Review Flashcards

Question

Thiazolidinediones Name 3 what are they?

Answer 1

Rosiglitazone (Avandia®), Pioglitazone (Actos®) & Troglitazone (Rezulin®) (original) Agonists of peroxisome-proliferator-activated receptor gamma (PPARγ, nuclear receptor highly expressed in adipose tissue) insulin sensitizers

Answer 2

– Agonists of PPARγ – Promote uptake & storage of fatty acids into adipose tissue (prevents excess fat from being stored in other organs) – Improves muscle insulin sensitivity – Takes 6-12 weeks to reach full effect - Increases differentiation of maturation of adipocytes which will store more fat and away from other organs - Excess fat in muscle and liver causing hepatic and insulin resistance - putting fat where it should be - Takes 2-3 months to work - Lipid is used as fuel source for energy - Type 2 diab - Elevated lipid is always delivered to muscle, has more fat stored in organ - Lower circulating lipid levels, decreased delivery to muscle, when it use the excess fat stored, it dissipates over time and doesn't get replenished - Insulin sensitivity is restored and can cause glucose to enter muscle, decrease gluconeogenesis

Answer 3

– Fluid retention (can aggravate pre-existing heart failure) – Cardiovascular (… and now cancer) complications limiting use of rosiglitazone and pioglitazone - rosi disproved for cardio – Weight gain - fat into adipocytes CV death is number 1 death cause for T2D ppl, so drugs must undergo CV outcome studies

Answer 4

* Drug Class: biguanides | * First line therapy for type 2 diabetes

Answer 5

AMPK inhibits acetyl CoA carboxylase (ACC) to reduce hepatic lipid content - AMPK inhibits ACC - ACC synthesizes malonyl CoA which inhibits fat oxidation - Low ACC - increases fat oxidation in liver, lowers hepatic lipid accumulation - inhibit glucagon signaling prevents activating hepatic gluconeogenesis - Decreased hepatic glucose production and subsequent blood glucose levels

Answer 6

– Does not cause hypoglycemia, insulin sparing – Weight neutral or no weight gain - Weight loss GDF 15 increase secretion (grwoth diff factor) – GI symptoms most common side effect – *Lactic acidosis? (more for phenformin), build up of lactate due to it being renal excreted so ppl with renal failure should not use it – Vitamin B12 absorption??? (take calcium supplements)

Answer 7

Canagliflozin (Invokana®), Dapagliflozin (Forxiga®), Empagliflozin (Jardiance®), Ertugliflozin (Steglatro®) newest therapy for type 2 diabetes

Answer 8

– Inhibit SGLT2 (SGLT2 inhibitors induces glucosuria, gluc excretion) • Our kidneys filter 160-180 grams of glucose/day • The vast majority of this glucose (up to 99%) is reabsorbed by the kidneys (proximal tubule) • Hyperglycemia increases both the amount of filtered glucose and reabsorbed glucose by the kidneys • SGLT2 is the primary mediator of glucose reabsorption

Answer 9

▪ Does not cause hypoglycemia (glucose independent) ▪ Can be prescribed with other therapies for diabetes ▪ Are effective at all stages of type 2 diabetes ▪ Have beneficial effects on the cardiovascular system - Almost every SGLT inhibitor shows benefits for CV functions - Empagliflozin (Jardiance®)shows best outcomes for CV, may be a heart disease drug

Answer 10

Sodium Glucose Cotransporter 2 (SGLT2) Inhibitors what disadvantages does it have? (4) ▪ *Increases genital and urinary tract infections -increasing glucose in urine - conducive of bacterial growth ▪ May increase hepatic glucose production (via increasing glucagon secretion?) - SGLT2 in alpha cells in islets increases glucagon sec ▪ *May increase ketoacidosis - can be due to increased fat oxidation with glucagon - ketone bodies may lead to increased CV benefits with increased signaling pathways ▪ *Increased risk of amputation (only seen with canagliflozin)

Answer 11

pancreas - increase insulin (PRIMARY) and decrease glucagon secretion liver - dec glucagon reduce hepatic glucose production, decrease blood sugar levels intestine - GLP-1 is expressed in intestine, delay gastric emptying, delay absorption of sugar from eating brain - Lower food intake, reductions in appetite - approved for obesity adipose tissue - decreased adiposity with low appetite

Answer 12

``` • SGLT2 is expressed in the following tissues – Kidney – Islet α-cells • SGLT1 is expressed in the following tissues – Kidney – Heart – Small intestine ➢May delay intestinal glucose absorption ➢May enhance incretin hormone secretion - may be beneficial to inhibit SGLT1 ``` - canagliflozin shows some SGLT1 inhibitory action

Answer 13

• promotes glucose stimulated insulin secretion ➢ Ability to enhance glucose-stimulated insulin secretion is glucose dependent, being more potent at higher plasma glucose levels (low risk for hypoglycemia) • inhibits glucagon secretion, which reduces hepatic glucose production in patients with diabetes • inhibits gastric emptying ➢ Delays appearance of nutrients (e.g. glucose) into the circulation • inhibits appetite ➢ Leads to reductions in body weight and adiposity

Answer 14

➢Exenatide (Byetta®) [T1/2 ~ 2 hours] ❖Synthetic version of the Gila monster salivary hormone, exendin-4 - DPP-4 can't access ➢Liraglutide (Victoza®) [T1/2 ~ 12 hours] ❖Acylated GLP-1 analog that noncovalently binds to albumin - alanine still there but bind to albumin so DPP-4 can't access ➢Albiglutide (Tanzeum®) [T1/2 ~ 4-7 days] ❖GLP-1 dimer fused to albumin ➢Lixisenatide (Lyxumia®) [T1/2 ~ 2.5 hours] ❖Structurally related to exendin-4 ➢Semaglutide (Ozempic®) [T1/2 ~ 1 week] ❖Longer-acting alternative to liraglutide • Proteins, therefore must be injected ➢ Can lead to formation of neutralizing antibodies (exenatide) - oral recently approved

Answer 15

▪ Also cause body weight loss (liraglutide approved for obesity) ▪ Less risk of hypoglycemia (do not promote insulin secretion when circulating glucose levels are low/normal) ▪ Reduced cardiovascular risk with GLP-1R agonists (seen with all GLP-1R agonists for most part except lixisenatide and exenatide)

Answer 16

Disadvantages (3) ▪ Primarily gastrointestinal concerns (nausea, diarrhea, vomiting), transient ▪ *Increase in heart rate, no CV risk ▪ *Pancreatitis??? ▪ Increased risk of hypoglycemia if co-prescribed with sulfonylureas

Answer 17

``` ➢Sitagliptin (Januvia®, Janumet®) ➢Vildagliptin (Galvus®) ➢Saxagliptin (Onglyza®, Komboglyze®) ➢Alogliptin (Nesina®, Kazano®, Oseni®) ➢Linagliptin (Tradjenta®, JentaDueto®) ``` Oral Administration (tablets taken once/day)

Answer 18

Less risk of hypoglycemia (do not promote insulin secretion when circulating glucose levels are low/normal) ▪ Oral versus injectable (patient preference)

Answer 19

▪ Primarily gastrointestinal concerns (nausea, diarrhea, vomiting) ▪ *Pancreatitis??? ▪ Increased risk of hypoglycemia if co-prescribed with sulfonylureas ▪ Increased risk of hospitalization for heart failure (only seen with the DPP-4 inhibitor saxagliptin) ▪ Don’t cause weight loss like GLP-1 receptor agonists, no improvement of CV outcomes

Answer 20

– nuclear estrogen receptors (ER) α and β, regulate transc factors, gene expression –Vascular actions mediated via a GPCR also known as GPR30 or GPER - Activation of endothelial nitric oxide (NO) synthase (eNOS) increases NO causing vasodilation - influence lipid metabolism

Answer 21

– Endogenous estrogens: estradiol (most potent), estrone, and estriol – Synthetic forms: ethinylestradiol & mestranol – endog. are heptatically metaboilized, most contra uses synth via nuclear estrogen receptors (ER) a and b may also act via GPCR (vascular actions)

Answer 22

– Estrogen is usually ethinylestradiol (synth) – Progestogens can be ▪ Noresthisterone (Norethindrone), levonorgestrel, or ethynodiol (2nd generation) ▪ Desogestrel, gestodene (3rd generation) – Taken for 21 consecutive days followed by 7 pill-free days (can differ)

Answer 23

– Mild nausea, Breast tenderness, Flushing – Breakthrough bleeding (amenorrhea no mens for no hromone free intervals) – Dizziness – Depression or irritability – Skin changes (e.g. acne) - estrogen reduces acne as they increase sex hormone binding globulin, less free androgens - prog component causes acne - 3rd gen prog less likely to cause acne, higher thromboembolism risk – Weight gain: Fluid retention - mineralocorticoid activities – *Thromboembolism: obstruction in blood vessel due to clot - Smoking, HTN increases risk for thromboemolism, should not use - Blood pressure increased in small percent of women, increase angiotensinogen, reversible increase in bp

Answer 24

– Reduction in risk of ovarian and endometrial cancer - earlier detection in breast cancer – Decreased menstrual symptoms (e.g. irregular periods) – Reduced iron deficiency anemia (risk)

Answer 25

– Progestogen includes norethindrone or ethynodiol – Taken daily without interruption – A suitable alternative for people who experience blood pressure increases resulting from estrogen or other contraindications of estrogen

Answer 26

Postcoital (Emergency) Contraception – Oral administration of levonorgestrel (2nd gen) ▪ Can be taken alone or combined with an estrogen – Effective up to 72 hrs post-unprotected intercourse with a repeat dose 12 hrs later (now usually just give 1 dose of 1.5mg) – Nausea and vomiting are common (can be taken with diphenhydramine (Gravol)) Long-Acting Progestogen-Only Contraception – Depot medroxyprogestogen given intramuscularly – Menstrual irregularities are common – Infertility may persist for months upon stopping treatment – Non-biodegradable capsules - release over 5 year period

Answer 27

– Oxytocin receptor is a GPCR that promotes increases in intracellular calcium – Activation of calmodulin (CaM) stimulates myosin light chain kinase (MLCK) to induce uterine contraction more details – Gq coupled to phospholipase C acts on membrane phospholipids, release IP3 which activates calcium channels in sarc ret to release Ca2+ - binds to calmodulin and activate it, MLCK phsophorylates myosin light chain -> contractile response

Answer 28

As a peptide cannot be taken orally and has an extremely short half-life (3 min) -> IV – *Hypotension (when administered rapidly) - must be strarted at low dose and increased every 30 mins until max dose – *Higher doses can cause sustained contractions reducing blood flow & O2 delivery to the placenta that lead to fetal distress & potentially death – Uterine rupture (contraindicated in people with previous rupture) – Antidiuretic effect, vasopressin from pituitary

Answer 29

– Action on uterine smooth muscle is not completely understood – May act partly on α-adrenoceptors and partly on 5-HT (serotonin) receptors (similar to ergotamine) Beta adrenoceptors inhibit uterine contraction

Answer 30

– Mifepristone followed by a prostaglandin analog (e.g. misoprostol) is used to induce medical *abortion – Gemeprost is another alternative given intravaginally following mifepristone – Dinoprostone (prostaglandin E2 analog) and carboprost (prostaglandin F2⍺ analog)

Answer 31

Mifepristone is an antiprogestogen that acts as a competitive progesterone receptor antagonist in the presence of progesterone – Misoprostol/gemeprost are prostaglandin E1 analogs that induces myometrial contraction leading to expulsion of tissue (e.g. fetus) - mife partial agonist, sensitizes uterine muscle so lower doses of prostaglandins needed

Answer 32

– *Vomiting (D2 receptors in the chemoreceptor trigger zone) – Vasoconstriction and increased blood pressure ▪ Nausea ▪ Blurred Vision ▪ Headache ▪ Angina: vasospasms of coronary arteries

Answer 33

delay for 48 hr window – Atosiban is a competitive antagonist of the oxytocin receptor and thus can be used to delay labour ▪ Prevents intracellular increase in inositol triphosphate (IP3) and intracellular calcium ▪ Also suppresses oxytocin-induced release of prostaglandins (PGE and PGF) – Salbutamol is a β2-adenoceptor agonist that can inhibit spontaneous oxytocin-induced contractions of the pregnant uterus

Answer 34

– Clomiphene (often leads to twins) – Gonadorelin (synthetic GnRH) – Follitropin (recombinant FSH) – Lutropin (recombinant LH) ``` – Other GnRH analogues include ▪ Buserelin ▪ Leuprorelin ▪ Goserelin ▪ Nafarelin ```

Answer 35

– Clomiphene is an estrogen antagonist that promotes gonadotrophin release by inhibiting the negative feedback effects of estrogen on the hypothalamus and anterior pituitary – Promotes FSH secretion Increase Release of GnRH and LH to promote ovulation - fertility purpose

Answer 36

– Flushing – Vaginal dryness – Bone loss – Reversible ovarian enlargement (clomiphene), more FSH

Answer 37

– During sexual stimulation nitrergic nerves release nitric oxide (NO) into smooth muscle cells – NO activates guanylyl cyclase to generate cyclic GMP (cGMP) – Inhibition of PDE V prevents breakdown of cyclic GMP – cGMP is an allosteric activator of protein kinase G (causes vasodilation)

Answer 38

– *Hypotension: contraindicated in anyone taking vasodilators – Flushing – Headache – *Visual disturbances (inhibition of PDE VI): not for ppl with hereditary degenerative retinoic diseases varden is more for V but still not recommended

Answer 39

– Uptake of plasma iodide by follicle cells – Iodination of thyroglobulin – Secretion of thyroid hormone - Thyrotropin (TSH) regulates uptake of iodine into follicular cells - Viscous liquid surround follicular lumen called colloid - Thyrotropin stimulates NIS (sodium iodine symporter) causing it to be taken up - PDS is iodide chloride transporter, thyroperoxidase and H2O2 - Iodine gets oxidized and incorported into tyrosine residues of thyroglobulin Thyroperoxidase + H2O2 oxidizes iodine and incorporates iodine radicals into tyrosine residues of thyroglobulin incorporates iodine radicals into tyrosine residues of thyroglobulin

Answer 40

– Increases NIS expression (NIS transportes iodine into follicular cell) – Synthesis/secretion of thyroglobulin (TG) (increase TG secretion into foll lumen) Thyroglobulin is the other major component needed for synthesis of thyroxine and triiodothyronine. – Generation of H2O2 & iodination of tyrosine – Endocytosis/proteolysis of TG – Secretion of T3 & T4 – Increased blood flow through the gland

Answer 41

``` – Low metabolic rate, lethargy – Slow speech – Bradycardia – Sensitivity to cold – Myxedema (severe cases), swelling of skin with waxy composition - use IV T3 in severe cases ```

Answer 42

▪ Metabolism: Increased body temperature & reduced weight - T3 leads to greater basal metabolic rate initially vs T4 - Metabolism - not due to expression of more metabolic enzymes but interaction of other hormonal systems, increasing other receptors for hormones ▪ Cardiovascular: Increased heart rate & blood pressure ▪ GI: Increased motility ▪ Musculoskeletal: Required for skeletal development and peak bone mass ▪ Reproductive: Enhance ovulation & spermatogenesis

Answer 43

T4 half life 7 days in a person w/ normal health 3-4 days for hyperthyroidism 9-10 days for hypothyroidism T3 a few hours T4 is preferred, circulating Thyroid hormone is strongly bound to thyroxine-binding globulin (unbound hormone is active)

Answer 44

– *Tachycardia (contraindicated) – *Atrial Fibrillation elevate heart rate

Answer 45

``` – High basal metabolism (increased appetite associated with body weight loss) – Increased skin temperature – Heat intolerance – Sweating – Nervousness & tremor – Tachycardia ```

Answer 46

– 1st line treatment for hyperthyroidism – Dose generally 5 – 15 mCi – Avoid in children and in pregnant mothers – Following use and destruction of the gland, individuals will become hypothyroid and require administration of levothyroxine (T4) beta radiation

Answer 47

– Propylthiouracil – Methimazole, Carbimazole (prodrug converted to methimazole) 3-4 wks to work

Answer 48

– Contain a thiocarbamide (S-C-N) group required for antithyroid activity – Prevent synthesis of thyroid hormone • Inhibit thyroperoxidase • Block iodine oxidation • Block coupling of iodinated tyrosines • Inhibit peripheral deiodination of T4 to T3 (propylthiouracil - active form)

Answer 49

``` – *Skin rash: 25% common – Fever – Arthralgia – *Neutropenia: low neutrophils, WBCs – *Agranulocytosis: low granulocytes – Hepatotoxicity – Vasculitis ```

Answer 50

– To treat individuals with pituitary dwarfism (GH deficiency) – To promote growth and correct short stature in women with Turner’s Syndrome (one X chromosome missing or altered) – Used illicitly by athletes to increase muscle mass (e.g. Barry Bonds) - similar to acromegaly: hypertension, carpal tunnel syndrome*, diabetes - cardiomegaly*: enlarged heart - cardiomyopathy: dysfunc in absence of atherosclerosis

Answer 51

GH receptor is a class I cytokine receptor – GH and its analogues stimulate growth – Stimulates hepatic production of insulin-like growth factor (IGF) – IGF promotes uptake of amino acids and protein synthesis in skeletal muscle & cartilage of long bones – Mecasermin can also be used (recombinant IGF-1) Back then - get from cadavers - degenrative diseases Now with recombinant technology, bacterial culture Humans only respond to human GH

Answer 52

Acromegaly – A disorder characterized via excess growth hormone secretion in adults (surgical removal is an option) • Pegvisomant – Modified analogue of GH that prevents actions of GH on liver receptors to stimulate IGF secretion • Pharmacokinetics – Subcutaneous injection (protein) – Addition of polyethylene glycol increases half-life to ~2 days

Answer 53

– Elevated liver enzymes (contraindicated in people with severe liver disease)

Answer 54

Somatostatin inhibits secretion of ant pit growth hormone (and many others) – Octreotide - primary use for excess GH – Lanreotide - used for thyroid – Pasireotide - excess glucocorticoid secretion

Answer 55

– Mimic actions of somatostatin (octreotide signals through somatostatin receptor 2/5) - act on ant pit to prevent GH release – Inhibit GH secretion

Answer 56

– Cardiovascular (*sinus bradycardia) – GI (abdominal pain, diarrhea, nausea) – CNS (headache, fatigue) - pain at injection site • Contraindicated/Use Caution – Type 1 diabetes ▪ Hypoglycemia Somatostatin can cause hypoglycemia or hyperglycemia Decreases insulin from beta and glucagon from alpha cell -Depends on balance of insulin and glucagon secretion • Surgery/Radiation therapy arepreferred treatment options (most effective in small tumors)

Answer 57

– Cyclical withdrawal bleeding – *Increased risk of endometrial cancer (w/o progestogen) – *Increase risk for breast cancer (related to duration of use) – Increased risk of thromboembolism, greater than 5 year use

Answer 58

``` – *Infertility with continued use (decreased gonadotropin release) – *Salt & water retention (edema) – *Acne – Impaired growth (children) – Masculinization in women ```

Answer 59

``` – Gonadorelin (synthetic GnRH) – Buserelin – Leuprorelin – Goserelin – Nafarelin ```

Answer 60

– Chronic administration inhibits the release of gonadotropins (FSH & LH) – Leads to suppression of testicular steroidogenesis due to decreased levels of LH and FSH, and subsequent decrease in testosterone GnRH - pulsatile can increase FSH or LH and increase testosterone Given chronically, will decrease secretions

Answer 61

– *Transient surge of testosterone secretion: intial actions elevate LH and FSH, need to use with anti-androgen in the first few months – *Decreased libido – Hot flash/flush

Answer 62

Degarelix – Reversibly binds to GnRH receptors in anterior pituitary to block receptor, decreasing FSH and LH secretion – Results in rapid androgen deprivation and decrease in testosterone levels avoids transient surge

Answer 63

– Hot flash/flush

Answer 64

– Bicalutamide – Enzalutamide – Tlutamide – Nilutamide – Cyproterone: steroidal - deriverate of progesterone Low activity, can compete with testosterone receptors and prevent action

Answer 65

– Inhibit androgen actions by competing with androgens for binding to androgen receptors in target tissue – Can also be used to control testosterone surge (“flares”) caused by GnRH analogues

Answer 66

Abiraterone – Selectively inhibits CYP17 (an enzyme expressed in and required for androgen biosynthesis in testicular, adrenal and prostatic tumor tissues - prevent synthesis of testosterone

Answer 67

– Hypertension – Hypokalemia – *Peripheral Edema: CYP17 also metabolizes neurocorticoids - Now we are preventing their breakdown which leads to water rentention and can lead to edema

Answer 68

Androgens – Stimulate hair growth on face, chest, back – Inhibit hair growth on scalp Finasteride – Inhibitor of 5α-reductase (prevents conversion of testosterone into the more potent dihydrotestosterone) (most potent forma nd affinity for receptor) – Applied topically and can take months to produce effects takes a long time to see effects

Answer 69

- *reduced libido (impotence) | - tenderness of the breasts

Answer 70

Minoxidil - better for alopecia ▪ Vasodilator originally developed for hypertension ▪ In hair follicles is converted to the more potent metabolite, minoxidil sulfate ▪ Minoxidil sulfate increases blood supply to hair follicles, thereby stimulating growth of new hair - Hair follicle is often resting and not in state to grow more - Need to shed hair first - Often initially, there will be noticeable hair loss before growth

Answer 71

Excessive body hair in men and women on parts of the body where hair is normally absent Eflornithine - gets rid of hair growth on face ▪ Originally developed as an antiprotozoal agent ▪ Irreversibly inhibits ornithine decarboxylase in hair follicles to reduce cell replication and the growth of new hair follicles - Required for formation of polyamines - stabilize DNA during replication ▪ May cause acne

Answer 72

– GnRH analogues (inhibit FSH/LH secretion with chronic use) – Non-steroidal anti-androgens – Abirateronev

Answer 73

– Finasteride – Eflornithine – Minoxidil