PDA 2 Exam 1

Osmolal Gap

Difference between serum osmolality and serum osmolarity Normal < 10mOsm Elevated gap could mean Alcohol, ispropanolol, methanol, ethylene glycol

Opioid as a toxidrome

Clinical Manifestation hypopnea, lethargy, miosis, decreased BP, decreased bowel sounds, decreased consciousness Typical Agents opioids, clonidine, phenothiazeines, hypoglycemic agents

Developmental Toxicity

"...any chemical administered under appropriate conditions of dose and time of development can cause some disturbances in embryonic development in some laboratory species." Karnofsky, 1965 The term teratogenesis is used to signify the production of gross structural malformations during fetal development. A teratogen is a substance/toxicant/influence that contributes to a teratogenic outcome.

Factors Affecting Metabolism by P450s

(1) INDUCTION by drugs or other environmental chemicals - increased metabolism reduces availability of parent drugs Ex: St. Johns Wort induction of cP450/CYP3A4 Co-Mediation 1. Cyclosporin 2. Oral contraceptive 3. Warfarin 4. Theophylline 5. Amitriptyline 6. Indinavir (2) INHIBITION by drugs or other environmental chemicals -Reduction in Active P450, to which other drugs might be metabolized -decrease metabolism of parent drugs (increased half-life), increasing effect or potential adverse reaction (unless the metabolite is active form and thus reduced pharmaceutical effect) (3) GENETIC POLYMORPHISMS within the CYP genes - Subjects show extensive or poor metabolism of drugs transformed through specific P450s. Best characterized for CYP2D6, where Poor metabolizers make up 10% of caucasian subjects

Opiate metabolism

*CYP2D6: O-demethylation to oxymorphone, hydromorphone N-demethylation to norhydrocodone Poor metabolizers have increased noroxycodone, norhydrocodone • CYP3A4: N-demethylation to noroxycodone, norhydrocodone Poor metabolizers have increased oxymorphone, hydromorphone production • 6-Keto Reduction to a,b-hydrocodol, a,b-oxycodol • Conjugation of all of above •Excreted Unchanged: 12% hydrocodone, 8-14% oxycodone Any Others? 39 functional genes encoding at least 19 isoforms of CYPP450, many of which have polymorphisms - minor pathways involving other isoforms? Saturation of major pathways: minor pathways activated?

FDA Teratogen Classifications

*Category -Description of Risk *A -No fetal risk shown in controlled human studies *B -No human data available and animal studies show no fetal risk or Animal studies show a risk but human studies do not show fetal risk *C -No controlled studies on fetal risk available for humans or animals or Fetal risk shown in controlled animal studies but no human data available (Benefit of drug use must clearly justify potential fetal risk in this category) *D -Studies show fetal risk in humans (Use of drug may be acceptable even with risks, such as in life-threatening illness or where safer drugs are ineffective) *X Risk to fetus clearly outweighs any benefits from these drugs All new drug applications filed with the United States Food and Drug Administration (FDA) include data from animal developmental and reproductive-toxicologic studies. Although major new teratogenic drugs in humans have been predicted from animal studies, there are problems in extrapolating animal data to humans. Animals have a different "gestational clock" to humans, there is marked interspecies variability in susceptibility to teratogens and no experimental animal is metabolically and physiologically identical to humans. Animal studies are important because, in some instances, they have shed light on mechanisms of teratogenicity and because when an agent causes similar patterns of anomalies in several species, human teratogenesis should also be suspected. For obvious ethical considerations no studies of teratogenicity are conducted during embryogenesis in humans. The studies are, therefore, either retrospective in nature (case reports, case-series and case-control studies), or prospective cohort studies, where a specific maternal exposure in question is ascertained during pregnancy and the pregnancy outcome is evaluated and compared to a control group. Retrospective case-control studies are less costly and easier to conduct but they have other weaknesses such as the inaccuracy of data collected from medical records and recall bias. There is one additional category, "Pregnancy Category N", which is a transitional identification indicating that the FDA has not yet classified the drug into a specified pregnancy category.

Key Points So Far

-The cytochrome P450 system is found predominately in the liver and is responsible for most phase I oxidative biotransformations -Most drugs undergo phase I followed by phase-II metabolism -The liver is the major site of drug metabolism -Usually phase II conjugates are water soluble and biologically inactive -Isoforms of P450 that are polymorphic may lead to vastly different rates of metabolism

General categories for chemotherapeutics

. DNA-binding Agents: a.Alkylating Agents form covalent bonds with DNA thus impeding replication b.Platinum-Containing DNA-Binding Drugs 2.Antimetabolites: block or subvert one or more of the metabolic pathways involved in DNA synthesis 3.Cytotoxic Antibiotics: microbial origin, which prevent mammalian cell division 4.Microtubule Inhibitors: (vinca alkaloids, taxanes, campothanins) specifically affect microtubule function...interfere with formation of mitotic spindles (Plant derivatives) 5.Hormones drugs that suppress hormone dependent tumor types (i.e. hormone responsive or hormone dependent cancers) 6.Miscellanious Agents

Cellular Efflux Mechanisms

1. ATP transporter pump 2. Present in GI, renal, hepatic cells, blood-brain barrier, testes, and some immune cells 3. Present to reduce/eliminate toxicant uptake 4. Associated with efflux of Cancer chemotherapeutics from the brain 5. Can be modulated by diet, drugs, stress, and disease 6. MRP (multidrug resistance protein) , BCRP (breast cancer resistant protein)

Chemotherapeutic Treatment Regimens and Protocols

1. Combinations of drugs: •cytotoxic agents with qualitative different toxicities and with different molecular sites and mechanisms of action are often combined at full doses of each. Results in higher response rates. •In contrast, agents with similar dose-limiting toxicities (i.e. mylosuppresion) can be combined safely only by reducing the doses of each 2.Advantages of drug combinations: •Provide maximal cell kill •Effective against a broader range of cancer cell types and stages •May slow or prevent the development of resistant cell lines 3.Protocols: •many cancer protocols have been developed based on the specific cancer type and stage of the cancer •Treatment of acute lymphocytic leukemia: Example: POMP (Prednisone, Oncovin, Methotrexate, and Purinethol)

Cancer Causes

1. Environmental • food additives • pollution • occupation • industrial • chemicals 2. Lifestyle • tobacco • alcohol • diet (obesity) - meat vs. veg/fruits • sexual behavior 3.Infection •Papilloma virus •Hepatitis C/B •Epstein-Barr virus •Helicobacter pylori 4.Injury •physical tissue damage - burns, breaks, etc. 5.Genetic •hereditary disposition •BRCA1 and BRCA2 •Lynch syndrome 6.Ionizing Radiation •X-rays •UV light •Gamma-radiation 7.Pharmaceutics*** •Anti-cancer chemotherapy 8. Unknown

Report Interpretation issues

1. Patients on chronic pain medications, esp. large doses, may see pharmaceutical impurities (and sometimes metabolites) in urine samples (<1% of parent drug). Not indicative of non-compliance. 2. May be alternate routes of metabolism at high drug doses, giving rise to apparent non-related metabolites. 3. Patients with rapid metabolism may be negative more quickly than expected. 4. Patients with slow metabolism or taking multiple drugs may have plasma drug levels higher than expected. 5. Artefacts vs non-compliance may be difficult to determine in some cases. How will these findings affect patient treatment?

Solid Tumors

1. Small tumors: higher growth rate (greater sensitivity to chemotherapeutic drugs) 2. Large tumors: slow-growth rate (i.e. few dividing cells). Larger tumors have lower sensitivity to chemotherapy and radiation treatment. The primary reason for the low sensitivity of larger tumor masses involves the relative central ischemia with such tumors (due to low perfusion). Thus, central tumor cells, which are distal (i.e. removed from) to the capillary, are spared the exposure to blood-borne cytotoxic drugs (i.e. chemotherapy). Also, as radiation treatment works partly via free radical formation, which requires oxygen, larger tumors are also more resistant to radiation. For large tumors, surgical bulk removal of tumor, followed by radiation and/or chemotherapy is the primary approach, when applicable.

Teratogens Anti-Neoplastic agents

1.Alkylating agents: cyclophosphamide 2.Antimetabolites: 6-mercaptopurine •Folate antagonists: Methotrexate When chemotherapeutic drugs interfere with the division of cancer cells, they also interfere with the division of normal cells, including those in the reproduction system. This may affect a woman's ability to become pregnant. For most women, reproductive function may return to normal within months after chemotherapy has been completed. For some it may take several years. The degree of effect that these agents have on reproductive function varies from one drug to another. Some agents inhibit reproductive function completely and others have only a limited effect. In general, younger women are more likely to regain reproductive function than older women. The risk for birth defects is less when chemotherapy is administered in the second or third trimester. With a few exceptions (such as the brain and the reproductive system), most fetal organ system development is completed by the beginning of the second trimester. Many alkylating agents (e.g. chlorambucil and cyclophosphamide) and antimetabolites (e.g. azathioprine and mercaptopurine) cause malformations when used in early pregnancy but more often lead to abortion. Folate antagonists (e.g. methotrexate) produce a much higher incidence of major malformations, evident in both live-born and still-born fetuses. Alkylating Agents form covalent bonds with DNA thus impeding replication Antimetabolites: block or subvert one or more of the metabolic pathways involved in DNA synthesis 6MP: Blocks biosynthesis (blocks conversion of inosinate to AMP and GMP), blocking purine synthesis Methotrexate: inhibiting dihydrofolate reductase, which converts folic acid to active form (tertrahydrofolic acid FH4), thus acting as an antagonist. Consequences of decreased FH4 decreases biosynthesis of thymidylic acid, methionine and serine and purines (adenine and guanine) depresses DNA and RNA and protein synthesis. The use of methotrexate in the first trimester has been associated with a specific pattern of birth defects. This pattern of birth defects includes malformations of the infants' head, face, and bones. Poor growth and developmental delay have also been described. For other birth defects, like heart defects and oral clefts, the evidence is currently not strong enough to show that methotrexate is the cause. During the second and third trimesters of pregnancy, the baby is still growing and the brain is still developing. Poor growth and learning problems have been associated with methotrexate, so use after the first trimester is a potential concern. Methotrexate may cause an increased risk for infertility. Low sperm count has been seen in some men using methotrexate. Most of these men were using high doses of the medication, as well as other medications used to treat cancer. Sperm levels returned to normal after the men stopped using methotrexate. Women must not take the Methotrexate during pregnancy, if there is a risk of becoming pregnant, or if they are breastfeeding. Men who are trying to get their partner pregnant must also not take the drug. To engage in any of these activities (after discontinuing the drug), women must wait until the end of a full ovulation cycle and men must wait three months.

Principles of cancer treatment

1.Arrest tumor/cancer progression (radiation, surgery, chemotherapeutics) 2.Attack is generally directed against metabolic sites essential for cell replication. - unfortunately current therapy attacks all proliferating cells 3.Treatment: a. Goal of Treatment: b. Indications for Treatment: c. Tumor susceptibility and growth cycle: d. Drugs have a narrow therapeutic index therefore treatment is a balance between toxic effects and efficacy growing cells, which are most sensitive, are killed. Most anticancer drugs are antiproliferative-most damage DNA and thereby initiate apoptosis. They also affect rapidly dividing normal cells and are thus likely to depress bone marrow, impair healing and depress growth. Most cause nausea, vomiting, sterility, hair loss and teratogenicity. • •Goal of Treatment: cure and increase survival and/or reduce symptoms (palliative) •Indications for Treatment: chemotherapy is necessary when cancer is not amenable to surgery (Tumors most susceptible to chemotherapy grow fast) or in concert with surgery/irradiation. •Tumor susceptibility and growth cycle: The growth fraction (currently replicating) influences the susceptibility of cells (tumors and healthy cells) to most chemotherapeutics. The faster the cell divides, the more susceptible it is to chemotherapeutics. •Drugs have a narrow therapeutic index, therefore treatment is a balance between toxic effects and efficacy. Growing cells are the most sensitive to being killed. Adverse effects are seen heavily in non-neoplastic cells that have high cell division rates(e.g. hair cells, blood-cells)

Combined Previous Cancer Stages

1.Initiation (induction event) 2. Promotion (Proliferation event)** a. Proto-oncogenes to oncogenes b. Inactivation of Tumor suppressor genes 4.Progression (invasive event - from benign to malignant) a.Dedifferentiation and loss of function b.Metastasis Uncontrolled proliferation involves both a transformation of Proto-oncogenes to oncogenes & inactivation of Tumor suppressor genes ** 1. The activation of proto-oncogenes to oncogenes These changes are a result of point mutations, gene amplification or chromosomal translocation, often due to the action of certain viruses or chemical carcinogens. •A proto-oncogene is a normal gene that can become an oncogene, either after mutation or increased expression. Proto-oncogenes code for proteins that help to regulate cell growth and differentiation. Proto-oncogenes are often involved in signal transduction and execution of mitogenic signals, usually through their protein products. •An oncogene is a modified gene, or a set of nucleotides that codes for a protein, that increases the malignancy of a tumor cell. Some oncogenes, usually involved in early stages of cancer development, increase the chance that a normal cell develops into a tumor cell, possibly resulting in cancer. 2. The inactivation of tumor suppressor genes. Normal cells contain genes that have the ability to suppress malignant change-termed tumor suppressor genes -and there is now good evidence that mutations of these genes are involved in many different cancers. The loss of function of tumor suppressor genes can be the critical event in carcinogenesis. About 30 tumor suppressor genes and 100 dominant oncogenes have been identified. Unlike oncogenes, tumor suppressor genes generally follow the 'two-hit hypothesis,' which implies that both alleles that code for a particular gene must be affected before an effect is manifested. This is due to the fact that if only one allele for the gene is damaged, the second can still produce the correct protein. However, there are cases where mutations in only one allele will cause an effect. A notable example is the gene that codes for p53. The suppressor gene most frequently altered in human tumors is the p53 gene. Damaged p53 genes have been identified in over 50% of human cancers. Example with retinablastoma: https://www.youtube.com/watch?v=C-Njz_iSvLI Complete carcinogen: a substance possessing the ability to induce cancer from normal cells, usually possessing properties of initiation, promotion, and progression.

Problems associated with chemotherapy

1.Resistance: some neoplastic cells are inherently resistant to most anticancer drugs Some cancers may acquire resistance, over prolonged period 2. Sanctuaries: Sites that are immunepriveleged (Brain, Testes, Eyes) 3.Multi-drug Resistance efflux mechanisms: 4.Treatment Induced Tumors: Most antineoplastic agents are mutagens 5.Toxicity: long-list of side-effects & a narrow therapeutic index Severe vomiting Alopecia - Hair loss. Hair is fast growing cells so they get targeted and destroyed Mylosuppression Digestive tract Gonads Kidney Fetus Impaired Wound Healing

*cohort study

A type of epidemiologic study where a group of exposed individuals (individuals who have been exposed to the potential risk factor) and a group of non-exposed individuals are followed over time to determine the incidence of disease •can be prospective or retrospective, with controls, large populations generally required (cost) for statistical validity. Can derive causation.

Teratogens Retinoids (vitamin A derivatives)

18% spontaneous abortion 28% live births with one major malformation Teenagers are a large focus for this tox Vast majority terminate pregnancy Fat soluble Effects • Malformations of ears, heart, brain, thymus • Lower IQ (age 5 assessment) Retinoids, a retinoid (i.e. vitamin A derivative) with marked effects on epidermal differentiation, is a known teratogen and causes a high proportion of serious abnormalities (notably skeletal deformities) in exposed fetuses. The risk for having a miscarriage may be as high as 40% when a woman takes isotretinoin in early pregnancy. Isotretinoin causes a pattern of birth defects in more than 35% of infants whose mothers take the drug during pregnancy. Most of the infants with birth defects will have small or absent ears, hearing and eyesight problems. Some will have a small jaw, small head, cleft palate and some will be born with a small or missing thymus gland. Life threatening heart defects and fluid around the brain are seen in almost half of the exposed infants. In the U.S. more than 2,000 women have become pregnant while taking the drug between 1982 and 2003, with most pregnancies ending in abortion. About 160 babies with birth defects were born. Consequently, the iPLEDGE program was introduced by the U.S. Food and Drug Administration on 12 August 2005 in an attempt to ensure that female patients receiving isotretinoin do not become pregnant - as of 1 March 2006, only prescribers registered and activated in iPLEDGE are able to prescribe isotretinoin, and only patients registered and qualified in iPLEDGE will be able to have isotretinoin dispensed. Dermatologists use retinoids to treat skin diseases including several, such as acne and psoriasis, which are common in young women. Etretinate accumulates in subcutaneous fat and is eliminated extremely slowly, detectable amounts persisting for many months after chronic dosing is discontinued. Because of this, women should avoid pregnancy for at least 2 years after treatment. Acitretin is an active metabolite of etretinate. It is equally teratogenic, but tissue accumulation is less pronounced and elimination may, therefore, be more rapid. A proposed mechanism is that biologically active retinoic acid binds retinoic acid receptors which in turn bind DNA enhancer elements such as the retinoic acid response elements. Several Hox genes (responsible for early patterning of the embryo) contain this enhancer element in their promotors. Therefore, Hox signaling may be altered due to increased retinoic acid concentrations resulting in multiple birth defects

Teratogens Warfarin

1st trimester 25% of fetuses deformations of the face and bones (fetal warfarin syndrome) 2nd-3rd trimester Cateracts Mental retardation Microcephaly Microphthalmia hemorrahage Coumarin anticoagulants (e.g. warfarin) are anticoagulants normally used in the prevention of thrombosis and thromboembolism, the formation of blood clots in the blood vessels and their migration elsewhere in the body respectively. It was initially introduced in 1948 as a pesticide against rats and mice and is still used for this purpose. It was approved for use as a medication in 1954 and has remained popular ever since; warfarin is the most widely prescribed oral anticoagulant drug in North America Administration of warfarin in the first trimester is associated with nasal hypoplasia and various central nervous system (CNS) abnormalities, affecting roughly 25% of exposed babies. In the last trimester it must not be used because of the risk of intracranial haemorrhage in the baby during delivery. First trimester exposure to coumarin derivatives is associated with a characteristic pattern of malformations termed the foetal warfarin syndrome. Clinical features consist of nasal hypoplasia and calcific stippling of the epiphyses. Intrauterine growth retardation and developmental delay due to central nervous system damage, eye defects, and hearing loss have also been described. The critical period of exposure for the foetal warfarin syndrome appears to be between 6 and 9 weeks of gestation. A prospective study found evidence of warfarin embryopathy in about one third of the cases where a coumarin derivative was given throughout pregnancy. Oral anticoagulants are also associated with a high rate of miscarriage. Exposure to oral anticoagulants after the first trimester presents a risk of central nervous system damage due to haemorrhage. Unlike heparin, oral anticoagulants readily cross the placental barrier.

Teratogens Cocaine

375,000 children are born each year to mothers who use cocaine during pregnancy (1990's) Potent vasoconstrictor Effects • abruptio placenta • Premature birth • SIDS • growth retardations • in utero stroke • Significant post-birth behavioral complications Cocaine crosses the placenta and enters the baby's circulation. Cocaine can be found in the urine, meconium (stool), umbilical cord and hair of an exposed newborn. Cocaine is cleared more slowly in the fetus and newborn than in an adult. Therefore, the cocaine remains in the baby's body for a longer period of time. Cocaine is thought to induce birth defects by disrupting the vasculature in the placenta thereby inducing intrauterine hypoxia and malnutrition, as well as vasoconstriction. Exposed fetuses often have intrauterine growth retardation, microcephaly, cerebral infarction, urogenital anomalies, an increased risk of sudden infant death syndrome as well as neuronal and behavioral abnormalities. These pregnancies are at risk for premature labor, spontaneous abortion, increased perinatal mortality and fetal death. Cocaine-exposed infants, especially those exposed near birth, have been found to be more irritable, jittery, and have interrupted sleep patterns, visual disturbances, and problems with sensory stimulation. Some of these complications may last 8 to 10 weeks after birth or even longer. Cocaine can cause significant central nervous system problems that may not be seen until the child is older. These effects may include problems with sustained attention and behavioral self-control, like increased aggression. Delays in learning, abnormal muscle tone, slower growth rate, language difficulties and an increased need for special education in school-aged children have been reported. Cocaine may increase the risk for preterm delivery. Babies who are born prematurely often start life with serious health problems, especially breathing difficulties. These babies may also have an intracranial hemorrhage (bleeding in the brain) before or soon after birth, and this can cause permanent brain damage and other disabilities. Using other drugs, including alcohol or cigarettes, can also harm the baby. The combined effect of cocaine and other drugs may be worse than cocaine alone. abruptio placenta is the separation of the placental lining from the uterus of a female. Abruptio (ab-RUP-she-oh) placentae (pla-SEN-tee) Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. It is a stimulant of the central nervous system and an appetite suppressant, creating what has been described as a euphoric sense of happiness and increased energy. Though most often used recreationally for this effect, cocaine is also a topical anesthetic used in eye, throat, and nose surgery.

*Case-control study

A type of epidemiologic study where a group of individuals with the diseases, referred to as cases, are compared to individuals without the disease, referred to as controls retrospective (looking back after an outcome), with controls, historical "bias" recall, can not prove causation

Toxidromes

A constellation of signs and symptoms that are typically produced by particular toxins Ex: opioids, anticholingergic, cholingeric, sympathoimetic, sedative-hypnotic

Teratogens Angiotensin-converting enzyme inhibitors (ACE-Is) or Angiotensin receptor-II antagonists (ARBs)

ACE-Is: captopril, enelapril) (ARBs: lorsartin, valsartan) hypotension, neonatal skull hypoplasia craniofacial deformation fetal limb contractures hypoplastic lung development, reversible or irreversible renal failure death ACE inhibitors and ARBs cross placenta and interfere with fetal renal hemodynamics. ACE inhibitor-induced decline in GFR in fetal kidneys leads to decreased urine production and oligohydramnios (deficiency of amniotic fluid). The reported adverse fetal and neonatal effects (e.g., hypotension, neonatal skull hypoplasia and craniofacial deformation, fetal limb contractures, hypoplastic lung development, anuria, oligohydraminos, reversible or irreversible renal failure, and death) have been proposed to result from ACE inhibitor exposure during the second and third trimesters, and have been presumed not to be related to first trimester exposure. However, a recent observational study based on Tennessee Medicaid data has reported that the risk of congenital malformations is significantly increased during first-trimester exposure to ACE inhibitors. Based on this epidemiological evaluation, the FDA has decided not to revise the pregnancy risk category for ACE inhibitors at this time. Hypoplasia: incomplete or arrested development of an organ

Amphetamines

Amphetamine, Methamphetamine, MDMA - Ecstasy Medically used for narcolepsy, hypotension, obesity. CNS stimulant.

Narcotic analgesics (Opioids)

Act like opiates, but chemically are not. Fentanyl, meperidine, Tramadol, Buprenorphine Methadone - also used for opiate dependence

drug abuse- Addiction

Addiction is defined as a chronic, relapsing brain disease that is characterized by compulsive drug seeking and use, despite harmful consequences It is considered a brain disease because drugs change the brain—they change its structure and how it works. These brain changes can be long-lasting, and can lead to the harmful behaviors seen in people who abuse drugs."

Teratogens Aminoglycosides (Principally streptomycin)

Aminoglycosides are excreted into breast milk Effect ototoxicity and eighth cranial nerve Aminoglycosides should be used cautiously in women who are breast-feeding. Aminoglycosides are excreted into breast milk. However, aminoglycosides are poorly absorbed from the gastrointestinal tract are not likely to cause problems in nursing infants. There have been no reports of problems in nursing infants of women receiving aminoglycosides Streptomycin crosses the placenta. The potential of streptomycin to cause ototoxicity and eighth cranial nerve damage are well known. Use of streptomycin during pregnancy should be avoided unless the potential benefit justifies the added risk to the fetus.

*idiosyncratic reaction

An idiosyncratic drug reaction denotes an abnormal reaction that is non-expected based on defined understanding of the drug mechanism. It is what is known as a Type B reaction. Type B reactions have the following characteristics: They are usually unpredictable, might not be picked up by toxicological screening, not necessarily dose-related, incidence and morbidity low but mortality is high.

Teratogens Hormones

Androgens including DHEA and testosterone Estrogens -Diethylstilbestrol (DES) "DES sons" and "DES daughters Feminization of male children and masculinization of female children. Diethylstilbestrol (DES) is a synthetic nonsteroidal estrogen that was first synthesized in 1938. Human exposure to DES occurred through diverse sources, such as dietary ingestion from supplemented cattle feed and medical treatment for certain conditions, including breast and prostate cancers. From about 1940 to 1971, DES was given to pregnant women in the mistaken belief it would reduce the risk of pregnancy complications and losses. In 1971, DES was shown to cause a rare vaginal tumor in girls and women who had been exposed to this drug in utero. The United States Food and Drug Administration subsequently withdrew DES from use in pregnant women. Follow-up studies have indicated that DES also has the potential to cause a variety of significant adverse medical complications during the lifetimes of those exposed. The United States National Cancer Institute recommends. women born to mothers who took DES undergo special medical exams on a regular basis to screen for complications as a result of the drug. Individuals who were exposed to DES during their mothers' pregnancies are commonly referred to as "DES daughters" and "DES sons". •DES gained notoriety when it was shown to cause a rare vaginal tumor in girls and young women who had been exposed to this drug in utero. Studies have shown an approximate 40-fold increased risk of vaginal/cervical clear cell adenocarcinoma in women exposed in utero to DES. DES-exposed daughters are at an increased risk of abnormalities of the reproductive tract, including vaginal epithelial changes such as vaginal adenosis (which means a type of cell normally found in the uterus, columnar cells, are also present in the vagina), an increased cervical transformation zone, and uterine abnormalities, such as T-shaped uterus. • •Initially, fewer studies documented risks of prenatal exposure to diethylstilbestrol on males (referred to as "DES sons"). In the 1970s and early 1980s, studies published on prenatally DES-exposed males investigated increased risk of testicular cancer, infertility and urogenital abnormalities in development.

Antidotes and antagonists

Antitodes/Antagonists - Toxins Anti-digoxin Fab Antibody fragments - Digoxin Atropine (anticholinergic) - Cholinergic agents Flumenazil (receptor antagonist) - Benzodiazepine overdose Naloxone/Naltrexone - Opiate overdose Ethanol (ADH competitor) - Methanol Chelation therapy - Metals Antivenins - Snakebites (venom) Supportive care after receiving antidote, monitor vital signs, psychiatric assessment

**Atropine *Difference between toxic and pharmacological effects

Atropine is a tropane alkaloid extracted from deadly nightshade (Atropa belladonna), jimsonweed (Datura stramonium), mandrake (Mandragora officinarum) and other plants of the family Solanaceae. It is a secondary metabolite of these plants and serves as a drug with a wide variety of effects. It is a competitive antagonist for the muscarinic acetylcholine receptor. Datura intoxication typically produces delirium, hyperthermia, tachycardia, bizarre behavior, and severe mydriasis (enlargement-dilation of pupils) with resultant painful photophobia that can last several days. Pronounced amnesia is another commonly reported effect. The onset of symptoms generally occurs around 30 to 60 minutes after ingesting the herb. These symptoms generally last from 24 to 48 hours, but have been reported in some cases to last as long as two weeks. -Also atropine is used as a treatment for organophosphate overdose (SLUDGE)- which results in a parasympathetic system "overload" effect (i.e. to much acetylcholine via inhibition of acetylcholinesterase

*Toxin

Biological Origin

*Metabolism (i.e. Biotransformation)

Biotransformation is the process whereby a substance is changed from one chemical to another (transformed) by a chemical reaction within the body. Metabolism or metabolic transformations are terms frequently used for the biotransformation process. However, metabolism is sometimes not specific for the transformation process but may include other phases of toxicokinetics. Toxicants that are lipophilic, non-polar, and of low molecular weight are readily absorbed through the cell membranes of the skin, GI tract, and lung. These same chemical and physical properties control the distribution of a chemical throughout the body and it's penetration into tissue cells. Lipophilic toxicants are hard for the body to eliminate and can accumulate to hazardous levels. However, most lipophilic toxicants can be transformed into hydrophilic metabolites that are less likely to pass through membranes of critical cells. Hydrophilic chemicals are easier for the body to eliminate than lipophilic substances. Biotransformation is thus a key body defense mechanism. • Major focus: to make lipid-soluble substances more water-soluble • The more water-soluble a substance, the more easily it is eliminated from the body • Some drugs are converted to active metabolites Sites of biotransformation: Liver - major site Kidneys Lungs GI tract mucosa Skin Nasal mucosa ((Phase I metabolism (oxidation, reduction, hydrolysis, hydroxylation) CYP450's and various enzymes Usually a small increase in hydrophylicity May produce toxic/adverse reaction ((Phase II metabolism (bioinactivation conjugation) glutathione, sulfation, acetylation, methylation, glucuronidation) ((Elimination phase 21. Oxidation/Reduction by the P450 system Relative contribution of the major P450 isoforms to human drug metabolism • Haem-containing proteins within the smooth ER responsible for most PHASE I biotransformations • Large superfamily of enzymes - 12 gene families expressed in humans. • Diverse range of xenobiotics are substrates for the P450 system - but all show high lipid solubility. • CYP3A4 is the major isoform in humans with substantial extrahepatic expression especially in the gut wall.

Forensic Samples

Blood- indicates what is currently in the system Oral Fluid- Similar to blood, but fewer metabolites. Urine- Prior use Breath- Alcohol currently in the blood Hair- Prior exposure Vitreous Fluid- Similar to blood but only available postmortem

Contributing factors to Cancer induction-promotion

Breakdowns in immunity -Healthy immune system can target and destroy cancer cells -When cancer cells have altered proteins at its surface, cells are not destroyed -Risk of cancer increases: •With age •When an immune system has been suppressed for a long time -HIV infection -Immunosuppressant drugs -Anxiety and depression

Anticholinergic types of Toxidromes

Clinical Manifestation Hyperthermia, tachycardia, hypertension, agitation, seizures, mydriasis, decreased bowel sounds, dry flushed skin Typical agents Anti-histamines, TCAs, graditional antipsychotics, gcopolamine, atropine, jimsonweed

*Adverse reactions

Can be related to pharmacological action, but also can be unrelated If unrelated often caused by reactive metabolites or immunological reactions Can be unpredictable, serious, and uncommon

Drug Testing

Can test Plasma for a variety of drugs in Cp Can test urine for things like amphetamine, opiates, tricyclics, methadone, cannabinoids and so on Plasma tests therapeutic ranges so we can see what's over level, and urine tests for prior exposure

Soma

Carisoprodol or Soma, which turns into meprobamate, equanil. Muscle relaxant/anti-anxiety Frequently a drug of abuse. Not widely appreciated. Chemically unrelated to any other compounds tested for.

Sympathomimetic types of Toxidromes

Clinical Manifestation Hyperthermia, tachycardia, hypertension, agitation, seizures, mydriasis, increased bowel sounds Typical Agents Cocaine, amphetamines, theophylline, caffeine, salicylates, MAOI's, sedative withdrawl

Cholinergic types of Toxidromes

Clinical manifestation Bradycardia(muscarinic), tachycardia(nicotinic), miosis, bronchorrhea, salvation, lacrimation, urination, diarrhea, GI upset, emesis (sludge) Typical Agents organophosphates, carbamates, physostigmine, pilocarpine mushrooms, betel nut

Sedative-Hypnotic types of toxidromes

Clinical manifestation Hypothermia, bradypnea, hypopnea, hypotension, lethargy, stupor Typical agents Ethanol, benzodiazepines, barbiturates, meprobamate

Opiates

Codeine, Hydrocodone, Hydromorphone, Morphine, Oxycodone, Oxymorphone, Heroin Oxycodone is the most popular opiate Opiate Metabolism Difficult to monitor since they metabolize together Heroin to 6-Mam, to morphine which can go between codeine or hydromorphone which could both metabolize into hydrocodone. Oxymorpohne can go to oxycodone, into hydrocodone or noroxycodone. and hydrocodone itself can go to norhydrocodone. So it goes around A LOT. Picture applied

Creatine levels out of range for validity testing

Creatine < 20mg/dL Drank too much liqiud recently Creatine >370mg/dL dehydrated Creatine Too low/high kidney disease Specific gravity too low/high Same as creatine. Kidney disease pH <4 dietary component Nitrites > 200 blood in urine; rhabdomyolysis Chromates > 50 (slightly) chromium supplements

Anion Gap

Difference between serum (NA+) and serum (Cl- + HCO3) Normal is < 12mmol/L Elevated levels with metabolic acidosis can indicate many things like Alcohol, Toluene, Methanol, Uremia, Diabetic ketoacidosis, paraldehyde, iron, lacatic acid, ethylene glycol, salicylates. Abbreviated to AT MUDPILES Na is a little higher than the Cl- + HCO3

Cannabinoids

Delta-9-tetrahydrocannabinol (THC) Medically used for emulsion in chemotherapy pateints THC-COOH most common metabolite Lab testing cannot tell the difference between medical/recreation cannabis

validity Testing

Designed to ensure that the specimen submitted is authentic human urine. Not adulterated, diluted, substitued Creatine normalization Creatine is a product of muscle metabolism. Excretion is constant. Level in urine varies due to how much water in urine. Repeated low creatinine tells you patient is trying to hide something or has a kidney function issue.

Bath Salts

Designer stimulants of varying composition. Makes you energized. Metabolism not well studied

Reasons for Non-Compliance of Patients

Did not take because of various reasons in misunderstanding, forgetfulness, cant afford, side effects, felt like it etc etc etc. Took as not supposed to because of misunderstanding, substance abuse, unstable living situation, didnt tell doc info, doctor shopping.

Factors That Determine the Effects of Teratogens

Dose reaching fetus • Placental contributions: Ø Altered Metabolism Ø Altered Transport Ø Reduced blood flow Ø Reduced size Point in development when drug exposure occurs Duration of exposure Environmental factors Susceptibility of the fetus Several factors determine the effects teratogenic drugs may have on the fetus during pregnancy. The dose reaching the fetus is an important determinant of its effect. Most drugs cross the placenta by simple diffusion. •Teratogens may demonstrate a dose-effect relationship. At low doses there can be no effect, at intermediate doses the characteristic pattern of malformations will result, and at high dose the embryo will be killed. •A dose-response may be considered essential in establishing teratogenicity in animals, but is uncommonly demonstrated in sufficient data among humans. A threshold dose is the dosage below which the incidence of adverse effects is not statistically greater than that of controls. With most agents, a dose threshold for teratogenic effects has not been determined; however they are usually well below levels required to cause toxicity in adults. •Teratogens must reach the developing conceptus in sufficient amounts to cause their effects. Large molecules with molecular weights greater than 1,000 do not easily cross the placenta into the embryonic-foetal bloodstream to exert potential teratogenic effect. Other factors influencing the rate and extent of placental transfer of xenobiotics include polarity, lipid solubility and the existence of a specific protein carrier.

*Identification of hazard

Epidemiology Toxicology In vitro & animal tests SAR Genetic predisposition

What medications can have a REMS?

FDA can require a REMS for prescription drugs and biologics if the agency determines it is necessary to ensure that the benefits of the medication outweigh the risks. FDA can also require a REMS for generic prescription medications, but there are some different requirements for generic medications. REMS do not apply to over-the-counter (OTC) medications. Without a REMS, these medications would not be approved or would be withdrawn from the market because of known or potential serious risks associated with medication.

Are REMS permanent? Will FDA ever sunset a REMS?

FDA may release a REMS or remove certain components of a REMS, if, after review of REMS assessments or other information, we determine that the extra measures in a REMS are no longer necessary to ensure a medication's benefits outweigh its risks.

How does FDA determine that a medication needs a REMS?

FDA staff (e.g., clinical reviewers, safety reviewers, etc.) use these considerations: whether there is a particular risk or risks associated with the medication that, on balance, outweigh(s) its benefits; whether additional interventions beyond FDA-approved labeling are necessary to ensure that the drug's benefits outweigh its risks. The potential burden of the REMS requirements are also considered. For further information, please see FDA's Application of Statutory Factors in Determining When a REMS is Necessary: Guidance for Industry. The FDA may also seek information from outside experts who provide advice to the agency through advisory committees, as well as patients and caregivers who are living with the problem the drug is designed to treat.

Designer Opioids

Fentanyl, and morphine analogs Change the subject a little bit to make it a slightly different Krokodil is a morphine analog

Teratogens Alcohol (Ethanol)

Fetal Alcohol Syndrome (FAS). -Abridged list: Growth deficiencies Low nose bridge Cardiovascular disorders Small brain size Mental retardation -Approximately 2 in 1000 live births -Dose dependant Approximately 2 in 1000 live births, depending upon culture and socioeconomic status. For instance, there is an occurrences of FAS in 19.5:1000 live births in American Native Indian culture verses a rate of 1.9:1000 in middle class Caucasian families. There is no safe level of alcohol established during pregnancy. While technically there is no known safe amount of alcohol, a single drink is unlikely to cause a problem. The best thing you can do for your baby is to avoid further use of alcohol during your pregnancy. Alcohol crosses the placenta easily, but differences in genetics and metabolism of alcohol by both the mother and the developing baby may result in a wide range of risk. The risk may be different even in the same mother in different pregnancies. Ethanol impairs placental blood flow to the fetus by constricting blood vessels: inducing hypoxia and fetal malnutrition. Drinking alcohol during pregnancy is a leading cause of mental retardation. When a mother uses alcohol in large amounts and/or regularly during pregnancy, her baby is at risk for Fetal Alcohol Syndrome (FAS). The features of FAS include a pattern of certain birth defects that include small head and body size, specific facial features, and learning and behavioral problems. FAS is the most severe outcome of alcohol use during pregnancy. When a child has some but not all of the findings of FAS, doctors may use another term, such as Fetal Alcohol Spectrum Disorder (FASD). The risks from heavy alcohol use and daily alcohol use have been well established. The risks from infrequent binge drinking (5 or more standard drinks at one sitting) are less clear. The risks for occasional use of lower amounts of alcohol are also not clear. FASD is associated with lifelong challenges, such as difficulties with learning and memory. Individuals with FASD are more likely to have difficulty understanding the consequences of their actions, have poor judgment, and difficulty with social relationships. Higher rates of dropping out of school, mental health problems, and alcohol or drug abuse have also been reported in individuals with FASD. Though FASD cannot be cured, children with FASD benefit from early diagnosis. The best outcomes occur when these children are diagnosed early and receive appropriate support and assistance. Being raised in a stable and nurturing home where basic living and social skills can be taught leads to better outcomes for children with FASD.

Phenytoin and birth defects :(

Fetal Hydantoin syndrome Heart defect Low nasal bridge Growth retardation Mental retardation Cleft lip/palate There have also been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. Women taking phenytoin should be counseled regarding the risks to the fetus should they become pregnant. If a woman taking phenytoin does become pregnant, there is debate as to what course of action is best; other anticonvulsants also have been associated with fetal disorders, and seizures themselves can be equally harmful to both the fetus and the mother. Maintenance of anticonvulsant therapy may be essential for the mother. Results from a prospective, multi-center, long-term, observational study of fetal death and malformations during in utero exposure to phenytoin, carbamazepine, lamotrigine, or valproate indicate that valproate poses the greatest risk for serious adverse outcomes.

*Systemic toxin/toxicant

Gained access to body's systemic circulation, and can cause multiple effects

genotoxic carcinogens

Genotoxic carcinogens: interaction with DNA -Mutagenic -Tumorigenicity is dose responsive -No theoretical threshold •Most genotoxic carcinogens are electrophiles that interact directly with DNA through the formation of covalent bonds, resulting in DNA-carcinogen complexes (DNA adducts). These complexes lead to various types of DNA damage, including the formation of cross-links between the two helices, chemical bonds between adjacent bases, removal of DNA bases (hydration) and cleavage of the DNA strands, all of which result in modifications to the information stored within the DNA. Such mutations are typically fixed by DNA repair mechanisms; however, if DNA replication occurs prior to the action of a repair mechanism, mutations can become permanent and may eventually cause tumors.

Parent Compound

Less active drug moiety Inactive drug moiety Toxic Drug moiety More active drug metabolite

Wilson's General Principles of Teratology

I.Susceptibility depends on genotype of conceptus and how it interacts with environment. II.Susceptibility varies with developmental stage at time of exposure. III.Teratogenic agents act by specific mechanisms to initiate pathogenesis. IV.The access of adverse influences to developing tissues depends on the nature of the influence V.Deviant development includes death, malformation, growth retardation and functional deficit. (carcinogenesis, mutations) Defects increase in frequency and degree as dose increases The most common teratogenic effects attributed to drugs are spontaneous abortion, congenital malformations, intrauterine growth retardation, mental retardation, carcinogenesis and mutagenesis.

Non-prescription drugs

Ibuprofen/Acetaminophen can cause liver toxicity/pediatric overdose Diphenhydramine can make you sedated Pseudphed can make you dizzy, agitated, tremors Guaifenesin can make your CNS depressed Dextromethorphane can make you sedation Prescribed doses/Instructions cannot cause serious effects. Many liquid forms have significant amounts of ethanol

Pharmaceutical Impurities

Impurities of a pharmaceutical product that already exists. Pretty ez. Not a new thing

*Control of risk

Information Regulation Substitution Treatments/antidotes THE PHARMACIST

Cancer Stage- Initiation

Initiation stage- induction event •Irreversible DNA modification •Mutations •Deletions • Single treatment can induce mutation • •Modification itself is not enough to produce cancer Outcomes: -Cell can remain static: non-dividing -Mutation results in non-viability (apoptosis) -Cell may undergo cell division -Becomes "fixed" if not repaired before cell division In this stage, DNA is irreversibly changed by genotoxic agents called initiators. DNA damage to a cell most frequently results in cell death, but sometimes DNA mutation creates rapidly dividing cells. Cell division is normally limited by cell-to-cell contact, but cancer cells have lost this ability to control cell division.

Carcinogen classification

International Agency for Research on Cancer (IARC) classification: •Group 1: the agent (mixture) is definitely carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans. • •Group 2A: the agent (mixture) is probably carcinogenic to humans. The exposure circumstance entails exposures that are probably carcinogenic to humans. • •Group 2B: the agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans. • •Group 3: the agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. • •Group 4: the agent (mixture) is probably not carcinogenic to humans.

*Measure toxicity

LD 50 = lethal dose that kills 50% of the population TD 50= Toxic dose that gives an unwanted response in 50% of the population

*therapeutic index

LD50/ED50 measure of relative safety of drug The therapeutic index (TI) of a drug is a statement about the relative safety of that drug/substance expressed as the ratio of the lethal or toxic dose to the therapeutic dose, but is determine from the median response (i.e. 50% of the population exhibiting the therapeutic and toxic response respectively). Thus, the TI does not take into account the extremes within a given population (i.e. end of the respective slope on the dose-response curves), and therefore it is plausible that base on the slope of the respective curves (i.e. LD vs ED) there may be crossover between the lethal/toxic effects and therapeutic effects. Whereas, the margin of safety (MOS) takes the extreme points on the respective lethality (LD) and effectiveness (ED) curves of a given drug (i.e. lethality in 1% of the population and effectiveness in 99% of the population) as its parameter of measure. Thus, respective to the MOS, the relative slopes become irrelevant.

Transport (Phase-III) Polymorphisms

MRP1 • Rare (<1% in Caucasians) Gln to Ser causes increased resistance of HeLa cells to doxorubicin • Clinical significance?? P-gp (MDR1) • Numerous polymorphisms • Potential relevance to bioavailability of anticancer drugs that are P-gp substrates

Benzodiazepines and Barbiturates

Mainly anti-anxiety, xanax, diazepam, clonazepam, lorazepam, temazepam Often metabolize to each other, similar to how opiates do with the spider web of garbage.

Cancer Incidence

Majority of cancers in U.S. tend to be slow growing "solid" tumors Approximately 25% of the U.S. population will have cancer over their lifetime Each of the tumor types is a separate disease Cancer is "generally" an age associated disease Cancer deaths have dramatically decreased since the 1960s Cancer is fundamentally a disease of failure of regulation of tissue growth. In order for a normal cell to transform into a cancer cell, the genes which regulate cell growth and differentiation must be altered. Cancer has been known to humans since ancient times, but considerable and effective steps were not made towards its treatment until the twentieth century. Though most commonly thought of as a single disease, cancer is actually a group of as many as 200 different diseases typified by the uninhibited growth of abnormal cells. Due to this fact, as well as the occurrence of cancer in various stages of development, a wide array of treatments are required to effectively control it. Broadly, these treatments most commonly include surgery, radiation therapy, chemotherapy, or a combination of these therapies.

Compliance Monitoring

Make sure you are treating patients appropriately. Have to monitor use of the drugs that you give patient Patient has to agree to Compliance program contracts. If violated contract, pt can be discharged by doctor. Could cause patient to sue even

Forensic Vs. Clinical

Many of the same drugs, analytical techniques, interpretation issues, toxicology, lab organization. Very similar Forensic though, focus of legal rather than medical. Different oversight bodies (CAP, CLIA vs ASCLD-lAB, ABFT), more illicit and novel drugs, varied matrices, more concern with alcohol, breath alcohol testing a forensic sub-discipline, standarized Field Sobriety Tests - OWI-specific.

Therapeutic Drug Monitoring (TDM)

Measuring specific drugs at designated intervals to maintain a constant conc. in a patients bloodstream thereby optimizing individual dosage regimens Has to be monitored to make sure they are in the safe region Ex: Antiarrhythmics - digoxin, digitoxin Anticonvulsants - Phenobarbital, phenytoin, valproic acid Antipsychotics - clozapine, pimozide Anticoagulants - warfarin Immunosuppresants - cyclosporine Mood stabilizers - lithium Initial TDM - Dose given based on pop. data, demographics, clinical findings Continuing TDM- Plasma conc tested, dose adjusted to keep within therapeutic range

Cocaine

Medically used ENT surgery. Derivates are topical anesthetics- lidocaine xylocaine CNS stimulant. Test for major metabolite benzoylecgonine

Teratogens Lithium Salts (lithium carbonate, lithium citrate)

Mood stabilizer Crosses placental barrier freely Effect: Ebtein's anomaly Other cardiac abnormalities Lithium salts such as lithium carbonate (Li2CO3), lithium citrate, and lithium orotate are mood stabilizers. They are used in the treatment of bipolar disorder, since unlike most other mood altering drugs, they counteract both mania and depression. Lithium can also be used to augment other antidepressant drugs. It is also sometimes prescribed as a preventive treatment for migraine disease and cluster headaches. It crosses the placental barrier freely and has been associated with fetal toxicity. Data from lithium birth registers suggest an increased incidence of neonatal goiter and an increase in cardiac anomalies, especially Ebstein's anomaly. In some cases, however, lithium therapy may be warranted during pregnancy, but patients should be warned about possible damage to the fetus. If possible, lithium should be withheld during the first trimester. Women of childbearing age who require lithium therapy should be counseled about becoming pregnant. Lithium is secreted into breast milk and is contraindicated in women who are breast-feeding. Symptoms of lithium toxicity, including ECG changes, have been observed in some breast-fed infants, whose mothers were taking lithium. Background: Ebstein anomaly is a congenital malformation of the heart that is characterized by apical displacement of the septal and posterior tricuspid valve leaflets, leading to atrialization of the right ventricle with a variable degree of malformation and displacement of the anterior leaflet. In Ebstein's Anomaly, the Tricuspid valve, normally present between the upper and lower chambers on the right side, is displaced into the right ventricle.In this situation, when the right ventricle contracts, blood goes backward to the right atrium.

*Margin of Safety

Most commonly used LD01/ED99 MOS above 1 is preferred

Carcinogenesis General Definitions

Neoplasia: New growth of tissue Neoplasm: Abnormal tissue, associated with uncontrolled cell division via abnormal regulation of gene expression (i.e. loss of normal cell growth control processes). Benign: Lesion associated with growth, but NOT invasive Malignant: Lesions demonstrating invasive growth, capable of metastases to other tissues Metastases: Secondary growths derived from a primary malignancy Tumor: Lesion characterized by grouping of cells (may or may not be malignant) Cancer: Malignant neoplasm (disease of cellular mutation, proliferation and aberrant cell growth) Carcinogen: A physical or chemical agent that causes or induces neoplasia

I have heard that having a REMS means there won't be a generic for the drug, is this true?

No. The law requires that when a drug has a REMS, any generics for these drugs must also have a REMS. Sometimes, the brand name manufacturer and the generic version's manufacturer jointly develop and implement a REMS (i.e., a shared system REMS). At other times, the brand name drug and the generic each have different REMS, but both have the same goal(s), the same requirements, and comparable processes in place to meet those goals and requirements.

Nongenotoxic (epigenetic) carcinogens

Nongenotoxic (epigenetic) cancinogens: modify gene expression, but do not damage DNA -Non-mutagenic -Threshold (how much, how often one is exposed) -Tumorigenicity is dose responsive -No direct DNA damage -Species, strain, tissue specificity •Non-genotoxic (epigenetic) carcinogens are a diverse group of chemicals that induce tumor formation by mechanisms other than direct DNA damage. Unlike genotoxic carcinogens, non-genotoxic carcinogens often exhibit organ-, sex- and species-specific effects and require sustained exposure. It appears that repeated exposure to cytotoxicants can result in chronic cell injury, compensatory cell proliferation, hyperplasia and ultimately tumor development. In addition, a second class of epigenetic carcinogens act by interfering with signal transduction mechanisms and gene expression involved in the regulation of cell growth, cell death and differentiation. Others include the disturbance of hormonal balance, immunosuppression and chronic inflammation. Examples on non-genotoxic carcinogens have been shown to act as tumor promoters (1,4-dichlorobenzene), endocrine-modifiers (17β-estradiol), receptor-mediators (2,3,7,8-tetrachlorodibenzo-p-dioxin), immunosuppressants (cyclosporine) or inducers of tissue-specific toxicity and inflammatory responses (metals such as arsenic and beryllium).

Industrial Chemicals Linked to Cancer

On the picture

Synthetic Cannabinoids (SPice, K2)

Originally synthesized by researchers for research into endocannabinoids. Chemically not THC, so would be legal since it would work the same way. Structures are modified slightly to skirt regulations once a compound gets outlawed

*sublethal effects

Other effects not directly resulting in death (still not good though)

*Characterization of risks

Potency Dose (dose-response relationship) Duration Mechanism of toxicity Co-factors (co-morbidities, age, pregnancy, gender)

Other Street Drugs

PCP or angel dust. Phencyclidine Powerful anesthetic, bizarre behavior ketamine (special k) Veterinary anesthetic, related to PCP but not as potent Abused for hallucinogenic qualities

* Father of Toxicology "The dose makes the poison"

Paracelsus "the dose makes the poison" (1564) •Even innocuous things can become toxic at high doses. •High oxygen levels cause "oxygen intoxication" •Too much water (several gallons) can cause osmotic imbalance -Other examples include: •1 Tylenol vs. a bottle of Tylenol •1 beer vs. a case of beer •many drugs are actually more toxic than "toxic chemicals", especially heart medicine - Synergism

Metabolism issues

Patients experience changes in dose effectiveness due to multiple interactions. Synergy, inhibition, and induction Slow/ Rapid metabolizers Tolerance/Addiction May need to increase dose or change to a different compound

*Drug approval phases

Phase 0: Initial Pharmacodynamics and Pharmacokinetics screen are the first-in-human trials. Single subtherapeutic doses of the study drug are given to a small number of subjects (10 to 15) to gather preliminary data on the agent's pharmacodynamics (what the drug does to the body) and pharmacokinetics (what the body does to the drugs). Phase 1: Screening for safety researchers test an experimental drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects. Phase 2: Establishing the testing protocol the experimental treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety. Phase 3: Final testing the treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow it to be used safely. Phase 4: Post-approval studies post-marketing studies delineate additional information, including the treatment's risks, benefits, and optimal use.

Metabolism (biotransformation) Phases

Phase I: results in addition or exposure of functional group on parent compound Includes oxidation, reduction, hydrolysis Cytochrome P450s (CYPs) v. important hydroxylations, O-dealkylations, N-dealkylations, etc. etc. Phase II (conjugation): addition of polar group to increase water solubility and hence excretion Donor + Acceptor (drug) -------> Conjugate Additionally, metabolites may also be more pharmacologically active than parent!!!!!! In a good way Straight to phase II for drugs like morphine, heroin, and codeine (glucuronidation)

Cancer Stage- Progression

Progression stage- invasive event •Irreversible •Removing the carcinogen is irrelevant at this point • •Normal tissue is invaded • •Cells lose differentiation •phenotypical changes occur and the tumor becomes more aggressive and acquires greater malignant potential In this stage, cells rapidly divide, normal tissue is invaded by cancerous cells, metastasis increases, and cells lose differentiation. Progression is similar to initiation in that both are irreversible. In this stage, the cells are not affected by removing the carcinogen.

Cancer Stage- Promotion

Promotion stage- proliferation event •No direct DNA modification/mutation at this point • •Non-genotoxic promotor • •Multiple cell divisions necessary •Increased cell division •Decreased cell apoptosis • •Reversible upon removal of the promoting agent Tumors are considered to be in the promotion stage when they continue growth without stimulation from a carcinogen-DNA interaction. Promotion can be an increased expression of the altered DNA formed in the initiation stage, but can occur without DNA involvement. The carcinogen that caused the initiation stage may or may not be the toxin driving the promotion stage. Promotion can be stopped through removal of the promoter carcinogen, while the initiation stage cannot be reversed.

*What is the purpose of a Risk Evaluation and Mitigation Strategy (REMS)

REMS are designed to help reduce the occurrence or severity of a particular serious adverse event. They help support a drug's safe use as described in the product's FDA-approved prescribing information. Once FDA determines a REMS is necessary for a drug, pharmaceutical manufacturers must develop, implement, and assess the specific REMS for their drug product. It is important for health care professionals, patients, and all others whom REMS affect to be aware that REMS can provide safe access for patients to certain drugs with serious risks that may otherwise not be approved and available on the market.

How does a REMS mitigate a medication's risk?

REMS may include interventions that support the safe use of the medication. One example might involve a drug that can cause a severe allergic reaction immediately after administration. A REMS is required to ensure the drug is administered only in a health care facility with personnel trained to manage severe allergic reactions and immediate access to necessary treatments and equipment to managing such events. Another example might be to ensure certain lab testing is completed and the results are checked before a medication prescription is refilled. Other REMS may mitigate risks by educating health care providers about which patients may be at greatest risk of experiencing an adverse event and who therefore should not be prescribed a medication.

*Safety Pharmacology

Safety pharmacology is the study of the potential undesirable pharmacodynamic effects of a substance in relation to dosage within the substance's therapeutic range and above (i.e. medical-based toxicology). Safety pharmacology studies have to be designed for defining the dose-response relationship of the adverse effect observed. The time course (e.g., onset and duration of response) of the adverse effect has to be investigated. Generally, the doses eliciting the adverse effect have to be compared to the doses eliciting the primary pharmacodynamic effect in the test species or the proposed therapeutic effect in humans. Safety pharmacologists may be responsible for planning, conducting, and reporting of in vivo and in vitro assays (e.g. carditerm-17ovascular, respiratory and neurobehavioral based) to evaluate potential unanticipated pharmacodynamic effects of test articles prior to introduction in humans

Cellular hallmarks of cancer

Self sufficiency in growth signals Insensitivity to anti-growth factors Tissue invasion (metastasis) Limitless potential to divide Angiogenesis Anti-apoptotic mechanisms

*Fractionating

Separating dose allows time for DNA repair Decreases risk for deterministic effects and adverse effects *Fractionating a total dose usually decreases the probability that the total dose will cause toxicity. The reason for this is that the body often can repair the effect of each subtoxic dose if sufficient time passes before receiving the next dose. In such a case, the total dose, harmful if received all at once, is non-toxic when administered over a period of time. For example, 30 mg of strychnine swallowed at one time could be fatal to an adult whereas 3 mg of strychnine swallowed each day for ten days would not be fatal.

Acute medical treatment

Stabilize Patient Assessment of physical condition/Clinical history Determination of symptoms Look for toxidromes

Teratogens Examples Thalidomide

Thalidomide: sedative anti-inflammatory The fetal and infant death rate with maternal thalidomide use is estimated to be as high as 40% or greater. The cause of death has been attributed to the severe birth defects caused by the thalidomide exposure. The half-life of thalidomide is 8.7 hours, which is the time it takes for 50% of the drug to be cleared from your body. Therefore, after a few days to a week, any remaining drug level would be fairly low. To be safe, it is recommended that women stop use of thalidomide one month before conception to reduce the risk of thalidomide-related birth defects. Thalidomide was one of the first drugs recognized to cause birth defects in humans. Although thalidomide was not released in the United States until 1998, it is now being used for treatment of several medical conditions including leprosy, cancer, and complications from HIV infection. Thalidomide is a sedative, hypnotic, and anti-inflammatory medication. It was sold from 1957 to 1961 in almost fifty countries under at least forty names, including Distaval, Talimol, Nibrol, Sedimide, Quietoplex, Contergan, Neurosedyn, and Softenon. Thalidomide was chiefly sold and prescribed during the late 1950s and 1960s to pregnant women, as an antiemetic to combat morning sickness and as an aid to help them sleep. Thalidomide is racemic - it contains both left- and right-handed isomers in equal amounts. One enantiomer is effective against morning sickness. The other is teratogenic, and causes birth defects. The enantiomers are converted to each other in vivo - that is, if a human is given (R)-thalidomide or (S)-thalidomide, both isomers can be found in the serum - therefore, administering only one enantiomer will not prevent the teratogenic effect in humans. The mechanism by which thalidomide causes birth defects is not completely understood, although recent papers suggest that it alters TNFα production, modulates integrins, alters T-cell ratios and inhibits angiogenesis. It is known to intercalate into DNA at guanine sites, which may alter expression of certain genes thereby causing the dramatic malformations. Lenalidomide is a derivative of thalidomide introduced in 2005. It was initially intended as a treatment for multiple myeloma, for which thalidomide is an accepted therapeutic modality, but has also shown efficacy in the hematological disorders known as the myelodysplastic syndromes. The exact mechanism of the immunomodulatory drugs (i.e. thalidomide, CC-4047/Actimid and lenalidomide) is not known. Apart from interfering with the immune system, they are also thought to act on angiogenesis.

Whom do I contact for information about a particular REMS?

The REMS@FDA website includes information about the current approved REMS, or you can contact FDA at (855) 543-3784 or (301) 796-3400, or by email at [email protected]. You can also refer to the medication's REMS website that includes information about the specific programs, and contact information for the manufacturer or the REMS administrator.

*Exposure dose

The amount of a xenobiotic found in an environment

*Epidemiology

The branch of health sciences that studies and analyzes the incidence, distribution, and possible control of diseases and other factors relating to health, at the population level. It shapes public health policy decisions and evidence-based practice by identifying risk factors for disease and targets for preventive healthcare.

Cell Cycle (Chemotherapy Style)

The cell cycle is important to cancer chemotherapy due to the ability to categorize diverse agents into two groups: Cell Cycle (phase)-Specific (CCS) drugs that act only in a particular phase of cell division, and Cell Cycle (non-phase) Non-Specific (CCNS) drugs that action on dividing cells independent of the particular phase of the cell. Thus, the majority of cancer agents act only on dividing cells and resting phase (Go) are typically spared. A clinical extension to the cell cycle specificity of a drug is that most CCS drugs are maximally effective by prolonged administration, which maximizes the cell kill rates by presenting drug over a long enough time to effect different cell populations as they enter the sensitive phase for that respective CCS drug. Conversely, most CCNS drugs are not schedule dependent in their cell killing and thus can often be given in single weekly or monthly injections. *PICTURE IMPORTANT

Clinical Toxicology

The discipline within toxicology concerned with the toxic effect of agents whose intent is to treat, ameliorate, modify, or prevent disease states, or the effect of drugs which, at one time, were intended to be used as such. Purposes: • Acute medical treatment (poisonings, ER admissions) •Therapeutic drug monitoring (drugs with a narrow therapeutic window) •Compliance monitoring (chronic pain, addiction patients)

*absorption, distribution, metabolism, excretion

The disposition of a toxicant along with its' biological reactivity are the factors that determine the severity of toxicity that results when a substance (i.e. xenobiotic) enters the body. Specific aspects of disposition of greatest importance are: •rate and amount that can be absorbed •distribution in the body and concentration at specific body sites •efficiency of biotransformation and nature of the metabolites •the ability of the substance or it's metabolites to pass through cell membranes and come into contact with specific cell components (e.g., DNA) •the amount and duration of storage of the substance (or it's metabolites) in body tissues •the rate and sites of excretion

Developmental Impact Part: #3

The effect produced by a teratogenic agent depends upon the developmental stage in which the foetus is exposed to the agent. Several important phases in human development are recognized: •The time from conception until implantation known as the "all or none" period, when insults to the embryo are likely to result in death of the conceptus and miscarriage (or resorption), or in intact survival. At this stage, the embryo is undifferentiated and repair and recovery are possible through multiplication of the still totipotential cells to replace those which have been lost. Exposure of embryos to teratogens during the preimplantation stage usually does not cause congenital malformations, unless the agent persists in the body beyond this period. •The embryonic period, from ~18 to 54-60 days after conception is the period when the basic steps in organogenesis occur (First trimester: ~0-12 weeks). This is the period of maximum sensitivity to teratogenicity since not only are tissues differentiating rapidly but damage to them becomes irreparable. Exposure to teratogenic agents during this period has the greatest likelihood of causing a structural anomaly. Since teratogens are capable of affecting many organ systems, the pattern of anomalies produced depends upon which systems are differentiating at the time of teratogenic exposure. •The second and third trimester, known as fetogenesis, from the end of the embryonic stage to term, is the period when growth and functional maturation of organs and systems already formed occurs. During this period drugs are less likely to be associated with major malformations, but they may influence neurologic development, growth, physiologic and biochemical functioning, mental development, and reproduction. The term foetal toxicity is commonly used to describe such an effect. Of particular interest is the potential effect of psychoactive agents (e.g., antidepressants, antiepileptics, alcohol and other drugs of abuse) on the developing central nervous system, which has led to a new field of behavioural teratology.

How do we know if the REMS is mitigating risk?

The manufacturer of the specific medication is responsible for developing an assessment plan to determine if the REMS is meeting its risk mitigation goal. At periodic intervals following REMS approval, manufacturers submit a REMS assessment report to FDA that includes analysis, findings and conclusions related to whether the REMS is meeting its goals and what if any, modification may be needed. FDA reviews the REMS assessment reports, determines if the REMS assessment report is complete, if the REMS is meeting its goals, and if the REMS goals, elements, tools or assessment plan should be modified.

*route of exposure

The route of exposure is an important factor that can affect the concentration of the toxicant (or its' metabolites) at any specific location within the blood or lymph. This can be important since the degree of biotransformation, storage, and elimination (and thus toxicity) can be influenced by the time course and path taken by the chemical as it moves through the body. For example, if a chemical goes to the liver before going to other parts of the body, much of it may be biotransformed quickly. In this case, the blood levels of the toxicant "downstream" may be diminished or eliminated. This can dramatically affect its potential toxicity. Gastrointestinal Tract The gastrointestinal tract (the major portion of the alimentary canal) can be viewed as a tube going through the body. Its contents are considered exterior to the body until absorbed. Salivary glands, liver, and the pancreas are considered accessory glands of the GI tract as they have ducts entering the GI tract and secrete enzymes and other substances. For foreign substances to enter the body, they must pass through the gastrointestinal mucosa, crossing several membranes before entering the blood stream. Respiratory Tract -Many environmental and occupational agents as well as some pharmaceuticals are inhaled and enter the respiratory tract. Absorption can occur at any place within the upper respiratory tract. However, the amount of a particular substance that can be absorbed at a specific location is highly dependent upon its physical form and solubility. Dermal In contrast to the thin membranes of the respiratory alveoli and the gastrointestinal villi, the skin is a complex, multilayer tissue. For this reason, it is relatively impermeable to most ions as well as aqueous solutions. It thus represents a barrier to most xenobiotics. However, some notable toxicants can gain entry into the body following skin contamination.For example, certain commonly used organophosphate pesticides have poisoned agricultural workers following dermal exposure. The neurological warfare agent, Sarin, readily passes through the skin and can produce quick death to exposed persons. Several industrial solvents can cause systemic toxicity by penetration through the skin. For example, carbon tetrachloride penetrates the skin and causes liver injury. Hexane can pass through the skin and cause nerve damage.

Are there any medications with approved REMS, where the drug has been removed from the market either because of new serious safety issues or due to risks that could not be mitigated by REMS?

To date, FDA has not removed a drug with a REMS from the market due to new or serious issues that could not be mitigated by the REMS.

Acute Treatment: Prevention of Further absorption

Topical: remove contaminated clothing/wash skin Inhale: adequate ventilation Oral: Induction of emesis (Vomit), gastric lavage, activated charcoal, whole bowel irrigation Enhanced removal Hemiodialysis, Hemoperfusion, Hemofiltration, exchange transfusion, alkalinization of urine (increases renal clearance of weak acids)

*Toxicant (xenobiotic)

Universal term (anything can be a toxicant) (Xenobiotic formal term)

Does FDA develop the individual REMS?

While FDA determines that a REMS is necessary, specifies the requirements and approves the specific programs, the medication's manufacturer is responsible for developing and implementing the program. Some manufacturers develop these programs themselves while other manufacturers hire vendors or other companies to develop and implement the programs on their behalf.

Teratogens Smoke and Nicotine

Women who smoke during pregnancy are 80% more likely to have a spontaneous abortion as compared to a non smoker. Effects: • ???? • lower birth weights • Behavioral changes after birth Sudden infant death syndrome (SIDS)? Approximately 25% percent of pregnant women will continue to smoke while pregnant. Maternally inhaled nicotine can be detected in fetal lung, trachea, kidney, adrenal glands and intestines. Women who smoke during pregnancy are 80% more likely to have a spontaneous abortion as compared to a non smoker. Nicotine restricts uterine blood vessels and restricts blood flow to the fetus resulting in chronic hypoxia and malnutrition leading to birth defects. On average, offspring of smoking women weigh 170-200 g less at birth as compared to a non smoker's child. There is a dose dependence in that the child's weight decreases in proportion to number of cigarettes smoked by the mother. There is also a reduction in overall fetal length, reduced head circumference, intrauterine growth retardation as well as behavioral alterations after birth. Other possible malformation (which are still controversial) are cleft lip and palate, cardiac malformations and anencephaly. Smoking during pregnancy increases the risk for premature delivery, abruptio placentae, placenta previa and perinatal mortality. Some data suggests increase incidence of sudden infant death syndrome (SIDS). Smoking is thought to reduce the supply of oxygen and the level of nutrition to fetus, and nicotine has shown to be a neuroteratogen in experimental animals. Cancer/toxicity-causing chemicals in tobacco smoke Tar - a mixture of dangerous chemicals Arsenic - used in wood preservatives Benzene - an industrial solvent, refined from crude oil Cadmium - used in batteries Formaldehyde - used in mortuaries and paint manufacturing Polonium-210 - a highly radioactive element Chromium - used to manufacture dye, paints and alloys 1,3-Butadiene - used in rubber manufacturing Polycyclic aromatic hydrocarbons - a group of dangerous DNA-damaging chemicals Nitrosamines - another group of DNA-damaging chemicals Acrolein - formerly used as a chemical weapon Other poisons in cigarette smoke Hydrogen cyanide - used as an industrial pesticide Carbon monoxide - found in car exhausts and used in chemicals manufacturing Nitrogen oxides- a major component of smog Ammonia - used to make fertilizers and explosives FYI Relatively expansive sites for smoking impact in general: http://www.cancerresearchuk.org/cancer-info/healthyliving/smokingandtobacco/smoking-and-cancer http://www.cancer.gov/cancertopics/tobacco/smokin

*REMS Example

Zyprexa Relprevv (olanzapine extended release injectable suspension) is a long-acting injectable (atypical) anti-psychotic medication used to treat schizophrenia in adults. Zyprexa Relprevv can cause serious reactions following injection called post-injection delirium sedation syndrome. Symptoms, including feeling sleepier than usual (sedation), coma, and feeling confused or disoriented (delirium) occurred in clinical studies within 3 hours after treatment with Zyprexa Relprevv. The risk of post-injection delirium sedation syndrome is present with every injection, although it is a small risk - less than 1 percent. To reduce the risk of post-injection delirium sedation syndrome, FDA required the manufacturer of Zyprexa Relprevv to develop a REMS. The purpose of the REMS is to ensure that the drug is administered only in certified health care facilities that can observe patients for at least three hours and provide the medical care necessary in case of an adverse event. Drugs or agents that increase the activity of the enzyme CYP1A2, notably tobacco smoke, may significantly increase hepatic first-pass clearance of olanzapine; conversely, drugs that inhibit CYP1A2 activity (examples: ciprofloxacin, fluvoxamine) may reduce olanzapine clearance ((Olanzapine has a higher affinity for 5-HT2A serotonin receptors than D2 dopamine receptors, which is a common property of most atypical antipsychotics, albeit it also has affinity for several other 5-HT and dopamine receptors, as well as histamine and muscarinic receptors))

*case study or case series

an observation technique in which one person is studied in depth in the hope of revealing universal principles qualitative, retrospective, no controls

Teratogens Tetracycline Example

broad-spectrum antibiotic produced by the streptomyces bacterium excreted in breast milk Effect: Weakeded bone and teeth enamel Permanent yellow or brown discoloration and enamel hypoplasia Tetracycline is a broad-spectrum antibiotic produced by the streptomyces bacterium, indicated for use against many bacterial infections. It is commonly used to treat acne. All tetracyclines have a detrimental effect on the skeletal development and bone growth of the fetus or child. They should not be used in the second half of pregnancy unless benefits from treatment outweigh the risks to the fetus, and their use should be considered only with extreme caution. The discoloration of the baby teeth is due to calcification (hardening) of the teeth, which starts at about four months. This problem appears to be only cosmetic, and does not appear to affect the development of the enamel or the chance of getting cavities. Tetracyclines also have a serious effect on the dentin and enamel of developing teeth, causing permanent yellow or brown discoloration and enamel hypoplasia. Except when other therapy is ineffective, use in pediatrics, especially in children under 8 years, should be avoided. Mechanism: Calcium orthophosphate is a major constituent of calcification. In the second to third trimesters of pregnancy, calcium orthophosphate plays a huge role in initial calcification of the skeletal system. This heavy reliance on calcium orthophosphate continues for the child until about ages 6 to 8. As discussed above, tetracycline is a major chelator. This chelating aspect of tetracycline makes it so that the tetracycline binds to the calcium part of the calcium orthophosphate complex. This tetracycline-calcium orthophosphate complex is taken in by the bones/enamel, resulting in general weakness, impairment to long bone elongation, impairment to calcium uptake, and yellow-gray discoloration. Tetracycline given to a mother in her second to third trimester or a child under the age of eight could result in the skeletal/dental toxicity; however, it is also important to note that as the child grows older, the skeletal element of this toxicity is more or less mitigated while the discoloration enamel still plays a role. This adverse reaction occurs in fetuses/children even at low doses, so it is advised that pregnant mothers avoid tetracycline entirely during the relevant trimesters and it is advised that tetracycline is never administered to a child under the age of 8. (Drugs in pregnancy and lactation 10th ed.; POISONDEX)

Teratogens Antiepileptic drugs

dose-dependent effect for adverse outcomes Neural tube defects (Spinal bifida) Excreted in breast milk Midfacial hypoplasia Antiepileptic drugs Congenital malformations are increased two- to threefold in babies of epileptic mothers. Interestingly, all existing antiepileptic drugs have been implicated including phenytoin (particularly cleft lip/palate), valproate (neural tube defects) and carbamazepine (spina bifida and hypospadias-a malformation of the male urethra) as well as newer agents. Valproic acid was released in 1967 in Europe and in 1978 in the United States to treat epilepsy. Approximately 11,500 epileptic women become pregnant each year, many of which use valproic acid. By 1980, publications began linking malformed children to in utero exposure to valproic acid (greater than 500 mg/day). These children were born with lumbosacral spina bifida with menigomyelocele or menigocele, often accompanied by midfacial hypoplasia, deficient orbital ridge, prominent forehead, congenital heard disease and decreased postnatal growth. The proposed mechanism of action is that valproic acid influences folate metabolism, thereby altering the closure of the spinal column resulting in spina bifida.

*clinical trials

involving new drugs are commonly classified into four phases. Each phase of the drug approval process is treated as a separate clinical trial, with evaluation of safety and efficacy. The drug-development process will normally proceed through all four phases over many years.

Pharmacology

is the study of how chemical substances interact with living systems, within the context of drug action and medicinal properties.

Toxicology

is the study of the adverse effects of chemical, physical or biological agents on living organisms and the ecosystem, including the prevention and betterment of such adverse effects.

*risk assessment

is the systematic scientific characterization of potential adverse health effect resulting from human exposures to a hazardous agents or situations. **Hazard-is the capability of any substance to cause an adverse effect. **Risk-is defined as the probability of an adverse outcome under specified conditions, based on exposure and potency. **Risk management-refers to the process by which policy actions are chosen to control hazards. **Risk communication-is the process of relaying outcomes of risk assessments to the public in a comprehensible manner Understand how we can help to control risk (i.e. information, testing, regulation, substitution, treatments, education).

*LOAEL

lowest observed adverse effect level Lowest data point in which there (WAS) an adverse effect

*NOAEL

no observed adverse effect level Highest data point in which there was (NOT) an observed toxic/adverse effect

*selective toxicity

organism specific *Some medicine might affect dogs differently than humans and so on

Administered dose

quantity of drug given

*Acute toxicity

refers to the rapid development of symptoms/effects after the intake of relatively high dose(s) of the toxicant. •Often single dose, within a 24hr period. •Usually has an immediate life-threatening effect. •Is usually easily diagnosed. •Often there are antidotes that can reduce the toxicity of the chemical. o o In 1989, 5,000 people died and 30,000 were permanently disabled due to exposure to methyl isocyanate from an industrial accident in India. o o Many people die each year from inhaling carbon monoxide from faulty heaters. o o Non-lethal acute effects may also occur, e.g., convulsions and respiratory irritation.

*chronic toxicity

represents cumulative damage to specific organ systems and takes many months or years to become a recognizable clinical disease. •Does not have an immediate effect but could be life-threatening in the long term. •Is usually hard to diagnose and treat. •Is hard to distinguish effects from other influences •Represents cumulative damage to specific organ systems and takes many months or years to become a recognizable clinical disease. ØDamage due to subclinical individual exposures may go unnoticed. ØUltimately, the damage becomes so severe that the organ can no longer function normally and a variety of chronic toxic effects may result. Ø Examples: •Cirrhosis in alcoholics who have ingested ethanol for several years •Chronic kidney disease in workmen with several years exposure to lead •Chronic bronchitis in long-term cigarette smokers •Pulmonary fibrosis in coal miners (black lung disease) Cancers

*Pre-clinical trials

research on a new drug or a new medical device or procedure, usually done on animals, to learn about mechanisms of action, determine how well the treatment works, and see if it is safe to test on humans. Before clinical trial initiation

*subchronic toxicity

results from repeated exposure for several weeks or months. Generally lower doses than acute, but detectable. Examples: •Ingestion of coumadin tablets (blood thinners) for several weeks as a treatment for venous thrombosis can cause internal bleeding. • •Workplace exposure to lead over a period of several weeks can result in anemia.

*cross-sectional study

specific time ("present time"), no built in controls, does not identify causation

*Absorbed dose

the amount of drug that enters the body

Developmental Impact Part: #1

• Age of Mother • Genetics • Disease • Nutrition • Stress Interrelationships between maternal susceptibility factors, metabolism, induction of maternal physiologic or functional alterations, placental transfer and toxicity, and developmental toxicity. A developmental toxicant can cause abnormal development through any one or a combination of these pathways. Maternal susceptibility factors determine the predisposition of the mother to respond to a toxic insult, and the maternal effects listed can adversely affect the developing conceptus. Most chemicals traverse the placenta in some form, and the placenta can also be a target for toxicity. In most cases, developmental toxicity is probably mediated through a combination of these pathways.

Teratogens Cretinism

•Cretinism -Irreversible form of mental retardation -Caused by absence of thyroid hormone during period of active neurogenesis -Can be prevented if supplemented with thyroid hormone the first 2 weeks of life •Thyroid screening upon birth •Occurs in 1/4000 births -2 types •Endemic -Due to extreme iodine deficiency •Sporadic -Thyroid fails to develop normally or defect in the synthesis of thyroid hormone Thyroid hormones are critical for development of the fetal and neonatal brain, as well as for many other aspects of fetal growth. Hypothyroidism in either the mother or fetus frequently results in fetal disease; in humans, this includes a high incidence of mental retardation. Cretinism is characterized by mental and growth retardation and occurs when children who live in iodine-deficient regions are not treated with iodine or thyroid hormone to restore normal thyroid hormone levels during early life. These children are often born to mothers with iodine deficiency, and it is likely that maternal thyroid hormone deficiency worsens the condition. Thyroid hormone plays a critical role in brain development Important in period of active neurogenesis First 6 months of life Neurogenesis Neuronal migration Axonal projections Synaptogenesis Myelinization The absence of thyroid hormone during the period of active neurogenesis (up to 6 months postpartum) leads to irreversible mental retardation (cretinism) and is accompanied by multiple morphological alterations in the brain. These severe morphological alterations result from disturbed neuronal migration, deranged axonal projections, and decreased synaptogenesis. Thyroid hormone supplementation during the first 2 weeks of life prevents the development of these disturbed morphological changes.

Animal models for developmental toxicity studies

•Differences in gestational development in animal models. • •Is not just a matter of "scale" (ex - 3rd trimester in humans does not necessarily compare to last 1/3 of pregnancy for mice). • •Choice of animal model and time of treatment is very important. Studies designed to test the teratogenic potential of environmental agents use animal model systems (e.g., rat, mouse, rabbit, dog, and monkey). Early teratologists exposed pregnant animals to environmental agents and observed the fetuses for gross visceral and skeletal abnormalities. While this is still part of the teratological evaluation procedures today, the field of Teratology is moving to a more molecular level, seeking the mechanism(s) of action by which these agents act. Genetically modified mice are commonly used for this purpose. In addition, pregnancy registries are large, prospective studies that monitor exposures women receive during their pregnancies and record the outcome of their births. These studies provide information about possible risks of medications or other exposures in human pregnancies.

Problems with Drug Addiction

•Impact -health effects -effects on personal life -effects on being a contributing member of society -Increased criminal activity -Child development Lost productivity

The American College of Occupational and Environmental Medicine recognizes the following teratogens

•Ionizing radiation: atomic weapons, radioiodine, radiation therapy • Infections: cytomegalovirus herpes virus hominis I and II, parvovirus B-19, rubella virus (German measles), syphilis, toxoplasmosis, Venezuelan equine encephalitis virus • Metabolic imbalance: alcoholism, endemic cretinism, diabetes, folic acid deficiency, hyperthermia, phenylketonuria, rheumatic disease and congenital heart block, virilizing tumors • Drugs and environmental chemicals: 13-cis-retinoic acid (isotretinoin, Accutane), aminopterin and methylaminopterin, androgenic hormones, busulfan, captopril and enalapril (ACE inhibitors), chlorobiphenyls (PCBs), cocaine, coumarin anticoagulants, cyclophosphamide, diethylstilbestrol diphenylhydantoin (Phenytoin, Dilantin, Epanutin), etretinate, lithium, methimazole, organic mercury compounds, penicillamine, tetracyclines, thalidomide, trimethadione, and valproic acid.

Developmental Impact Part: #2

•Less than 1% of congenital fetal defects are attributed to drugs given to the mother. • Gross malformations are produced only if teratogens act during organogenesis. • The mechanisms of action for many teratogens are not clearly understood, though DNA damage is a factor in many cases. In general, most enzymatic pathways of drug biotransformation are at a much lower level in fetus in comparison to adult Phase specificity (i.e. critical period) corresponds with drug specificity (i.e. drug induces different effects at different stages) Assessment of teratogenicity in humans is a particularly difficult problem, for various reasons. One is that the 'spontaneous' malformation rate is high (3-10% depending on the definition of a significant malformation) and highly variable between different regions, age groups and social classes. Large-scale studies are required, which take many years and much money to perform, and they usually give suggestive, rather than conclusive, results. In vitro methods, based on the culture of cells, organs or whole embryos, have not so far been developed to a level where they satisfactorily predict teratogenesis in vivo, and most regulatory authorities require teratogenicity testing in one rodent (usually rat or mouse) and one non-rodent (usually rabbit) species. Pregnant females are dosed at various levels during the critical period of organogenesis, and the fetuses are examined for structural abnormalities. However, poor cross-species correlation means that tests of this kind are not reliably predictive in humans, and it is usually recommended that new drugs are not used in pregnancy unless it is essential.

human birth defects

•Less than 1/2 of conceptions result in birth of a normal healthy infant -postimplantation pregnancy loss = 31% -major birth defects at birth = 2-3% -major birth defects recognized at 1 yr = 6-7% -minor birth defects = 14% -low birth weight = 7% -infant mortality (before 1 yr) = 1.4% -abnormal neurologic function = 16-17% Note: these stats are not solely associated with teratogens. Congenital malformations can be defined as nonreversible functional or morphological defects present at birth (major birth defects). It is important to remember these defects may not be detectable at birth, but may only become evident later in life. Most sources speak of teratogenicity in terms of the presence of major congenital malformations. Major malformations are those that are either life-threatening, require major surgery, or have serious cosmetic effects. These do not necessarily include drug-induced defects, which are often not structural in nature, such as growth retardation, CNS depression, or biochemical abnormalities. Most sources use the figure of 3% prevalence rate for major congenital malformations recognized at birth, and another 3% rate for major congenital malformations unrecognized during the neonatal period. This combined 6% rate does not include mental and physical growth retardation or minor congenital malformations such as hydrocele, angioma, hernias and nevus, which are not of medical significance. Environmental factors alone, such as maternal disease or infection, chemicals and drugs, account for between 5% and 9% of the malformations (out of the total 6%). This category includes infections such as rubella (German measles), cytomegalovirus, and Toxoplasma gondii (a protozoan) as definitive teratogens. It also includes maternal diseases such as diabetes and seizure disorders. Rubella infection is the most well-known of the viral infectious teratogens. Maternal rubella can result in a group of defects, including heart disease, cataracts and deafness, known as fetal rubella syndrome. Diabetes is the most common of the chronic diseases that can result in teratogenesis, accounting for over 90% of all maternal disease that results in major congenital malformations.

*Species differences

•Quantitative and qualitative differences •Variations in ADME and mechanism of response

Drug Plasma Conc and Volume of Distribution

•Vd = the volume in which the amount of drug would need to be uniformly dissolved in order to give observed blood concentration •Allows calculation of body burden of drug (dose currently in system) •Compare to initial dose taken (if known) •Allows refinement of strategies to slow absorption/enhance elimination/administer antidote Cp (gm/L) = Grams/ (Weight in KG * Vd in Kg/L) Cp = plasma conc. Vd = volume distribution

*Individual differences in responses

•Within species differences •Genetic polymorphisms Idiosyncratic reactions -denotes an abnormal reaction that is non-expected based on defined understanding of the drug mechanism. It is what is known as a Type B reaction -Usually unpredictable -not necessarily dose related -incidence and morbidity low -Mortality high