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94 Cards in this Set

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Insulin
Drug Class: Antidiabetic Drug / Pancreatic Hormone
Mechanism of Action: Binds to insulin receptors in cell membranes consisting of alpha subunits on the outside surface and cytoplasmic beta subunits having tyrosine kinase activity. Binding of insulin to two receptors (forming a dimer) brings the beta subunits into close proximity, resulting in phosphorylation of tyrosine residues (autophosphorylation) on the beta subunits, and chronicly elevated tyrosine kinase activity. This ultimately results in the activation of other intracellular kinases including ras and MAPK. The network of phosphorylations within the cell results in multiple effects including a translocation of glucose transporters (GLUT 1-5 subtypes) to the cell membrane, with a resultant increase in glucose uptake, glycogen synthase activity & increased glycogen formation, increased protein synthesis, lipolysis, and lipogenesis.

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).
Insulin Preparations
* Ultra rapid- & short-acting: insulin lispro & insulin aspart.
o 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.
o permits more physiologic prandial insulin replacement.

* Short-acting: crystaline zinc (regular) insulin.
o 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.
o both are given by s.c. injection & are not suitable for i.v. use because of their particulate nature.
o 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.
o the protein (protamine) in NPH insulin delays absorption of insulin
o when mixing intermediate-acting with regular isulin, NPH is prefered over lente because lente can retard the onset of action of regular insulin.
o lente has a slightly longer duration of action than NPH.
o both lente & NPH are commonly used as twice daily basal insulins.
o 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).
o absorbed slowly in its zinc crystalline form.
o usually given in the morning only (or morning & evening) to provide maintenance or basal levels for 12-24hrs - a basal insulin formulation.
o 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.
o 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.
o a formulation designed to establish a basal insulin level
o glargine achieves steady-state in ~2 hrs after administration.

References: Handout & Katzung's text (see Fig 41-5 in 9th Ed.)
Insulin delivery systems
* 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.
Hazards of insulin use
* 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
Basal Insulins
* NPH
* lente
* ultralente
* glargine
Prandial Insulins
* regular
* lispro
* aspart
Drug: Acarbose (Precose ®) & Miglitol (Glyset ®)
Drug Class: oral hypoglycemic, alpha-glucosidase inhibitor
Mechanism of Action: inhibits the activity of enzymes required to break carbohydrates down into simple sugars within the intestine.
Indications: an adjunct therapy in type II diabetes mellitus. Not very efficacious at lowering A1c levels when used as monotherapy.
Contraindications:history of diabetic ketoacidosis, intestinal disorders, inflammatory bowel disease, liver or kidney disease, or gastric ulcers.
Pharmacokinetics: poorly absorbed
Side Effects: feelings of bloating, gas, abdominal discomfort, diarrhea.
Major drug interactions: MAO inhibitors.

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
Drug: Tolbutamide (Orinase ®, Oramide ®)
Drug Class: oral hypoglycemic, sulfonylurea, first generation
Mechanism of Action: Stimulates the release of insulin from pancreatic beta-cells.
Indications: type II diabetes
Contraindications:hypersensitivity to the drug. Diabetic ketoacidosis. Renal and hepatic insufficiency
Pharmacokinetics: PO. Hepatic metabolism.
Side Effects: hypoglycemia (true for all sulfonylureas)
Drug: Glimepiride (Amaryl ®),
Drug Class: oral hypoglycemic, sulfonylurea, second generation
Mechanism of Action: stimulates the release of insulin from pancreatic beta-cells
Indications: type II diabetes
Contraindications: patients with significant hepatic impairment (due to a high risk for hypoglycemia). Use with caution in patients with cardiovascular disease, or elderly patients (in whom hypoglycemia may be especially dangerous).
Pharmacokinetics: PO. Hepatic metabolism.
Side Effects: hypoglycemia
Glipizide (Glucotrol ®, Glucotrol XL ®)
Drug Class: oral hypoglycemic, sulfonylurea, second generation
Mechanism of Action: stimulates the release of insulin from pancreatic beta-cells
Indications: type II diabetes
Contraindications: patients with significant hepatic impairment (due to a high risk for hypoglycemia). Use with caution in patients with cardiovascular disease, or elderly patients (in whom hypoglycemia may be especially dangerous).
Pharmacokinetics: PO. Hepatic metabolism.
Side Effects: hypoglycemia
Glyburide (DiaBeta ®, Micronase ®)
Drug Class: oral hypoglycemic, sulfonylurea, second generation
Mechanism of Action: stimulates the release of insulin from pancreatic beta-cells
Indications: type II diabetes
Contraindications: patients with significant hepatic impairment (due to a high risk for hypoglycemia). Use with caution in patients with cardiovascular disease, or elderly patients (in whom hypoglycemia may be especially dangerous).
Pharmacokinetics: PO. Hepatic metabolism.
Side Effects: hypoglycemia
Chlorpropamide (Diabinese ®)
Drug Class: oral hypoglycemic, sulfonylurea, first generation
Mechanism of Action: Stimulates the release of insulin from pancreatic beta-cells.
Indications: type II diabetes
Contraindications:hypersensitivity to the drug. Diabetic ketoacidosis. Renal and hepatic insufficiency
Pharmacokinetics: PO. Hepatic metabolism.
Side Effects: hypoglycemia (true for all sulfonylureas)
Drug: Metformin (Glucophage ®)
Drug Class: oral hypoglycemic, biguanide
Mechanism of Action: decreases the liver's production of glucose, inhibits the breakdown of fatty acids used to produce glucose, and increases the removal of glucose from muscle, the liver, and other body tissues where it is stored.
Indications: type II diabetes mellitus
Contraindications:severe infection; congestive heart failure or emphysema; metabolic acidosis; a history of alcohol abuse; or kidney or liver disease.
Pharmacokinetics: diarrhea, nausea, vomiting, abdominal bloating, gas, diminished appetite.
Side Effects: diarrhea, nausea, vomiting, abdominal bloating, gas, diminished appetite

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).
Drug: Pioglitazone (Actos ®)
Drug Class: oral hypoglycemic, thiazolidinedione derivatives
Mechanism of Action: increases the body's sensitivity to insulin. Their primary action is the nuclear regulation of genes involved in glucose & lipid metabolism and adipocyte differentiation. Glitazones are ligands of the peroxisome peroliferator-activated receptor gamma (PPAR-gamma) part of the steriod and thyroid superfamily of nuclear receptors. PPAR receptors are found in muscle, liver and fat.
Indications: type II diabetes mellitus, also serves as a supplement to sulfonylurea or insulin therapy.
Contraindications: type 1 diabetes or for the treatment of diabetic ketoacidosis.
Pharmacokinetics: metabolized through the hepatic cytochrome P450 system
Side Effects: mild anemia, redistribution of body fat, edema (rare)

Notes: these drugs are also “euglycemics”
Rosiglitazone
Drug Class: oral hypoglycemic, thiazolidinedione derivatives
Mechanism of Action: increases the body's sensitivity to insulin. Their primary action is the nuclear regulation of genes involved in glucose & lipid metabolism and adipocyte differentiation. Glitazones are ligands of the peroxisome peroliferator-activated receptor gamma (PPAR-gamma) part of the steriod and thyroid superfamily of nuclear receptors. PPAR receptors are found in muscle, liver and fat.
Indications: type II diabetes mellitus, also serves as a supplement to sulfonylurea or insulin therapy.
Contraindications: type 1 diabetes or for the treatment of diabetic ketoacidosis.
Pharmacokinetics: metabolized through the hepatic cytochrome P450 system
Side Effects: mild anemia, redistribution of body fat, edema (rare)

Notes: these drugs are also “euglycemics”
Drug: Rapaglinide (Prandin ®)
Drug Class: oral hypoglycemics, insulin secretagogue
Mechanism of Action: regulates potassium efflux from pancreatic beta-cells
Indications: used as a supplemental therapy to dietary measures and exercise to help control blood sugar levels in patients with type II diabetes mellitus
Contraindications:type I diabetes mellitus; renal and hepatic insufficiency.
Pharmacokinetics: rapid onset and very short acting. Ingest just prior to meals.
Side Effects: hypoglycemia
Drug: Nateglinide (Starlix ®)
Drug Class: oral hypoglycemics, insulin secretagogue
Mechanism of Action: regulates potassium efflux from pancreatic beta-cells
Indications: used as a supplemental therapy to dietary measures and exercise to help control blood sugar levels in patients with type II diabetes mellitus
Contraindications: type I diabetes mellitus. Hepatic insufficiency.
Pharmacokinetics: rapid onset and very short acting. Ingest just prior to meals. Safe in patients with very reduced renal function.
Side Effects: has a lower incidence of hypoglycemia compaired to other secretagogues.
Drug: Estradiol or 17-beta Estradiol (generic, Estrace, Estarderm ®)
Mechanism of Action
Drug Class: Estrogen
Mechanism of Action: estrogens regulate the transcription of a limited number of genes. Estrogens diffuse through cell membranes, distribute themselves throughout the cell, and bind to and activate the nuclear estrogen receptor, a DNA-binding protein which is found in estrogen-responsive tissues. The activated estrogen receptor binds to specific DNA sequences, or estrogen-response elements, which enhance the transcription of adjacent genes and in turn lead to the observed effects. Estrogen receptors have been identified in tissues of the reproductive tract, breast, pituitary, hypothalamus, liver, and bone of women. Estrogens are important in the development and maintenance of the female reproductive system and secondary sex characteristics.
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
Drug: Estradiol or 17-beta Estradiol (generic, Estrace, Estarderm ®)
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
Drug: Estradiol or 17-beta Estradiol (generic, Estrace, Estarderm ®)
Pharmacokinetics: estrogens undergo hepatic metabolism where they are glucuronidated or sulfated to inactive forms, and excreted in the urine. They undergo first pass metabolism if given orally. Synthetic estrogen analogs (ethinyl estradiol & mestranol are metabolized more slowly & have a more prolonged action and higher potency than natural estrogens.
Side Effects: increased incidence of breast cancer (w/ or w/o a progestin) & endometrial carcinoma (if estrogen is taken w/o a progestin), nausea & vomiting, breast tenderness & enlargement, edema, hypertension, vaginal bleeding, headache, dizziness, increased risk of deep vein thrombosis w/ high doses, hyperpigemtation.
Major drug interactions: phenytoin, barbiturates & rifampin induce hepatic enzymes that increase the metabolism of estrogens. They will decrease the effectiveness of oral contraceptives. Antimicrobial drugs can also reduce the bioavailability of estrogens due to their effect on GI flora & alterations in enterohepatic cycling of estrogens.

Notes: Estradiol (E2) is the major secretory product of the ovary. Other naturally occurring estrogens include estrone (E1) and estriol (E3).
References: www.rxlist.com & Katzung
Drug: Conjugated Estrogens (Premarin ®)
Indications: treatment of postmenopausal women

Notes: contrains estrone and equilin sulfate from pregnant mare urine
References: McLachlan's handout
Drug: Diethylstilbestrol (Stilphostrol ®)
Drug Class:Synthetic estrogen
Indications: Treatment of prostatic carcinoma & as a postcoital contraceptive.
Pharmacokinetics: When used as a postcoital contraceptive, treatment should begin within 72 hrs (3 days) post-coitus. The recommended dose regimen is 50 mg daily for 5 days.
Side Effects: headache, dizziness, breast tenderness, abdominal & leg cramps. May cause feminizing effects in men.

Notes: Often administered with an antiemetic, since 40% of patients have nausea or vomiting.
References: Katzung's text
Drug: Ethinyl Estradiol (Estinyl ®)
Drug Class: Oral Contraceptive & Postcoital Contraceptive
Pharmacokinetics: As a "morning after pill" - take within 72 hrs of unprotected coitus to prevent blatocyst implantation w/ a dose regimen of 2.5 mg twice daily for 5 days. Metabolized more slowly than the naturally occurring estrogens & has prolonged action and potency. Fat soluble & stored in fat tissue, from which it is slowly released.

Notes: Ethinyl estradiol is the most common estrogen found in oral contraceptives.
References: McLachlan's handout
Drug: Mestranol (in Norinyl 1/50 & Ortho-Novum 1/50 ®)
Drug Class: Oral Contraceptive (the estrogen component)
Pharmacokinetics: Mestranol is a prodrug that must be converted to ethinyl estradiol before it is active. It has prolonged action and potency. Fat soluble & stored in fat tissue, from which it is slowly released.
Notes: Norinyl and Ortho-Novum contain a mixture of mestranol and a progestin. Few modern pills contain mestranol.
References: McLachlan's & Beckman's handout & Katzung's text
Drug: Clomiphene (generic, Clomid, Serophene, Milophene ®)
Drug Class: Anti-estrogen
Mechanism of Action: a competitive inhibitor (partial agonist) at estrogen nuclear receptors. An example of a SERM (Selective Estrogen Receptor Modulator). It interferes with the negative feedback of estrogens on the hypothalamus by binding to estrogen receptors and thereby causes an increase in the secretion of GnRH and gonadotropins.
Indications: treatment of infertility & anovulatory cycles. It is an ovulation-inducing agent.
Pharmacokinetics: administered orally & well absorbed.
Side Effects: it can lead to ovarian hyper-stimulation, with formation of multiple cysts and a 6-8% incidence of multiple births. Other side effects: hot flashes, nausea, vomiting, nervousness (estrogenic effects).
References: McLachlan's handout
Drug: Tamoxifen citrate (generic, Nolvadex ®)
Mechanism of Action: two mechanisms - 1) decreases estrogen-induced mitogen production by antagonizing estrogen receptors; 2) it can directly induces growth factor inhibitors.
Indications: pallative (does not cure) treatment for carcinoma of the breast. It is indicated in estrogen receptor-positive, postmenopausal, soft-tissue metastases of mammary carcinoma. Two thirds of breast cancers have estrogen receptors. Tamoxifen will not work in estrogen-negative cancer, or cancer from bony metastases.
References: McLachlan's handout
Drug: Raloxifene (Evista ®)
Drug Class: Estrogen partial agonist / antagonist
Mechanism of Action: has effects on bone, but does not stimulate the endometrium or breast.
Indications: prevention of post-menotpausal osteoporosis
References: Katzung's text
Drug: Progesterone
Drug Class: Natural progestin
Mechanism of Action: Similar to estrogens, but binds to different receptors in the cytoplasm or nucleus which then interact with preogesterone-response elements to activate gene transcription.

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).

Pharmacokinetics: progesterone itself is rapidly metabolized, which limits its use as a therapeutic agent. Synthetic progestins are not rapidly inactivated by first pass metabolism, and can be administered orally.

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.

References: McLachlan's handout, 10th Ed of G&G
Drug: Medroxyprogesterone (generic, Depo-Provera ®)
Drug Class: Contraceptive Injection
Indications: Contraception
Pharmacokinetics: Injection is effective for 3 months. There is an optional implants formulation

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.
References: www.rxlist.com & MacLachlan's handout
Drug: Norethindrone w/ mestranol (Ortho - Novum ®), w/ ethinyl estradiol (Lo/Ovral ®)
Drug Class: Contraceptive
Indications: the most common form of progestin used in oral contraceptives
References: MacLachlan's handout
Drug: Levonorgestrel (Triphasil, Tri-Levlen, Trivora ®)
Drug Class: Contraceptive
Pharmacokinetics: The progestin component in these triphasic combination tablet formulations (which also contains ethinyl estradiol). L-neorgestrel is also contained in the Mirena IUD, which continuously releases L-norgestrel. This lessens menstrual bleeding & contributes to contraception by this IUD.
References: Katzung's text
Hormonal Contraceptives
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.

References: Katzung & G&G texts
Drug: Mifepristone (Mifeprex, RU426 ®)
Drug Class: Termination of Pregnancy
Mechanism of Action: inhibition of progesterone receptor results in a termination of pregnancy.
Indications: medical termination of intrauterine pregnancy through the first 49 days of gestation. 96% effective during the first 49 days, and 96-98% effective in the first 42 days. Used to treat tamoxifen-resistant breast cancers (breast cancer cells can have both estrogen & progesterone receptors.)
Contraindications: confirmed or suspected ectopic pregnancy, undiagnosed adnexal mass, an IUD in place, current long-term systemic corticosteroid therapy, chronic adrenal failure, severe anemia, known coagulopathy, anticoagulant therapy and drug allergy.
Pharmacokinetics: 600 mg of mifepristone orally, followed 48 hrs later by 400 ug of the prostaglandin E1 analog (misoprostol) orally
Side Effects: minimal, but include bleeding, pain, nausea, vomiting, diarrhea, warmth or chills, headache, dizziness, fatigue.

Notes: a norethindrone derivative, approved by the FDA in 2000 for the medical termination of intrauterine pregnancy in the first 49 days of gestation.
References: www.rxlist.com
Drug: Finasteride ( Proscar, Propecia ®)
Drug Class: Inhibitor of DHT synthesis
Mechanism of Action: a specific inhibitor of steroid 5 alpha-reductase, an intracellular enzyme that converts the androgen testosterone into 5 -dihydrotestosterone (DHT). Finasteride has no affinity for the androgen receptor. By inhibiting 5-alpha reductase, it significantly lowers DHT levels in the plasma and prostatic tissue.

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 ®).

Contraindications: in women who are, or may become pregnant due to effects on developing genitalia in the male fetus.
Pharmacokinetics: a single 5-mg oral dose of finasteride produces a rapid reduction in serum DHT concentration, with the maximum effect observed 8 hours after the first dose. The suppression of DHT is maintained throughout the 24-hour dosing interval and with continued treatment. In male pattern baldness, treatment of 3-6 months is necessary to see increased hair growth, and treatment must be maintained to sustain any benefits.

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.
References: www.rxlist.com
Drug: Testosterone cypionate (generic, others)
Drug Class: Testosterone analog
Mechanism of Action: similar to testosterone. Testosterone is converted to dihydroxytestosterone (DHT) in many tissues, where DHT is the dominant androgen. Both hormones bind to intacellular androgen receptors, initiating events similar to those for estradiol and progesterone, leading to growth, differentiation, and the synthesis of a variety of enzymes & other functional proteins.
Indications: hypogonadism in males
Pharmacokinetics: a depot formulation

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.
References: MacLachlan's handout & Katzung's text
Drug: Danazol (generic, Danocrine ®)
Drug Class: Synthetic Testosterone Analog
Mechanism of Action: a synthetic steroid derived from 17-alpha ethinyltestosterone. Danazol binds to androgen, progesterone, and glucocorticoid receptors. Danazol suppresses the pituitary-ovarian axis. This suppression is probably a combination of depressed hypothalamic-pituitary response to lowered estrogen production, the alteration of sex steroid metabolism, and interaction of danazol with sex hormone receptors.
Indications: treatment of fibrocystic breast disease & endometriosis in women.
References: www.rxlist.com & Katzung's text
Drug: Stanozolol (Winstrol ®)
Drug Class: Anabolic Steroid, Synthetic Testosterone Analog
Mechanism of Action: Similar to testosterone
Indications: Hereditary Angioedema. (Abused by atheletes).
Side Effects: similar to testosterone
References: www.rxlist.com & McLachlan's handout
Drug: Fluoxymesterone (Halotestin ®)
Drug Class: Testosterone analog
Mechanism of Action: similar to testosterone, has increased potency

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).

References: www.rxlist.com
Contraceptive Mechanisms:

Estrogen

Progesterone
Estrogen: maintained levels exert a negative feedback control on the release FSH & LH from the pituitary.
Progestin: Low dose – causes a thickening of cervical mucus, makes the endometrial surface not receptive to implantation & decreases fallopian movement of eggs. High dose: decrease frequency of GnRH release
Drug: Levothyroxine (T4)
Drug Class: Thyroid hormone

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.
Indications: Hypothyroidism & Pituitary TSH Suppression (in the treatment or prevention of various types of euthyroid goiters).
Pharmacokinetics: Taken orally. T4 has a longer half life (7 days) compared to T3 (1 day).
Side Effects: those resembling the symptoms of hyperthyroidism, e.g. nervousness, anxiety, tremor, heat intolerance, weight loss w/ increased appetite, arrhythmias (palpitations). Hyperthyroidism will increase the metabolic clearance and decrease the half life of T3 (& T4).

Notes: Less expensive than T3. Lower cost & longer half-life make it a drug of choice for chronic treatment of hypothyroidism.
References: www.rxlist.com
Drug: Triodothyronine (T3),
Drug Class: Thyroid hormone
Mechanism of Action: see T4 above.
Indications: 1) replacement therapy or supplement in patients with hypothyroidism; 2) for short term suppression of the pituitary thyroid-stimulating hormone (TSH) in the treatment or prevention of various types of euthyroid goiters, including Hashimoto's goiter; 3) as diagnostic agents in suppression tests to differentiated suspected mild hyperthyroidism or thyroid gland autonomy.
Contraindications: heart disease (T3 can cause cardiotoxicity)

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.
References: www.rxlist.com
Liothyronine
Drug Class: Thyroid hormone
Mechanism of Action: see T4 above.
Indications: 1) replacement therapy or supplement in patients with hypothyroidism; 2) for short term suppression of the pituitary thyroid-stimulating hormone (TSH) in the treatment or prevention of various types of euthyroid goiters, including Hashimoto's goiter; 3) as diagnostic agents in suppression tests to differentiated suspected mild hyperthyroidism or thyroid gland autonomy.
Contraindications: heart disease (T3 can cause cardiotoxicity)

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.
References: www.rxlist.com
Thyroxine (Levoxyl, Levo-T Synthroid, Unithroid ®)
Drug Class: Thyroid hormone

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.
Indications: Hypothyroidism & Pituitary TSH Suppression (in the treatment or prevention of various types of euthyroid goiters).
Pharmacokinetics: Taken orally. T4 has a longer half life (7 days) compared to T3 (1 day).
Side Effects: those resembling the symptoms of hyperthyroidism, e.g. nervousness, anxiety, tremor, heat intolerance, weight loss w/ increased appetite, arrhythmias (palpitations). Hyperthyroidism will increase the metabolic clearance and decrease the half life of T3 (& T4).

Notes: Less expensive than T3. Lower cost & longer half-life make it a drug of choice for chronic treatment of hypothyroidism.
References: www.rxlist.com
Drug: Potassium Iodide (generic, SSKI ®)
Drug Class: Antithyroid
Mechanism of Action: A major action of iodide is to inhibit hormone release from the thyroid gland. This may result from inhibition of thyroglobulin proteolysis (which is necessary for production/excocytosis of thyroid hormones). It can also interfere with the synthesis of thyroid hormones by inhibiting thyroidal peroxidase inside the thyroid gland. The thyroid gland will "escape" from iodide block in 2-8 weeks.
Indications: hyperthyroidism & thyroid storm: Graves' disease, toxic adenoma, goiter, thyroiditis. Rarely used as sole therapy. Used prior to thyroid gland surgery to decrease the vascularity of the thyroid gland.
Contraindications: pregnancy - iodide can cross the placenta & cause fetal goiter.
Side Effects: acne-like rash, swollen salivary glands, ulcerations of mucous membranes (sore mouth), conjunctivitis, rhinorrhea, metallic taste in the mouth
Notes: Propranolol (blunts sympathetic stimulation) & large doses of PTU are also used to treat thyroid storm.
References: Katzung's text
Drug: Radioactive I -131 (Iodotope, Sodium Iodide 131 Therapeutic ®)
Drug Class: Antithyroid
Mechanism of Action: I-131 is rapidly absorbed & is concentrated in the thyroid, where it is incorporated into storage follicles. It's therapeutic effect depends on emission of beta rays with an effective half-life of ~56 days. Beta particles act on parenchymal cells with little damage to surrounding tissue.
Indications: Thyrotoxicosis - multinodular hyperthyroidism & toxic adenomas.
Contraindications: pregnancy or nursing mothers
Side Effects: delayed hypothyroidism
References: Katzung's text
Drug: Iopanoic acid (Telepaque ®)
Drug Class: Iodinated Contrast Media
Mechanism of Action: rapidly inhibit the conversion of T4 to T3 in the liver, kidney, pituitary gland & brain. Released iodine may also inhibit the release of hormone from the thyroid gland.
Indications: adjunct treatment for thyroid storm
References: Katzung's text
Ipodate sodium (Oragrafin sodium, Bilivist ®)
Drug Class: Iodinated Contrast Media
Mechanism of Action: rapidly inhibit the conversion of T4 to T3 in the liver, kidney, pituitary gland & brain. Released iodine may also inhibit the release of hormone from the thyroid gland.
Indications: adjunct treatment for thyroid storm
References: Katzung's text
Drug: Propylthiouracil or PTU (generic)
Drug Class: Antithyroid (Thioamide)
Mechanism of Action: Mulitple mechanisms. The major action is to prevent thyroid hormone synthesis by inhibiting the thyroid peroxidase-catalyzed reactions & blocking iodine organification. It also blocks coupling of iodotyrosines. Inhibits the peripheral deiodination (deiodinase D1) of T4 & T3.
Indications: thyrotoxicosis (high doses must be used if used to treat thyroid storm).
Pharmacokinetics: Since synthesis rather than release of thyroid hormone is effected, there is a slow onset of observable effects, often taking 3-4 weeks before stores of T4 are depleted.
Side Effects: rash (common), edema, agranulocytosis (infrequent but potentially fatal, usually reversible upon drug withdrawal)
Notes: PTU is used in preference to methimazole in nursing mothers since it does not accumulate in breast milk to the same extent.
References: Katzung's text
Drug: Methimazole (Tapazole ®)
Drug Class: Antithyroid (Thioamide)
Mechanism of Action: ~10 times more potent than propylthiouracil. Similar mechanism of action as PTU, except it does not effectively block deiodinase D1.
Contraindications: nursing mothers - methimazole is found in breast milk.
References: Katzung's text
Toxicon: Acetaminophen (Tylenol ® and others)
Source: NSAID
Mechanism of Action: Acetaminophen is rapidly absorbed from the stomach and small intestine and metabolized by conjugation in the liver to nontoxic agents, which then are eliminated in the urine. In acute overdose or when maximum daily dose is exceeded over a prolonged period, the normal pathways of metabolism become saturated. Excess acetaminophen is then metabolized in the liver via the mixed function oxidase P450 system to a toxic metabolite. Under conditions of excessive metabolite formation or reduced glutathione stores, the reactive metabolite is free to covalently bind to vital proteins and the lipid bilayer of hepatocytes; this results in hepatocellular death and subsequent centrilobular liver necrosis.
Symptoms: 0-24 hr: asymptomatic, pallor, anorexia, nausea & vomiting, malaise; 18-72 hr: right upper quadrant abdominal pain & rising liver enzymes (AST & ALT), tachycardia, hypotension; after 3-4 days: hepatic dysfunction with jaundice, recurrence of nausea & vomiting, renal failure, possible death; otherwise after 4day - 3 week: resolution of symptoms.
Antidote/Treatment: The antidote for acetaminophen poisoning is N-acetylcysteine (Mucomyst ®). It increases glutathione stores, combines directly with acetaminophen's reactive metabolite as a glutathione substitute, and enhances sulfate conjugation. It also functions as an anti-inflammatory and antioxidant.
Oral activated charcoal avidly adsorbs acetaminophen & should be given within 1-2 hours after ingestion of acetaminophen, or if the time of ingestion is unknown. Supportive therapy, including IV fluids, oxygen, and cardiac monitor
Notes: Acetaminophen is the most widely used pharmaceutical analgesic and antipyretic agent in the United States and the world. It is contained in more than 100 products. As such, acetaminophen is one of the most common pharmaceuticals associated with both intentional and accidental poisoning.The toxic dose of APAP after a single acute ingestion is 150 mg/kg or approximately 7 g in adults, although the at-risk dose may be lower in persons with alcoholism and other susceptible individuals. When dosing recommendations are followed, the risk of hepatotoxicity is extremely small.
Reference: http://www.emedicine.com/emerg/toxicolgy.htm
Toxicon: Amphetamines
Source: drug of abuse
Mechanism of Action: CNS and peripheral stimulant. Cause the release of catecholamines (dopamine, norepinephrine & serotonin) from nerve terminals. The signs & symptoms of amphetamine overdose are generally similar to those of cocaine; however, while effects of cocaine last for 10-20 minutes, the duration of amphetamine action is much longer, lasting as long as 10-12 hours.
Symptoms:agitation & hyperactivity, euphoria, skin flushing, chest pain, palpitations, dry mouth, hyperthermia, nausea & vomiting, mydriasis, anorexia & weight loss, symptoms of stroke.
Treatment: Patients with amphetamine intoxication manifesting no life-threatening signs or symptoms may be treated with sedation and observation and may require no laboratory workup. Patients suffering seizures or prolonged mental status changes require glucose and electrolyte testing. Complications may require the physician to perform procedures to establish airway management, fluid resuscitation, or initiate vigorous cooling measures. Use benzodiazepine sedation (nonspecific sympatholysis) to initially manage hypertension, if present. Aggressively cool hyperthermic patients with evaporative cooling and ice packs to the groin and axilla
Reference:http://www.emedicine.com/emerg/toxicolgy.htm
Toxicon: Anticholinergics (antimuscarinics)
Source: Atropine-like drugs, H-1blockers, plants (jimson weed, nightshade & various "non commercial" mushrooms).
Mechanism of Action: block muscarinic receptors in the CNS and peripheral nervous system.
Symptoms: red as a beet, dry as a bone, blind as a bat, mad as a hatter, and hot as a hare." The mnemonic refers to the symptoms of flushing, dry skin and mucous membranes, mydriasis with loss of accommodation, altered mental status, and fever, respectively. Also: tachycardia, urinary retention, decreased bowel sounds.
Antidote/Treatment: The antidote for anticholinergic toxicity is physostigmine salicylate. Physostigmine is the only reversible acetylcholinesterase inhibitor capable of directly antagonizing the CNS manifestations of anticholinergic toxicity; it is an uncharged tertiary amine that efficiently crosses the blood brain barrier. (However, physostigmine is contraindicated in patients with cardiac conduction disturbances such as prolonged PR and QRS intervals). GI decontamination with activated charcoal is usually necessary after anticholinergic poisoning by ingestion. Ipecac syrup is contraindicated because of the potential for seizures. Most anticholinergic agents have large volumes of distribution and are highly protein-bound; therefore, hemodialysis and hemoperfusion are ineffective treatment methods. Following GI decontamination, patients often recover well with supportive care. Manage seizures with benzodiazepines, preferably diazepam or lorazepam. Phenothiazines are contraindicated because of their anticholinergic properties. Perform bladder catheterization if signs or symptoms of urinary retention exist
Notes: According to the American Association of Poison Control Centers, almost 2.2 million cases of human poison exposure were reported to 65 US poison control centers in 1998.
Reference:http://www.emedicine.com/emerg/toxicolgy.htm
Toxicon: Arsenic
Source: Arsenic poisoning occurs through industrial exposure (e.g. metal foundaries, glass production & semiconductor industries), rodenticide, from contaminated wine, or because of malicious intent (remember the Borgias).
Mechanism of Action: Inorganic forms of arsenic are more toxic than organic forms. Very few organ systems escape the toxic effects of arsenic. Trivalent inorganic arsenic inhibits pyruvate dehydrogenase (via binding to sulfhydryl groups), resulting in decreased citric acid cycle activity, and decreased production of cellular ATP. Trivalent arsenic inhibits numerous other cellular enzymes through sulfhydryl group binding. Trivalent arsenic inhibits cellular glucose uptake, gluconeogenesis, fatty acid oxidation, and further production of acetyl CoA; it also blocks the production of glutathione, which prevents cellular oxidative damage.
Symptoms: Acute exposure: garlic smell on the breath & tissue fluids, acute distress, dehydration (often), choleralike gastrointestinal symptoms of vomiting and severe diarrhea (watery & bloody) and hypovolemic shock. Chronic exposure: whitish lines (Mees lines) that look much like traumatic injuries are found on the fingernails, peripheral neuorpathy & dermal hyperpigmentation/ depigmentation (salt/pepper) of the skin, scaly palms, hepatic & renal damage, prolongation of the QT, cardiac arrhythmias & ventricular fibrillation. Microcytic hyprochromic anemia is also common with all heavy metal intoxications.
Treatment: Dimercaprol (BAL in oil) is a first line agent in arsenic poisoning. (Some other chealators may also be effective although they are not approved for this indication.) Hemodynamic stabilization (crystalloid solutions - to replace what is lost by diarrhea & vomiting). Do not delay with definitive chelation therapy and hemodialysis. Activated charcoal does not absorb arsenic very well. The use of GI decontamination is controversial.
Reference:http://www.emedicine.com/emerg/toxicolgy.htm
Toxicon: Barbiturates
Source: sedative/hypnotic/anesthetic
Mechanism of Action: .Barbiturates bind to specific sites on gamma-aminobutyric acid (GABA)-sensitive ion channels found in the central nervous system (CNS), where they allow an influx of chloride into cell membranes and, subsequently, hyperpolarize the postsynaptic neuron.
Symptoms: Neurologic: lethargy, coma, hypothermia, decreased pupillary light reflex, nystagmus, impairment in thinking, respiratory depression, tachycardia or bradycardia, hypotension
Treatment: ABCs. Check for hypothermia (& if present, warm the patient to avoid preciptating a fall in blood pressure). Perform GI decontamination once the airway is protected and hemodynamic stabilization addressed. Activated charcoal orally or by nasogastric tube is recommended for all patients with potential barbiturate toxicity. (Induction of emesis with ipecac syrup is contraindicated in these patients because the depressed neurologic response increases risk of aspiration). Alkalinization of the urine with sodium bicarbonate to enhance the elimination of phenobarbital and, likely, other long-acting barbiturates by ion trapping. Urinary alkalinization is not recommended for short-acting barbiturate toxicity. Aggressively initiate fluid therapy if the patient is hypotensive or appears to be in hypovolemic shock. Hemodialysis and hemoperfusion enhance elimination of barbiturates.
Reference:http://www.emedicine.com/emerg/toxicolgy.htm
Toxicon: Benzodiazepines
Source: sedative hypnotic, antiepileptic
Mechanism of Action: potentiates the activity of GABA. In the CNS this results in sedation, striated muscle relaxation, anxiolysis, and anticonvulsant effects. Stimulation of peripheral nervous system (PNS) GABA receptors may cause decreased cardiac contractility, vasodilation, and enhanced perfusion.
Symptoms: drowsiness, nystagmus, confusion, slurred sppech, ataxia, coma, weakness, amnesia, hypotension, respiratory depression
Antidote/Treatment: Flumazenil is the DOC to reverse effects of benzodiazepines. Other treatments: ABCs. Single-dose activated charcoal is recommended for GI decontamination in patients who present within 4 hours of ingestion or in symptomatic patients when the time of ingestion is unknown.Ipecac syrup is contraindicated for prehospital or hospital use because of the risk for CNS depression and subsequent aspiration with emesis. Respiratory depression may be treated with assisted ventilation.
Notes: In 1998, a total of 40,004 benzodiazepine exposures were reported to US poison control centers. Benzodiazepines generally are thought to be safe and death is rare.
Reference:http://www.emedicine.com/emerg/toxicolgy.htm
Toxicon: Carbon monoxide (CO)
Source: a colorless, odorless gas produced by incomplete combustion of organic compounds. Although most fatalities result from fires, stoves, portable heaters, and automobile exhaust cause approximately one third of deaths. These often are associated with malfunctioning or obstructed exhaust systems and suicide attempts. Cigarette smoke is a significant source of CO. Natural gas contains no CO, but improperly vented gas water heaters, kerosene space heaters, charcoal grills, hibachis, and Sterno stoves all emit CO.
Mechanism of Action: CO toxicity causes impaired oxygen delivery and utilization at the cellular level. CO affects several different sites within the body but has its most profound impact on the organs with the highest oxygen requirement (eg, brain, heart). Toxicity primarily results from cellular hypoxia caused by impedance of oxygen delivery. CO reversibly binds hemoglobin, resulting in relative anemia. Because it binds hemoglobin 230-270 times more avidly than oxygen, even small concentrations can result in significant levels of carboxyhemoglobin (HbCO).
Symptoms: Malaise, flulike symptoms, fatigue, dyspnea on exertion, chest pain, confusion, lethargy, dizziness, coma, death.
Treatment: 100% oxygen or hyperbaric oxygen.
Notes: Misdiagnosis commonly occurs because of the vagueness and broad spectrum of complaints; symptoms often are attributed to a viral illness. Specifically inquiring about possible exposures when considering the diagnosis is important. Lab test: HbCO analysis requires direct spectrophotometric measurement in specific blood gas analyzer.
Reference:http://www.emedicine.com/emerg/toxicolgy.htm
Toxicon: Caustic agents (acid or base)
Source: corrosive agent toxicity, acidic or alkaline substance toxicity, toilet bowl cleaning product ingestion, automotive battery liquid ingestion, rust removal product ingestion, metal cleaning product ingestion, cement cleaning product ingestion, drain cleaning product ingestion, etc.
Mechanism of Action: Alkaline ingestions cause tissue injury by liquefactive necrosis (saponification of fats and solubilization of proteins). The hydroxide ion of the base reacts with tissue collagen and causes it to swell and shorten. Small vessel thrombosis and heat production occurs. Acid ingestions cause tissue injury by coagulation necrosis (desiccation or denaturation of superficial tissue proteins).
Symptoms:Oropharyngeal burns, dyspnea & impending airway obstruction, drooling, nausea & vomiting
Treatment: Airway control (equipment for endotracheal intubation should be made available); gastric lavage. DO NOT ADMINISTER EMETICS because of risk of re-exposure to the caustic agent. If within 30 min of ingestion, try dilution: tap water in doses of 250 cc for adults and 5 cc/kg in children can be given. Do not administer a weak acid in alkaline ingestions or a weak base in acid ingestions. Excessive heat production and risk of emesis make this a hazardous intervention. Antibiotics (ampicillin) can be given for prophylaxis if there is evidence for perforation. H-2 receptor antagonists may reduce exposure of injured esophagus to gastric acid. Glucocorticoids may help prevent esophageal strictures.
Notes: Ingestion of caustic substances, accidental and intentional, is an extremely common event. Approximately 80% of caustic ingestions occur in children younger than 5 years. Most intentional ingestions occur in adults.
Reference:http://www.emedicine.com/emerg/toxicolgy.htm
Toxicon: Cocaine
Source: drug of abuse
Mechanism of Action: CNS stimulant (blocks the reuptake of catecholamines:5-HT, DA, NorEpi); Na and K channel blocker; commonly coadministered with ethanol to create cocaethylene which has a longer half-life
Symptoms:Chest pain, MI, arrhythmias, cardiomyopathy, hypertension, psychatric symptoms (including paranoia, psychosis & the sensation of something crawling on the skin or itchy skin), seizures, hyperthermia, hypertension, tachycardia, dilated pupils (mydriasis). Most acute cocaine-related nontraumatic deaths are the result of tachydysrhythmias. Other causes of sudden death associated with cocaine use include stroke, subarachnoid hemorrhage, hyperthermia, and the consequences of agitated delirium. MI can result from acute vasospasm, dysrhythmias, or chronic accelerated atherogenic disease.
Treatment: Establish ABC's, provide oxygen, i.v. access, monitor vital signs & glucose levels, administer benzodiazepines to manage seizures. Warning: cocaine toxicity can cause patients to become aggressive, & combative. The role of lidocaine in treating ventricular arrhythmias is unclear (there are concerns with it's use due to the fact that it is a Na channel blocker - like cocaine, and "may" worsen cardiac conduction disturbances or induce seizures). Non-selective beta blockers should be avoided. Administer sodium bicarbonate to manage acidosis. Nitroglycerin for cocaine-related MI if present. Treat hyperthermia with convection cooling (spray patient with tepid water in the presence of fans), ice packs or cooling blankets. In the absence of serious toxic reactions, the (non-lethal) acute effects of cocaine are generally short-lived due to its short half life (~50 mins) although this may be prolonged 2-3 fold if alcohol is coingested.
Reference:http://www.emedicine.com/emerg/toxicolgy.htm
Toxicon: Cyanide
Source: fumigates & insectisides (e.g. termites), smoke inhalation from industrial fires
Mechanism of toxicity: Cyanide affects virtually all body tissues, attaching itself to ubiquitous metalloenzymes and rendering them inactive. Its principal toxicity probably results from inactivation of cytochrome oxidase (cytochrome aa3) and, thus, cellular respiration, even in the presence of adequate oxygen stores. Consequently, the tissues with the highest oxygen requirements (eg, brain, heart, liver) are the most profoundly affected by acute cyanide poisoning. Cyanide cabinduce fatality in seconds to minutes following inhalation or intravenous injection, in minutes following ingestion of soluble salts, or minutes (hydrogen cyanide) to several hours (cyanogens) after skin absorption.
Symptoms: bitter almond odor on breath, bitter taste, burning throat, lock jaw, convulsions, coma, respiratory failure.
Antidote: ABC's including aggressive airway management with delivery of 100% oxygen, amyl nitrite (inhaled), sodium nitrite (i.v.) to induce the formation of methemoglobin (F3+) from hemoglobin, which will bind cyanide to form a non-toxic complex. Treatment must be rapid (w/in 5-10 min). Sodium thiosulfate (Tinver ®) -- Second-line therapy because of slower mechanism of action. Regenerates sulfur-dependent rhodanese activity. Coadminister with or after sodium nitrite or hydroxocobalamin. Useful adjunct in prolonged (cyanogen) poisonings.
Reference:http://www.emedicine.com/emerg/toxicolgy.htm
Toxicon: Digoxin
Source: positive intropic drug
Mechanism of Toxicity: inhibits Na/K ATPase; cardiac arrhythmias (delayed after-depolarizations w/ abnormal automaticity, depolarization & conduction block, 1st - 3rd degree AV node conduction block, enhanced vagal tone); CNS effects
Symptoms: GI disturbances (abdominal pains, diarrhea), cardiac arrhythmias & ECG changes (various arrhythmias, bigeminy, 1st-3rd AVN block; ST depression, etc.); neurological (nausea, vomiting, fatigue, anorexia, dizziness, dreams, psychic complaints, headache), visual disturbances (yellow green color hues, halos, blurred vision, photophobia).
Antidote/Treatment: Digoxin Fab fragments (Digibind) are generally indicated for potentially fatal overdose (e.g. hemodynamically unstable arrhythmias, hyperkalemia greater than 6 mM, digoxin level greater than 10 ng/ml in adults or ingestion of greater than 10 mg = 40 x 0.25 mg tablets or greater than 0.3 mg/kg in children). Other treatments: oxygen, cardiac monitoring, i.v. access, check electrolyte levels & correct any imbalances. Note: diuretics that are commonly taken in patients with CHF can cause hypokalemia which will increase digitalis toxicity (potassium supplements should be used to correct hypokalemia). Give atropine for unstable bradyarrhythmias or to correct severe AV node conduction block, lidocaine for ventricular arrhythmias (consider magnesium therapy as a temporizing antiarrhythmic agent until Fab fragments are available). Activated charcoal or cholestyramine can be used for acutely ingested digoxin/digitoxin; (note: gastric lavage may intensify vagal tone & may worsen arrhythmias - pretreat with atropine; Digibind makes gastric lavage unnecessary). Treat any hyperkalemia >5.5 mM with Na bicarb, glucose & insulin. Kayexalate (0.5 g/kg PO) also is helpful in binding potassium and enterohepatically-recycled digitalis, but may cause hypokalemia when combined with glucose & insulin.
Major drug Interactions: verapamil, amiodarone, quinidine can increase digoxin plasma levels (e.g. two-fold).
Reference: http://www.emedicine.com/emerg/toxicolgy.htm
Toxicon: Hydrocarbons (e.g. gasoline, kerosene)
Source: found in homes & almost every industrial business
Mechanism of Action:
Symptoms: odor of hydrocarbons (HCs) on the breath or clothes, mild burning of the mouth, fever, grunting respirations, coughing & respiratory distress, aspiration pneumonitis, lethargy & depressed sensorium, nausea, vomiting, diarrhea, dyspnea, sudden cardiac death due to arrhythmias. The lungs are affected most commonly (due to aspiration). A patient who ingests turpentine or gasoline is more likely to aspirate than a patient who has ingested grease or petroleum jelly. Even small amounts of HCs may cause a chemical pneumonitis; because many HCs have poor water solubility, they penetrate deep into the bronchopulmonary tree, causing bronchospasm followed by an inflammatory response
Treatment: Management for HC ingestion is supportive. No specific antidotes are available. Observe patients in a monitored setting for signs of respiratory distress. Cardiac monitor and pulse oximetry are recommended. Patients who show signs of impending respiratory failure, despite supplemental oxygen, may require rapid intubation & ventilation. Decontamination of the GI tract generally is not recommended because of the risk of aspiration and the low GI toxicity of most HCs. Indicated medications include dextrose, thiamine, and naloxone for altered mental status and albuterol for bronchospasm.Elevated aminotransferases may be observed with HC ingestions. The halogenated HCs are particularly hepatotoxic.
Notes:The American Association of Poison Control Centers lists HCs as the 12th most common poison exposure. In 1997, 3% of cases reported to US poison control centers involved HC exposure; of these cases, 95% were unintentional and approximately 60% were pediatric. More than 80% of the 1997 reported exposures were to aliphatic compounds, such as gasoline, kerosene, and turpentine; toxic ingestions by children younger than 5 years often involve these aliphatic HCs.
Reference: http://www.emedicine.com/emerg/toxicolgy.htm
Toxicon: Lead
Source: paints, dyes.
Mechanism of Action: heavy metals bind to sulfhydryl groups in proteins, resulting in alterations in enzymatic activity. Nearly all organ systems are involved, but the nervous system, GI, hematopoietic, renal & cardiovascular systems are most commonly affected the most.
Symptoms: In children: encephalopathy with seizures (most common). In adults: GI complaints, neurological dysfunction and anemia are most common. Anemia. Lead line (blue black deposit along gum margin). Wrist and/or foot drop.
Treatment: ABCs, diazepam, EDTA or BAL plus EDTA. Aggressive hydration.
Notes: Of the heavy metals, toxicity by chronic lead exposure is the most commonly encountered. Toxicity is more common in lower socioeconomic areas.
Reference: http://www.emedicine.com/emerg/toxicolgy.htm
Toxicon: LSD (lysergic acid dieethylamide)
Source: drug of abuse
Mechanism of Action: interacts with several different serotonin receptor subtypes (agonist at 5-HT1A & 5-HT1C ) and antagonist at 5-HT2 (the later is believed to be not important for producing hallucinations).
Symptoms: hallucinogenic (organized visual illusions), patient may be confused or disoriented, have distorted perceptions & impaired judgment, mydriasis, tachycardia, mild hypertension & tachypnea, tremor. The patient may present themselves to the ER after having had a "bad trip" (uncomfortable hallucination). Flashbacks occur in most patients who have taken LSD more than 10 times. Intoxication usually lasts 8-12 hours, but psychotic behavior may persist for days.
Treatment: supportive care & benzodiazepines (diazepam) to decrease agitation, haloperidol for acute psychosis.
Reference: http://www.emedicine.com/emerg/toxicolgy.htm, Katzung's text.
Toxicon: Marijuana (cannabis, hashish)
Source: usually not revealed
Mechanism of Action: the active ingredient is delta-9 tetrahydrocannabinol (THC) which binds to CB1 and CB2 receptors in the brain.
Symptoms: Acute: euphoria, relaxation, subjective feelings of well-being or grandiosity, perceptual changes (including visual distortions), drowsiness and sluggishness, diminished coordination, paradoxical hyperalertness, a subjective sense of slowing of the passage of time, increased appetite (the "munchies"). Dysphoric effects can also occur - e.g. feelings of panic, paranoia, depersonalization (a feeling that you can step outside of yourself). Use is sometimes associated with an "amotivational syndrome". Medically it has an effect to decrease intraoccular pressure in glaucoma patients as well as antinausea effects which has permited the use of marijuana (e.g. in cancer patients) in some states in the US.
Treatment: supportive care. Frequent reassurance and maintenance of a nonthreatening environment, minimal stimuli, judicious use of benzodiazepines when significant anxiety is present
Notes: Marijuana remains the most commonly used illicit drug in the United States. The 1998 National Household Survey on Drug Abuse (NHSDA) reported that more than 72 million Americans (33%) aged 12 years and older have tried marijuana at least once in their lifetimes. It is a DEA category I drug (but see above).
Reference: http://www.emedicine.com/emerg/toxicolgy.htm
Toxicon: Mercury
Source: mercury vapors, inorganic or organic forms
Mechanism of Action: heavy metals bind to sulfhydryl groups in proteins, resulting in alterations in enzymatic activity.
Symptoms: CNS dysfunction (irritability), tremors, painful extremeties with pink discoloration of the hands & feet & desquamation of the hands & feet. Gingivitis,
Treatment: Remove the source of mercury if possible. ABCs. GI decontamination with activated charcoal. Control diarrhea, administer chelation therapy (BAL)
Reference: http://www.emedicine.com/emerg/toxicolgy.htm
Toxicon: Methanol
Source: cleaning materials, solvents, paints, varnishes, Sterno fuel, formaldehyde solutions, antifreeze, gasohol, "moonshine," windshield washer fluid (30-40% methanol), and duplicating fluids.
Mechanism of Action: A CNS depressant, methanol is potentially toxic in amounts as small as a single mouthful. When metabolized by hepatic alcohol and aldehyde dehydrogenase, methanol forms formaldehyde and formic acid, both of which are toxic. The eyes, CNS, and GI tract are affected. Formic acid is the primary toxin that accounts for the majority of the anion gap, metabolic acidosis, and ocular toxicity. Lactic acid also contributes to the anion gap. Formic acid inhibits cytochrome oxidase in the fundus of the eye. Swelling of axons in the optic disc and edema result in visual impairment. Formaldehyde has a short half-life, lasting only minutes. Formic acid is metabolized much more slowly, and it bioaccumulates with significant methanol ingestion.
Symptoms: lethargy, confusion, headache, vertigo, blurry, nausea, vomiting, abdominal pain, indistinct, misty, or snowstorm-like visual disturbances, blindness, coma, seizures, respiratory depression/death.
Treatment: Supportive measures & provide airway protection. Dialysis may be needed to remove methanol and its principal toxic metabolite, formate. (While forced diuresis might be considered, since methanol is excreted renally - dialysis works better and has less danger of pulmonary edema, cerebral edema, or acute respiratory distress syndrome). Attempted correction of acidosis using sodium bicarbonate is indicated if pH is less than 7.20; note that patients may require large quantities. An alkalemic pH makes it more likely that formic acid will exist as its anion (formate), which cannot access the CNS and optic nerve as readily. Administer folic acid (leucovorin) 50 mg IV every 4 hours for several days to potentiate the folate-dependent metabolism of formic acid to carbon dioxide and water. Consider ethanol infusion in any patient with an unexplained osmolar gap and/or elevated anion-gap metabolic acidosis that is unaccounted for by ethanol, until a definitive diagnosis negating its administration is made.
Notes: A delay in treatment of methanol intoxication may lead to increased morbidity and mortality. Recognition and timely treatment are essential for a full recovery.
Reference: http://www.emedicine.com/emerg/toxicolgy.htm
Toxicon: Methaqualone (quaalude)
Source: sedative-hypnotic
Mechanism of Action: a non-barbiturate sedative hypnotic, stimuates the actions of GABA.
Symptoms: resembles barbiturate poisoning. Has more pronounced motor problems (e.g. ataxia) and is known as "wallbanger" because of this phenomenon. Can lead to severe muscular hypertonicity and seizures.
Treatment: no diuresis. Diazepam for severe tonicity or seizures (strongly consider phenytoin as an anticonvulsant because barbiturates potentiate the effect of methaqualone).
Reference:http://www.emedicine.com/emerg/toxicolgy.htm
Toxicon: Morphine & similar narcotics
Source: narcotic analgesic, drug of abuse
Mechanism of Action: opioid receptor agonist
Symptoms: clinical triad of CNS depression, respiratory depression, and pinpoint pupils (miosis) are present. (Note: meperidine & propoxyphene sometimes are associated with mydriasis or midpoint pupils.) Drowsiness, and euphoria are frequently seen. Hypotension & hypothermia.The leading cause of morbidity and mortality from pure opioid overdoses is respiratory compromise. Less commonly, pulmonary edema, status epilepticus, and cardiotoxicity.
Antidote/Treatment: Administer naloxone for significant CNS and/or respiratory depression.Naloxone can be given IV, ET, or IM. If an IV cannot be established, administer 2 mg of IM naloxone. By the ET, or IV route, the onset of action of naloxone is 1-2 minutes. A second dose can be repeated every 2-3 minutes. Discontinue treatment as soon as the desired degree of opioid reversal is achieved.The clinical half-life of naloxone is 20-60 minutes. In patients with opiate addiction, naloxone may precipitate opiate withdrawal symptoms, so the dose of naloxone should be titrated carefully in such patients. Activated charcoal is the GI decontamination method of choice for patients with opiate intoxication following ingestion. Because of impairment of gastric emptying and GI motility produced by opiate intoxication, activated charcoal still may be effective when patients present late following ingestion.
Reference: http://www.emedicine.com/emerg/toxicolgy.htm
Toxicon:Organophosphate & carbamate (anticholinesterases)
Source: pesticides, chemical warfare
Mechanism of Action: Organophosphates irreversibly bind to cholinesterase, causing the phosphorylation and inactivation of acetylcholinesterase. Carbamate poisoning exhibits a similar clinical picture to organophosphate toxicity. However, unlike organophosphates, carbamate compounds temporarily bind cholinesterase for approximately 6 hours with no permanent damage. Carbamates have poor CNS penetration and cause minimal CNS symptoms.
Symptoms: Mild flulike symptoms from minimal exposures frequently are unreported or untreated. Common presenting features include: headache, mental confusion, diffuse muscle cramping and/or fasiculations, miosis, bronchospasm, weakness, excessive secretions, nausea, vomiting, and diarrhea (remember: SLUDE). The condition may progress to seizure, coma, paralysis, respiratory failure, and fatality. Delayed or inadequate treatment of organophosphate poisoning can lead to prolonged (months) or permanent neurotoxic symptoms.
Antidote/Treatment: decontamination, atropine, oxygen, pralidoxime for organophosphates (not carbamates); benzodiazepines to control seizures.
Notes: In the US: Approximately 20,000 reported organophosphate exposures occur each year.
Reference: http://www.emedicine.com/emerg/toxicolgy.htm
Toxicon: Oxalate plant poisoning
Source: caladium, philodendron, calla lily, skunk cabbage, and others
Mechanism of Action: Nonsoluble calcium oxalate crystals are found in plant stems, roots, and leaves. These needlelike crystals produce pain and edema when they contact lips, tongue, oral mucosa, conjunctiva, or skin. Edema primarily is due to direct trauma from the needlelike crystals and, to a lesser extent, by other plant toxins (eg, bradykinins, enzymes).
Symptoms: Depending on the mode of contact (skin, eye or oral): local skin erythema and/or edema (typical of a contact dermatitis) due to contact with plant sap or juices. Keratoconjunctivitis and corneal abrasions after contact with plant material, edema, erythema, bullae, and local inflammation of mouth and oral mucosa after contact; esophagitis, slurred or unintelligible speech, laryngeal edema (with sufficient contact), superficial necrosis developing days after initial contact.
Treatment: Decontaminate mouth, eye, and skin by physically removing all plant material. Treat eye and skin exposure with copious water irrigation. Acetaminophen for pain control. Antihistamines (diphenhydramine).
Notes: Plant exposures are some of the most frequent poisonings reported to poison control centers. Exposures to plants containing oxalate crystals, such as Philodendron and Dieffenbachia, are among the most common toxic plant exposures reported in the US.
Toxicon: Phencyclidine (PCP, angel dust)
Source: drug of abuse, dissociative anesthetic
Mechanism of Action: a NMDA (Glutamate) receptor antagonist. It is primarily metabolized in the liver and undergoes significant enterohepatic recirculation. Clinical effects occur within minutes and can last several hours.
Symptoms:The presentation of the acutely poisoned PCP patient may range from catatonia to extreme agitation. Horizontal, vertical, or rotary nystagmus is usually present (>50%). Miosis with a blank stare, hypertension, tachycardia, disorientation, amnesia, analgesia, combativeness & paranoid behavior, catatonic posturing, hyperreflexia, muscle rigidity, dystonia, hallucinations, coma .
Treatment: ABCs, IV hydration and sedation are initial management considerations. Administer benzodiazepines (diazepam) to patients with severe agitation, with or without antipsychotics (haloperidol) to treat prlonged psychotic behavior. (Note: Because of the anticholinergic effects of PCP, neuoleptics with anticholinergic effects, such as chlorpromazine should be avoided.) Physical and chemical restraints may be necessary. Activated charcoal minimizes the enterohepatic circulation of the drug. PCP coma may last 7-10 days
Notes: Acute phencyclidine (PCP) intoxication can be one of the most challenging toxicologic emergencies for the emergency physician. The myriad of presentations may range from a "bad trip" to seizures and coma.
Toxicon: Phenothiazines
Source: antipsychotic medication (e.g. chlorpromazine)
Mechanism of Action: "Anti-transmitter" actions: block histamine, serotonin, norepinephrine and dopamine receptors. Block of alpha-adrenergic receptors.
Symptoms: drowsiness, agitation, convulsions, muscle spasms, tremor & rigidity, inability to sit still, miosis, orthostatic hypotension and hypothermia (poikliothermia), ventricular tachyarrhythmias, coma
Treatment: gastric lavage (even if several hours have elapsed since the drug was taken - these drugs decrease GI motility). Activated charcoal binds most phenothiazines, and may be followed by a saline cathartic. Hypotension often responds to fluid replacement. If a pressor agent is required, norepinephrine or dopamine is prefered over epinephrine due to the concern about the "epi reversal" effect on blood pressure (unopposed beta-2 effect in the presence of alpha receptor blockade by the phenothiazine). Seizures may be treated with diazepam or phenytoin.
Reference: Katzung's text
Toxicon: Phenytoin
Source: anticonvulsant
Mechanism of Action: sodium channel blocker, decreases neuronal excitability.
Symptoms: nystagmus (horizontal, vertical), ataxia, slurred speech, lethargy & confusion, coma & seizures, hypotension. Chronic side effects: gingival hyperplasia, hirsutism (excessive hairiness), rashes, acne.
Treatment: ABCs. Activated charcoal. Hemodialysis or hemoperfusion are ineffective for enhancing elimination. Benzodiazepine for seizures.
Toxicon: Salicylates
Source: aspirin
Mechanism of Action: Salicylates cause an uncoupling of oxidative phosphorylation. Catabolism occurs secondary to the inhibition of ATP-dependent reactions with the following results: increased oxygen consumption,increased carbon dioxide production, accelerated activity of the glycolytic and lipolytic pathways, depletion of hepatic glycogen,hyperpyrexia.
Symptoms: Acid-base disturbances vary with the severity of toxicity. Initially, hyperventilation a respiratory alkalosis develops secondary to direct stimulation of the respiratory centers. This may be the only consequence of mild salicylism. A severe metabolic (ketolactic) acidosis with compensatory respiratory alkalosis may develop with severe salicylate intoxication. Potassium moves from the intracellular space to the extracellular space. Excretion of hydrogen ions produces acidic urine. A paradoxical aciduria (hydrogen ion excretion) occurs with the depletion of sodium bicarbonate and potassium. Ototoxicity, tinnitus, tachycardia, CNS depression, seizures, nausea & vomiting, GI hemorrhage, prolonged bleeding time, dehydration.
Treatment: ABCs. Endotracheal intubation may be required. Gastric lavage may be beneficial, unless contraindicated, up to 60 minutes after salicylate ingestion.
Administer activated charcoal unless contraindications are present. Provide treatment for correction of fluid deficits and enhancement of excretion and elimination. Hemodialysis is the best method for enhanced elimination. Sodium bicarbonate to alkalinize the urine & increase salicylate excretion. Monitor glucose levels closely. Initial hyperglycemia may give way to hypoglycemia and worsening CNS symptoms.
Notes: Onset of chronic salicylism may be insidious; elderly individuals may consume an increasing amount over several days to alleviate arthralgias, subsequently becoming confused because salicylate pharmacokinetics change at higher concentrations. This may lead to a perpetual spiral of increased salicylate consumption and increased confusion. Similar scenarios occur in persons with underlying psychiatric disorders
Toxicon:Theophylline
Source: medication for asthma & COPD
Mechanism of Action: Theophylline affects the cardiovascular (CV), neurological, GI, and metabolic systems. Hypokalemia, hyperglycemia, hypercalcemia, hypophosphatemia, and acidosis commonly occur after an acute overdose. Medication, diet, and underlying diseases can alter its narrow therapeutic window. Adverse effects can be evident at therapeutic serum levels.
Symptoms: nausea, vomiting, abdominal pain, mild metabolic acidosis, hypokalemia, hypophosphatemia, hypomagnesemia, hyperglycemia, sinus tachycardia, tremors, seizures, hypotension, and significant dysrhythmias.
Treatment: ABCs. Aggressive gut decontamination with repeated doses of activated charcoal & whole bowel irrigation. Propranolol or other beta blockers can block a beta-mediated sinus tachycardia & hypotension. Phenobarbital is prefered over phenytoin for treatment of convulsions; most anticonvulsants are ineffective. Hemodialysis is indicated for serum levels >100mg/L and for intractable seizures.
Notes:
Toxicon: Tricyclic antidepressants
Source: Classical antidepressant
Mechanism of Action: TCAs affect the cardiovascular, central nervous, pulmonary, and gastrointestinal systems. The toxic effects on the myocardium are related to the blocking of fast sodium channels, which involves the same mechanism as type IA antiarrhythmics (eg, quinidine). CNS toxicity results from the anticholinergic effects and direct inhibition of biogenic amine reuptake.
Symptoms: tachycardia, hypotension, confusion or hallucinations, mydriasis, dry mucous membranes and skin, decreased bowel sounds, urinary retention, seizures, QRS prolongation & arrhythmias.
Antidote/Treatment: ABCs, activated charcoal to prevent further absorption, sodium bicarbonate (a 1st line thereapy if QRS >100 ms, seizures, acidosis or arrhythmias are present; alkalemia has been shown to protect against and treat dysrhythmias), benzodiazepines (lorazepam) for seizures. Intubate and hyperventilate if coma or depressed mental status is present. Perform orogastric lavage if ingestion is known to be lethal (after intubation).
Notes: In the US: Approximately 500,000 cases of TCA toxicity per year are reported. Fatality before reaching a healthcare facility occurs in approximately 70% of patients attempting suicide with TCAs. Tricyclic antidepressants are the number one cause of fatality from drug ingestion. Only 2-3% of TCA overdoses that reach a health care facility result in death.
Drug: EDTA (ethylene diamine tetra acetic acid)
Drug Class: Heavy Metal Chelator
Mechanism of Action: used as a disodium calcium salt. Forms a soluble heavy metal chelate in the blood which is excreted through the urine.
Indications: chelator for lead (Pb) & cadmium (Cd). Used in combination with BAL when lead levels are >70 ug/dl
Contraindications: Anuria. Ventricular arrhythmias. Use during pregnancy only if the benefits clearly outweigh the risks. Use with extreme caution in digitalized clients as EDTA and calcium may reverse the desired effect of digitalis. Use with caution in clients with heart disease (e.g., CHF) or hypokalemia.
Side Effects: Electrolyte imbalance including hypocalcemia, hypokalemia, hypomagnesemia, hyperuricemia may occur during treatment.
Pharmacokinetics: administered i.v.
Drug: Penicillamine (Cuprimine ®)
Drug Class: Heavy Metal Chelator
Mechanism of Action: chelating agent recommended for the removal of excess copper (e.g.in patients with Wilson's disease).
Indications: NAP - primary drug of choice for methyl mercury & copper poisoning. Penicillamine - secondary agent for treatment of copper & arsenic poisoning.
Side Effects: Penicillamine - generalized pruritus, early & late rashes
Pharmacokinetics: penicillamine is absorbed rapidly but incompletely (40-70%) from the gastrointestinal tract, with wide inter-individual variations. Food, antacids, and iron reduce absorption of the drug. The peak plasma concentration of penicillamine occurs 1-3 hours after ingestion; i
N-acetylpenicillamine (NAP)
Drug Class: Heavy Metal Chelator
Mechanism of Action: chelating agent recommended for the removal of excess copper (e.g.in patients with Wilson's disease).
Indications: NAP - primary drug of choice for methyl mercury & copper poisoning. Penicillamine - secondary agent for treatment of copper & arsenic poisoning.
Side Effects: Penicillamine - generalized pruritus, early & late rashes
Pharmacokinetics: penicillamine is absorbed rapidly but incompletely (40-70%) from the gastrointestinal tract, with wide inter-individual variations. Food, antacids, and iron reduce absorption of the drug. The peak plasma concentration of penicillamine occurs 1-3 hours after ingestion; i
Drug: Succimer (Chemet ® )
Drug Class: Heavy Metal Chelator
Mechanism of Action: metal chelating agent
Indications: Secondary drug to BAL & EDTA for use in the treatment of acute lead poisoning, to remove excess lead from the body, especially in small children. Used when lead concentration is > 45 ug/dl.
Side Effects: skin rash, nausea, diarrhea
Pharmacokinetics: can be administered orally.
Drug: Dimercaprol (BAL in oil)
Drug Class: Heavy Metal Chleator
Mechanism of Action: Forms a chelate by binding sulfhydryl groups with arsenic, mercury, lead, and gold, thus increasing both urinary and fecal excretion of the metals.
Indications: Acute arsenic, mercury, and gold poisoning. With EDTA in acute lead poisoning. Not effective for chronic mercury poisoning.
Contraindications: Iron, cadmium, silver, uranium, or selenium poisoning. Hepatic or renal insufficiency, except postarsenical jaundice. Use during pregnancy only if poisoning is life-threatening.
Side Effects: Most common include hypertension and tachycardia (dose dependent)
Pharmacokinetics: Administered deep IM only. To be fully effective, administer 1-2 hr after exposure. Peak plasma concentration: IM, 30-60 min. Mostly distributed to extracellular fluid. Time to peak levels: 30-60 min. Rapidly metabolized to inactive product and completely excreted in urine and feces in 4 hr.
Major drug Interactions:
Drug: Deferoxamine (Desferal ® )
Drug Class: Iron chelator
Mechanism of Action: an iron-chelating agent. Desferal chelates iron by forming a stable complex that prevents the iron from entering into further chemical reactions. It readily chelates iron from ferritin and hemosiderin but not readily from transferrin; it does not combine with the iron from cytochromes and hemoglobin. Desferal does not cause any demonstrable increase in the excretion of electrolytes or trace metals.
Indications: Desferal is indicated for the treatment of acute iron intoxication and of chronic iron overload due to transfusion-dependent anemias.
Contraindications: Desferal is contraindicated in patients with severe renal disease or anuria, since the drug and the iron chelate are excreted primarily by the kidney.
Side Effects: Fever, urticaria, rash. At injection site - localized irritation, pain, burning, swelling.
Pharmacokinetics: available in vials for intramuscular, subcutaneous, and intravenous administration. Desferal is metabolized principally by plasma enzymes, but the pathways have not yet been defined. The chelate is readily soluble in water and passes easily through the kidney, giving the urine a characteristic reddish color. Some is also excreted in the feces via the bile.
Patient Population: Pediatric (neonate to ~21 yrs)
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
Patient Population: Geriatric ( >65 yrs )
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.
Patient Population: Women
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.*

References: * Rathore SS et al., N Engl J Med 2002;347:1403-11.
Herbal Medications
Introduction: Herbal medications are available without a prescription & are legally considered dietary supplements rather than drugs. As such they are not as tightly regulated by the FDA. They are governed by the Current Good Manufacturing Practice in Manufacturing (CGMP) regulations that are administered by the FDA. However these regulations are often inadequate for ensuring product purity & potency. For example, in the past, doses for several Ma-huang preparations contained 3-5 X the medically recommended daily dose of ephedrine. Adverse effects can be caused by either the active ingredient, or an adulterant.
Reference: Katzung's text
Herb: Melatonin
Intended Use: Prevent jet lag & to induce sleep (reduce insomnia)
Mechanism of Action: A serotonin derivative that is released by the pineal gland & is believed to be inolved in regulating sleep-wake cycles. Melatonin release coincides with darkness & is suppressed by daylight.
Clinical Trials: Results for reducing jet lag are unclear due to flaws in trial design. It may or may not help one return to a normal sleep pattern. Maximizing exposure to daylight on arrival at a new destination may also aid in resetting one's circadian clock.Trials results for melatonin's ability to reduce insomnia are also unclear due to study limitations. However it seems to increase REM sleep & improve sleep onset & duration in healthy volunteers.
Contraindications: pregnancy or desire to conceive (see below)
Side Effects: Partial inhibition of ovulation in women (by supressing LH secretion), decreased sperm quality (by aromatase inhibition in the testes). Next-day drowsiness, tachycardia, depression.
Reference: Katzung's text
Herb: Ma-huang (ephedra)
Intended Use: diet suppressant, bronchodialator, stimulant
Mechanism of Action: contains ephedrine & ephedrine-like alkaloids. Ephedrine has both direct (alpha and beta) agonist effects and indirect (amphetamine or tyramine - like) sympathomimetic effects.
Clinical Trials: In Dec 2003, the FDA issued a consumer alert to alert consumers to immediately stop buying and using ephedra products. The alert was based mainly upon a review of recent adverse event reports that indicated an increased risk of stroke, myocardial infarction and sudden death in those using ephedra containing dietary supplements. The FDA also announced a plan to ban the sale of all food supplements containing ephedrine in the near future.
Contraindications: cardiovascular disease
Side Effects: higher than normal incidence of myocardial infarction, stroke and sudden death. Hypertension, insomnia.
Pharmacokinetics: tachyphylaxis develops with repeated dosing.
Notes: There is considerable variability in the amount of ephedrine & it's isomers from "batch to batch".
Reference: Katzung's text
Herb: St. John's wort (Hypericum perforatum)
Intended Use: Antidepressant
Mechanism of Action: A variety of compounds (e.g. hyperforin & hypericin) are believed to be involved in producing its antidepressant effect. Research suggests that they may inhibit the reuptake of serotonin, norepinephrine & dopamine, down-regulate the experssion of cortical beta receptors and up-regulate the experssion of serotonin receptors. Other mechanisms have also been proposed.
Clinical Trials: Clinical trials suggest that St. John's wort may have a similar efficacy as some prescribed antidepressants for mild to moderate depression. However, clinical trials indicate that it is not effective against major or severe depression.
Contraindications: Drugs metabolized by cyt-P450 or transported by P-glycoprotein
Side Effects: photosensitization
Pharmacokinetics: Onset of effect takes 2-4 weeks.
Major drug Interactions: use cautiously with other antidepressants, stimulants & MAO inhibitors due to the risk of producing a serotonin syndrome. St. John's wort can induce hepatic cyt- P450 enzymes and the P-glycoprotein drug transporter. This has led to case reports of subtherapeutic levels of digoxin, birth control drugs (& subsequent pregnancy), cyclosporin, HIV protease inhibitors (e.g. indinavir), warfarin, anticonvulsants, etc.
Notes: St. John's wort is a plant/bush that grows 1-3 feet tall. Found in Europe, US, Australia & other countries. The name Wort is thought to be derived from the Old English word for plant. The origins of the designator "St. John" might be attributable to it’s medicinal usage by the Knights of St. John in Jerusalem to heal the wounds of Crusaders or that it blooms around the Christian Feast of St. John.
Reference: www.rxlist.com & Katzung's text.
Herb: Ginkgo (Ginkgo Biloba)
Intended Use: treatment of cerebrial insufficiency & Alzheimer dementia
Mechanism of Action: has antioxidant and free-radical scavenging properties that may reduce ischemic injury and oxidative stress. Ginkgo has been shown to increase blood flow and reduce blood viscosity (antiplatelet effect). Enhancment of nitric oxide may be involved.
Clinical Trials: Trials have suggested that ginkgo is more effective than placebo, and possibly comparible to pentoxifylline in relieving the symptoms of intermittent claudication (a leg pain that develops after walking & is associated with peripheral artery disease). Analysis of ginkgo's effectiveness on cerebral insufficiency & dementia so far suggest either questionable or small improvements (e.g. a 3% increase in cognition) at best. Ginkgo is currently under investigation as a prophylactic agent for dementia of the Alzheimer type.
Side Effects: antiplatelet properties
Major drug Interactions: Ginkgo has antiplatelet properties & should not be used in combination with other anticoagulant medications.
Notes: an extract from the leaves of the ginkgo tree
Reference: Katzung's text & http://www.herbs.org/
Herb:Ginseng
Intended Use: to improve physical and mental performance, enhancement of immune function
Mechanism of Action: active principles appear to be a dozen or more triterpenoid saponin glycosides called ginsenosides or panaxosides.
Clinical Trials: Previous clinical trials have had small sample size & report either an improvement in mental function & physical performance, or no effect.Some randomized trials evaluating "quality of life" and enhancement of immune function have claimed significant effects. Others have indicated a decrease in postpradial glucose indices & a lower epidemiological incidence of cancer. To quote Katzung's text: "Until better clinical trials are published, no recommendation can be made regarding the use of ginseng."
Side Effects: weak estrogenic effects (vaginal bleeding & mastalgia), insomnia, nervousness, hypertension
Major drug Interactions: use cautiously when taking any other psychiatric, estrogenic or hypoglycemic medication. Should not be used in combination with warfarin (ginseng has antiplatelet properties).
Notes: derived from several plants belonging to the species Panax
Reference: Katzung's text
Herb: Saw Palmetto
Intended Use: Treatment of benign prostatic hyperplasia
Mechanism of Action: inhibits the 5-alpha reductase enzyme responsible for breakdown of testosterone to dihydrotestosterone. Active ingredients are unclear. The effect is similar to that produced by finasteride, which is also used for the same disorder. In vitro palmetto also inhibits the binding of dihydrotestosterone to androgen receptors, inhibits prostatic growth factors, blocks alpha-1 adrenergic receptors & inhibits inflammatory mediators produced by the 5-lipoxygenase pathway.
Clinical Trials: Clinical trials suggest it may be more effective than placebo in reducing nocturnal urinary frequency, daytime urinary frequency and increasing peak urinary flow. Another clinical trial found it to be less effective than finasteride at reducing prostate volume (6% vs 18%, respectively). Small comparitive trials of saw palmetto vs. alpha-blockers showed greater improvement with alpha-blockers.
Side Effects: 1-3% hypertension, decreased libido.
Notes: derived from saw palmetto berries.
Reference: Katzung's text
Herb: Dehydroepiandrosterone (DHEA)
Intended Use: Relief of age-related disorders, weight loss, reduced risk of heart disease, prevention of cancer, boosting the immune system
Mechanism of Action: a precursor hormone (to as many as 50 different hormones) that is secreted by the adrenal cortex & CNS. It is converted to androstenedione, testosterone & androsterone. In peripheral tissues aromatase converts DHEA to estradiol. In the plasma, DHEA is converted to DHEA sulfate (DHEAS).
Clinical Trials: Studies (often with small sample size) have shown unclear beneficial effects on weight loss, cholesterol levels, Alzheimer's dx. etc.
Side Effects: Adrongenic side effects are common. Women complain of masculinizing effects, men may experience gynecomastia & breast tenderness. May worsen prostrate cancer & other hormone-dependent cancers due to elevation of hormone levels. Euphoria, mania & cardiac arrhythmias may occur.
Reference: Katzung's text