Drug Profiles Spring Semester

Mechanism of Action: T4 is converted to T3 (the active form) inside cells by one of two distinct deiodinases, depending on the tissue. T3 binds to specific receptor proteins (alpha & beta) in the nucleus, resulting in altered gene expression, and increased formation of RNA and protein. Systemic effects include increased oxygen consumption by most tissues of the body and increases the basal metabolic rate and the metabolism of carbohydrates, lipids and proteins.

Notes: Less expensive than T3. Lower cost & longer half-life make it a drug of choice for chronic treatment of hypothyroidism.

Drug: Triodothyronine (T3), or Liothyronine (generic, Cytomel, Triostat ®)

Pharmacokinetics: Taken orally or parenterally. Short half life (24hrs) compared to T4 (7 days).

Notes: T3 costs more than T4 & has a shorter t1/2 & therefore is not used as commonly.

Tissue Effects:

• Liver: increased storage of glucose as glycogen. This involves insertion of GLUT 2 into liver cell membranes & increased synthesis of enzymes involved in glucose metabolism. Insulin also decreases the breakdown of proteins.
• Muscle: stimulates glycogen & protein synthesis. Increased GLUT 4 insertion into cell membranes.
• Adipose tissue: facilitates triglyceride storage by activating plasma lipoprotein lipase. Increased glucose transport into cells via GLUT 4, reduced breakdown of lipid (reduced intracellular lipolysis).

• Ultra rapid- & short-acting: insulin lispro & insulin aspart.
  • amino acid transposition (lispro) or substitution (aspart) alters the physical properties of the peptide so it dissolves more quickly & enters the circulation 2x as fast as regular crystaline insulin.
  • permits more physiologic prandial insulin replacement.

• Short-acting: crystaline zinc (regular) insulin.
  • used i.v. in emergencies or given s.c. in ordinary maintenance regimens, alone or mixed with intermediate- or long-acting forms.

• Intermediate-acting insulin: isophane insulin suspension (NPH insulin) & lente insulin.
  • both are given by s.c. injection & are not suitable for i.v. use because of their particulate nature.
  • clinically these are considered as basal insulins (despite the fact that they don't produce a steady-state like glargine insulin). See Fig 3B in Insulin lecture handout.
  • the protein (protamine) in NPH insulin delays absorption of insulin
  • when mixing intermediate-acting with regular isulin, NPH is prefered over lente because lente can retard the onset of action of regular insulin.
  • lente has a slightly longer duration of action than NPH.
  • both lente & NPH are commonly used as twice daily basal insulins.
  • neutral protamine lispro (insulin lispro protamine; NPL) & protamine cyrstaline (crystal) aspart which are available as pre-mixed insulins are functionally indentical to NPH.

• Long-acting: ultralente insulin (insulin zinc extended).
  • absorbed slowly in its zinc crystalline form.
  • usually given in the morning only (or morning & evening) to provide maintenance or basal levels for 12-24hrs - a basal insulin formulation.
  • basal insulin levels produced by long-acting insulin may be supplemented with injections of insulin lispro or regular insulin to meet the requirements of carbohydrate intake.

• Ultra Long-acting: insulin glargine.
  • a modified human insulin that forms a microprecipitate in the subcutaneous tissue is released slowly with a peakless delivery of 20-24 hrs in most patients.
  • a formulation designed to establish a basal insulin level
  • glargine achieves steady-state in ~2 hrs after administration.

• subcutaneous injection w/ disposable needle & syringe (standard mode of therapy).
• portable pen-sized injectors - disposable & facilitate s.c. injection.
• continuous s.c. insulin infusion pumps - can deliver a constant 24 hr basal rate of delivery. Manual adjustments can be made before meals or exercise.
• inhaled formulation - in clinical trials.

• hypoglycemia from excessive insulin effect (e.g. can occur due to "insulin stacking" if prandial insulin supplements are used between meals.
• antigenic toxic effects due to development of antibodies

• NPH
• lente
• ultralente
• glargine

• regular
• lispro
• aspart

Notes: should be taken with the first bite of breakfast, lunch, and dinner. The hypoglycemic goal in diabetics typically cannot be met with this drug alone.Miglitol is six times more potent in inhibiting sucrase than acarbose

Notes: in rare cases, metformin may lead to lactic acidosis (it can impair the hepatic metabolism of lactic acid). Considered a “euglycemic” (hypoglycemia does not occur).

Notes: these drugs are also “euglycemics”

Indications for Estrogens as a class:

• primary hypogonadism (replacement therapy in estrogen-deficient females starting at puberty, but not before)
• intractable dysmenorrhea (given along w/ progesterone for severe pain accompanying ovulation)
• Carcinoma of the prostrate - DES is used
• oral contraceptives (estrogen + progesterone combined, to inhibit ovulation & folliculogenesis, produce a "sperm inhospitable mucus" and increase oviduct activity)
• morning after pill (DES or ethinyl estradiol)
• endometriosis - the ectopic occurrence of endometrial tissue. Estrogen & progesterone are used to suppress ovulation for a long time, resulting in endometrial atrophy.
• postmenopausal hormonal therapy (HRT) - controversial benefit. It may increase the risk of breast cancer & thromboembolic disorders

Contraindications:

• known or suspected pregnancy. Estrogens may cause fetal harm when administered to a pregnant woman.
• undiagnosed abnormal genital bleeding.
• known or suspected cancer of the breast except in appropriately selected patients being treated for metastatic disease.
• known or suspected estrogen-dependent neoplasia.
• active thrombophlebitis or thromboembolic disorders (estrogens enhance the coagulability of the blood)
• heavy smoking

Notes: Estradiol (E2) is the major secretory product of the ovary. Other naturally occurring estrogens include estrone (E1) and estriol (E3).

Notes: contrains estrone and equilin sulfate from pregnant mare urine

Notes: Often administered with an antiemetic, since 40% of patients have nausea or vomiting.

Notes: Ethinyl estradiol is the most common estrogen found in oral contraceptives.

Physiolgocial Effects:

• promotes secretory activity of endometrium "primed" by estrogen
• negative feedback on anterio pituitary FSH and LH
• Important (along with estrogen) in breast development & lactation
• the cause of midcycle increase in body temperature at ovulation

Indications for progestins (synthetic):

• contraception - most commonly used in combination with estrogens. Progestin only "mini pills" are not as effective as combination pills. Progestins work as contraceptives via effects on cervical mucus, the uterine endometrium & uterine motility, all of which decrease the likelihood of conception & implantation. High dose formulations (e.g. depot medroxyprogesterone) also inhibit GnRH release & are therefore more effective contraceptives.
• Control of functional uterine bleeding.
• management of endometriosis (ectopic endometrial tissue) & dysmenorrhea (painful menstruation).

Side Effects:

• weight gain
• edema
• depression
• thrombophlebitis
• pulmonary embolism
• the more potent progestins, if used for a long period of time, will decrease HDL levels and lead to atherosclerosis.

Side Effects: Menstrual irregularities (bleeding or amenorrhea, or both), weight changes, headache, nervousness, abdominal pain or discomfort, dizziness,
asthenia (weakness or fatigue). Reversible reduction of glucose tolerance.Return

Return of Fertility:
Depo-Provera contraceptive injection has a prolonged contraceptive effect. Clinical trials indicate that following the last injection, 68% of women who do become pregnant may conceive within 12 months, 83% may conceive within 15 months, and 93% may conceive within 18 months from the last injection.

Contraceptive Mechanisms:

• Estrogen: 1) it exerts a negative feedback control on the release of FSH & LH from the pituitary; 2) it causes a thickening of cervical mucus, which decreases sperm penetration; 3) endometrial alterations that impair implantation; & 4) changes in the motility & secretion in the uterine tubes.
• Progestin: Low dose – changes to cervical mucus, endometrial & uterine changes similar to estrogen. High dose: inhibitory feedback on GnRH release from the hypothalamus.

Notes: a norethindrone derivative, approved by the FDA in 2000 for the medical termination of intrauterine pregnancy in the first 49 days of gestation.

Indications:

• Treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to: a) Improve symptoms; b) Reduce the risk of acute urinary retention; c) Reduce the risk of the need for surgery including transurethral resection of the prostate (TURP) and prostatectomy.
• Finasteride is also is indicated to reduce the risk of symptomatic progression of BPH when administered in combination with the alpha-blocker doxazosin
• treatment of male pattern baldness (or androgenic alopecia) (propecia ®).

Notes: The development and enlargement of the prostate gland is dependent on the potent androgen, 5 -dihydrotestosterone (DHT). 5 -alpha reductase metabolizes testosterone to DHT in the prostate gland, liver and skin. DHT induces androgenic effects by binding to androgen receptors in the cell nuclei of these organs.

Side Effects: increases LDL, decreases HDL, and other dose-related testosterone-like side effects such as increased aggression, psychotic episodes, impaired judgement, hepatic abnormalities, premature closure of epiphyses, edema, cholestatic jaundice, and sex-related changes (below).

In men: priapism & decreased sperm count.

In women: masculanization w/ acne, hypertrophy of the clitoris.

Notes: Testosterone cannot be given orally because of hepatic inactivation (1st pass effect). Synthetic testosterone analogs have decreased hepatic metabolism & increased plasma half life.

Indications:

• palliation of androgen responsive recurrent mammary cancer in postmenopausal women
• replacement therapy in conditions associated with symptoms of deficiency or absence of endogenous testosterone in men (e.g. hypogonadism or delayed puberty).

Issues:

• Body size: kids are smaller than adults & require different doses as a result. Body surface area (e.g. mg per meter squared) is better correlated with extracellular fluid volume compared to weight (e.g. mg/kg)
• Pharmacokinetics: newborns have immature hepatic enzymatic activity, including conjugation reactions, and immature renal function. Ex. can result aminoglycoside induced ototoxicity in infants (since these drugs undergo renal clearance). Low levels of hepatic glycuronyl tranferase conjugation of chloramphenical can produce potentially fatal cardiovascular collapse & death (gray baby syndrome).
• Bilirubin: higher than normal levels of uncongigated billirubin make the neonate susceptible to the effects of drugs that can displace it from albumin binding sites, resulting in CNS toxicity (kernicterus); examples include sulfonamides & ceftriaxone.
• Growing bones & teeth: Tetracyclines can stain developing teeth in children less than 9 yrs. Quinolone antibiotics should not be used before the epiphyses close due to potential damage to growing cartilage.
• Transplacental passage of drugs to the fetus: avoid use of drugs that can cross the placenta and cause harm to the fetus. These include: aminopterin (fetal death), thalidomide & other teratogens, sulfonamides (kernicterus), tetracyclines (bone growth & teeth), aminoglycosides (ototoxicity).
• Breast milk transfer of medications: not a common problem, but avoid drugs that are potential mutagens (metronidazole) or increase the risk of hemolysis in G-6-PD deficient infants (nalidixic acid, nitrofurantoin, sulfonamides).

Issues:

• Polypharmacy: the increase of drug use in elderly patients increases the risk of adverse drug (& drug-drug) reactions vs. younger subjects
• Increased Drug Sensitivity: there are a few examples of increased pharmacodynamic sensitivity in elderly patients (increased potency with age) and these include benzodiazepines & warfarin. With benzodiazepines this can contribute to ataxia induced injuries (broken hips, arms etc.). Older patients require lower doses of warfarin for anticoagulation. The elderly may also be more sensitive to the effects of CNS depressants (lower doses are required for sedation).
• Drug metabolism: there may be a slower rate of gastric emptying and a greater lag time before the onset of drug action. The major changes are a decrease in oxidative drug metabolism (e.g. P-450 mediated) with age, but not conjugation reactions. For example, librium and valium (diazepam) undergo oxidative metabolism and have very long half-lifes in young patients, and should therefore be completely avoided in the elderly. Instead one should give oxazepam or lorazepam which undergo glucuronidation instead of oxidative metabolism, and are therefore much safer to use in elderly patients.
• Body composition changes: older patients have decreased lean body mass (muscle) and increased total body fat. As a result, there is a decrease in the Vd for water soluble drugs (e.g. ethanol, acetaminophen), and and increase in Vd for lipid soluble drugs (diazepam, lidocaine). One should adjust the loading dose accordingly.
• Renal clearance changes: there is an age-related decrease in GFR. Drugs that undergo renal clearance (e.g. aminoglycosides, digoxin) will need to have their maintenance dosages adjusted according to changes in creatinine clearance. NOTE: serum creatinine levels are not a reliable measure of renal function, because there may be a decrease in creatine production due to decreased skeletal muscle mass with age, as well as a decrease in renal function, resulting in a normal serum creatine level.

Issues:

• Post menopausal osteoporosis: a controversial topic, but the current consensus seems to be to use diphosphonate drugs, Vit D & calcium supplements as first line drugs instead of estrogen due to the concerns about estrogens ability to increase the chances of (breast) cancer & thromboembolic events.
• Adverse drug reactions: are more common in women. One reason may be that "fixed doses" are often prescribed to patients (mg instead of mg/kg), and female patients typically weigh less than male patients, and hence receive more drug than required to produce a therapeutic level. Hormonal influences could also play a role on drug metabolism & response. Examples: women are more likely to suffer from drug-induced cardiac arrhythmias (Torsade de pointes - premenopausal women have a longer QT interval compared to men.) & digoxin induced toxicity/death.*