Front 755

what is the DOC for thyroid hormone replacement?

Back 755

levothyroxine sodium

Front 757

ANTIHISTAMINES

Front 759

what cofactor does the enzyme histidine decarboxylase require to function, and what is it derived from?

Back 759

PLP - a derivative of vitamin B6

Front 760

where is the H1 receptor found, and what is H1 signaling mediated by?

Back 760

nonvascular smooth muscle, including intestine and bronchi, brain, and vascular endothelial cells - H1 signaling is mediated by IP3/DAG3 and cAMP

Front 761

what does activation of H1 receptor cause?

Back 761

increased vascular permeability, vasodilation, and constriction of non-vascular smooth muscle

Front 762

where are H2 receptors found, and what is their action mediated by?

Back 762

found in gastric parietal cells, vascular smooth muscle cells, cardiac myocytes, and in the CNS - action is mediated by cAMP at target cells

Front 763

where are H3 receptors found, and what do H3 agonists cause?

Back 763

found in CNS, H3 agonists promote sleep

Front 764

what is the H4 receptor's function, and where are they expressed?

Back 764

like H3 receptors, but expressed on immune cells like eosinophils and neutrophils, where they regulate recruitment

Front 765

what may the new H4-specific antagonist (JNJ77771208400483314) have potential in doing?

Back 765

treating allergic and immune responses

Front 766

what are the two main cardiovascular effects, and which histamine receptor is responsible for each?

Back 766

1) vasodilation of terminal arterioles, capillaries, and postcapillary venules (H1); 2) hypotension (H2) - although hsitamine constricts larger vessels and can cause hypertension

Front 767

what do other actions on terminal vessels lead to?

Back 767

widening of endothelial gaps

Front 768

what are the respiratory effects and what histamine receptor is responsible?

Back 768

H1 - mediates bronchoconstriction

Front 769

what are the GI effects of histamine (2) and what receptor is involved with each?

Back 769

H1 - mediates intestinal smooth muscle contraction; H2 - promotes gastric secretion

Front 770

what does histamine do in the CNS (2), and what receptosr are respnsible?

Back 770

increases wakefulness and inhibits appetite through H1 receptor

Front 771

what are symptoms of histamine release?

Back 771

hyptension, flushing, headache, difficulty breathing, nausea, vomiting, diarrhea visual disturbances - massive doses can lead to shock, circulatory collapse, and death

Front 772

how do all antihistamines discussed in this lecture function?

Back 772

reversible, competitive inhibitors of the H1 receptor

Front 773

how are these drugs metabolized?

Back 773

P450 in the liver

Front 774

what do these H1 antagonists normally have a strong effect on, and weak effect on?

Back 774

strong effect on capillary permeability, but little effect on bronchoconstriction and hypotension

Front 775

what is the prototype first generation histamine, and what does it do, and not do?

Back 775

diphenhydramine (benadryl) is the prototype, and it is a competitive H1R antagonist but not an inhibitor of histamine release

Front 776

what is its adverse effect, and why does it have this effect?

Back 776

1) sedation via CNS depression; 2) antimuscarinic properties (dry mouth, tachycardia, blurred vision, constipation [GI effects minimal]) - crosses the BBB

Front 777

when is it best to administer diphenhydramine?

Back 777

prior to histamine release

Front 778

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?

Back 778

promethazine

Front 779

what is the main side effect of promethazine?

Back 779

sedative (also has antiemetic and central anticholinergic effects)

Front 780

what H1 antagonist is not like the others, and why is it different?

Back 780

doxepin is different, because it is used primarily as an antidepressant - it is much better tolerated by depressed patients

Front 781

what are the side effects of doxepin?

Back 781

drowsiness and anticholinergic effects

Front 782

what second generation H1 blockers were said to have the longest half lives (2)?

Back 782

loratidine (claritin) - >24 hours, cetirizine (zyrtec) 12-24 hours

Front 783

what other second generation H1 blocker must we know?

Back 783

fexofenadine (allegra) -duration 1-12 hours

Front 784

which 2nd generation H1 antagonist was said to have poor penetration of the BBB, and what are its side effects?

Back 784

cetirizine (zyrtec) - but it is still more prone to cause drowsiness than other second generation antihistamines

Front 785

what else should we know about loratidine?

Back 785

desloratidine (clarinex) is the active metabolite, and has same activity, duration of action, and lack of side effects

Front 786

how are first generation antihistamines metabolized and excreted?

Back 786

metabolized in liver, excreted in urine in a modified form

Front 787

how are second generation antihistamines metabolized and excreted?

Back 787

mexcreted in liver in unmetabolized form

Front 788

what is the implication of generation two antihistamines metabolism?

Back 788

there should not be P450 interactions

Front 789

what are drug interactions with antihistamines?

Back 789

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)

Front 790

what H1 blocker is effective in treating motion sickness, N/V, and as an adjuvant to Parkinson's disease and why?

Back 790

promethazine, because of antimuscarinic properties (but better drugs are available for Parkinson's than G1 H1 antagonists)

Front 791

how effective are H1 antagonists in treating anaphylaxis?

Back 791

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

Front 792

what else were first-generation antihistamines said not to be useful for?

Back 792

asthma

Front 793

how useful are antihistamines in treating colds/flu?

Back 793

not useful - may do more harm than good

Front 794

who is benadryl (diphenhydramine) contraindicated in?

Back 794

nursing mothers, neonates, and premature infants

Front 795

what are side effects of promethazine, and how does it compare in action to 2nd generation drugs?

Back 795

causes BP effects, skin rash, and drowsiness - rapid onset - less selectivity than 2nd generation drugs