toxicity

• Safe and effective drug therapy requires an understanding
• of the balance between the drug’s adverse (toxic) effects
• and its benefits

• intended and unintended tissue (correct receptor on target but diff tissue)
• on target- dose too high, chronic activation or inhibition effects
• off target- incorrect receptor is inhibited or activated

• - antipsychotic drug controls schizophrenia
• antagonist at D2 receptor in limbic areas
• of brain that control the symptoms of
• schizophrenia
• also, an antagonist at D2 receptor in
• striatal areas that cause motor
• impairment

• is used clinically to decrease cholesterol
• levels -its intended target tissue is the liver.
• The drug inhibits HMG CoA reductase which is the
• rate-limiting enzyme in cholesterol production.
• HMG CoA reductase also regulates the
• posttranslational modification of several muscle
• proteins.
• An adverse effect of simvastatin therapy is
• muscle toxicity.

• beneficial effect of stopping allergic inflammation, itching, sneezing and rhinorrhea but also have a number of adverse effects at this intended target.
• H1 antihistamine drugs also have unintended targets (cholinergic and α –
• adrenergic receptors) where they cause numerous adverse effects.

• of the same compound can differ in their targets and toxic effects.
• citalopram is a racemic antidepressant drug
• its toxic effects include : diaphoresis,
• drowsiness, fatigue, impotence, and insomnia
• escitalopram-(S)-citalopram was developed under
• the supposition that on-target
• antidepressant effects are produced by (S)-
• citalopram while off-target toxic effects
• come from the (R)-enantiomer

• activate β1 receptors and β2 receptors causing
• off-target (β1 receptor) activation – can cause tachycardia and palpitations
• when used to treat asthma

• block β1 receptors and β2
• receptors causing off-target (β2 receptor) blockade – can exacerbate
• asthma symptoms when used to treat heart disease

• 50% of hepatic necrosis cases are
• caused by overdose
• P450 induction (e.g. by
• alcohol) can increase amounts of toxic
• metabolite formation
• The toxic product is usually removed by glutathione
• Approximately 13g of acetamiophen intake
• depletes glutathione

• keep plasma acetaminophen levels
• below line
• prevent centrilobular hepatic
• necrosis
• n-acetylcysteine is an antidote
• that restores glutathione levels

form haptens that bind to proteins

(e.g., peptides, proteins) activate the immune system directly

• - hypersensitivity reactions and autoimmune
• reactions

• (IGE mediated) is most common
• Penicillin, lidocaine cause type 1 (immediate) hypersensitivity responses in some patients.
• Can cause anaphylaxis that may require treatment with epinephrine.

ciprofloxacin- type IV (delayed type hypersensitivity reaction) -can be very severe in some patients

• –antihypertensive agent
• Can cause hemolytic anemia and thrombocytopenia
• by eliciting an immune response to Rhesus antigens (Rh
• factors)

• –potent Class 1A antiarryththmic
• Causes reversible Lupus-like (SLE) symptoms in 25 to 30 % of patients
• approximately 80% show increased antinuclear antibody titers

• - rare adverse effect for which no obvious mechanism is apparent
• Some idiosyncratic effects are not related to drug metabolism

• -short-acting neuromuscular-blocking anesthetic
• drug
• IST -1 in 3000 patients have prolonged neuromuscular block due to abnormal or deficient plasma pseudocholinesterases that slows
• metabolic degradation of the drug

• -is considered a first-line agent in the treatment of
• tuberculosis. - metabolized by n-acetyltransferase 2 (NAT2) that acetylates the drug
• IST Patients who metabolize isoniazid slowly (slow acetylators) build up high levels of toxic metabolites
• This metabolite causes hepatitis in about 2.1% of drug recipients.
• Differences in metabolism run in families.

• 10 % of Africans and 10-20 % of Mediterraneans and
• Southeast Asians get from:
• anti-malarials, sulfonamide antibiotics, ibuprofen,
• acetaminophen and aspirin
• These patients have a deficiency in glucose-6-phosphate dehydrogenase that protects red blood cells from oxidative stress.
• This idiosyncrasy occurs more frequently in parts of the world where malaria is present.

• The study of genes causing variations in response to drugs is pharmacogenetics.
• Pharmacogenetics is helping to elucidate the mechanisms that underlie idiosyncratic drug toxicity.

an X-linked recessive genetic trait that is related to the sickle-cell trait that protects from malaria

curve describes the therapeutic effect.

curve describes any adverse effects.

curve describes mortality

inhibits phosphodiesterase type 5 (PDE5) and prolongs the action of cyclic GMP (cGMP) by partially preventing its breakdown

• stimulates guanylyl cyclase to increase cGMP levels in vascular smooth muscle that dilates blood vessels and
• lowers blood pressure

• additively increases cGMP levels and creates a risk of
• severe hypotension.

• increased risk of hepatotoxicity if echinacea tea is also consumed.
• Some species of echinacea may contain pyrrolizidine alkaloids that deplete glutathione.
• A reduction in glutathione levels lowers the dose at which acetaminophen causes hepatotoxity.

: adverse effects of a single exposure to a drug

: adverse effects that occur with repeated exposure over time

• chlorpromazine can lead to a type of motor system toxicity known as
• tardive dyskinesia.

• results in continued estrogen receptor pathway
• stimulation that can lead to endometrial cancer.

• with specific receptors to mediate on target or off-target adverse effects.
• damage proteins (especially in liver) or disrupt cellular function
• form unrepaired or misrepaired DNA adducts that are often mutagenic and may lead to cancer or teratogenesis
• impair oxidative defenses that can lead to inflammation and eventual cell death
• form drug-protein adducts that can trigger immune responses that can
• damage cells and tissues through inflammatory mechanisms

• The response to injury after cellular damage with drugs is largely determined by the regenerative capacity of the target organ.
• early indicator of drug induced damage.
• Fibrosis may lead to necrosis or apoptosis and organ failure.
• The lung, liver and kidney are especially susceptible to damage from drugs.

• P-450 in Clara cells
• cause fibrotic changes (pneumoconoisis) leading to compromised function (e.g., chronic obstructive pulmonary disease - COPD

• most effective drug for cardiac arrhythmias (heart rhythm disturbances); administered orally or IV; noteworthy lung toxin
• The most severe non-cardiac adverse effect – pulmonary fibrosis is often fatal (10% of cases)
• Risk increases gradually during chronic administration.
• easily masked by pre-existing cardiopulmonary disorders

• (25% of cardiac output)
• concentrates many drugs and other xenobiotics for excretion
• can further biotransform drugs into toxicmetabolites
• transport chemicals into tubular cells

• (aminoglycoside antibiotics especially gentamicin),
• NSAIDs, and angiotensin-converting enzyme (ACE)
• inhibitors

• is the induction of defects in the fetus, and a
• teratogen is a substance that can induce such defects.

• major congenital anomalies Teratogens have the
• most profound effect here.

Agents affect the growth and functional maturation of organs (e.g. fetal alcohol syndrome).

• --most notorious human teratogen
• upper limb phocomelia - after exposure during days 27 to 30
• Lower limb phocomelia - after exposure during days 30 to 33
• gallbladder aplasia – after exposure during days 42 to 43

• – one of the most potent teratogens still in common use (dermatologic conditions)
• regulator of cell reproduction, cell proliferation and differentiation
• Causes: CNS, skull, external ear, eye, and cardiovascular abnormalities; facial dysmorphia, cleft palate, thymus gland abnormality, parathyroid hormone deficiency and lower IQ scores

• –anticonvulsant for management of tonic-clonic (grand mal) and psychomotor seizures
• associated with folic acid deficiency which has been associated with neural
• tube defects
• Causes: 'fetal hydantoin syndrome‘, craniofacial strabismus, broad and/or depressed nasal bridge, high-arched palate (cleft palate), and smaller head circumference (microencephaly).

• low molecular weight, readily crosses the placenta, and can
• cause significant adverse teratogenic and fetal effects

• first trimester exposure, particularly during the 6th—12th weeks of gestation, embryopathy characterized by nasal hypoplasia
• Other CNS abnormalities: Agenesis of the corpus
• callosum, Dandy-Walker malformation, optic atrophy, and eye abnormalities have been observed following first trimester exposure.
• Seizures, deafness, blindness, and mental retardation can occur with exposure in any trimester.

is a chemical, physical, or biologic insult that acts by causing DNA damage (mutations).

• multiple genetic changes, over several years
• Drugs are a relatively uncommon (but not unimportant) cause of cancer.

• Drugs used in cancer therapy may also may be toxic to healthy human cells. In
• particular, increase the risk of leukemia.
• Immunosuppressive agents (e.g., 6-mercaptopurine)
• hormones and hormone antagonists (e.g.,
• estrogen and analogs)

• Initiation(genotoxic drugs, radiation,
• spontaneous)
• Promotion(drugs that release growth
• constraints

• (1) Proto-oncogenes encode proteins that encourage cell cycle progression.
• (2) Tumor suppressor genes encode proteins that inhibit growth and cell cycle progression

• (cyclophosphamide) target DNA in cancer cells but are also genotoxic to normal blood cell progenitors.
• genotoxic to blood cell progenitors in bone marrow.
• “Normal” cell progression is compromised.
• Myelodysplasia and acute myeloid leukemia (AML) can result.10%-20% of cases of AML in the United States are from treatment with such cancer drugs.

• Promoter- partial estrogen receptor agonist in the uterus
• where it alters gene expression to promote transformed cell development.
• development of endometrial cancer.
• raloxifene, no uterine estrogen receptors and may therefore be safer for treatment

• is a prototypic non-genotoxic tumor promoter.
• associated with moderately increased risks for cancers of the lung, ovary and gallbladder

• typically uses 2,000-4,000 patients.
• If an adverse effect occurs 1 per 1,000, only 2-4 incidents would be seen during clinical
• testing
• When 10 million patients take the same drug during
• marketing, 10,000 occurrences of severe toxicity might happen. marketed for a long time can be determined to be “relatively safe”

linked to increased heart attack risk,

is necessary especially during the use of newer drugs.

Effects on the part of practicing physicians and other providers is part of the solution.