Card Set Information
risk- benefit ratio
Safe and effective drug therapy requires an understanding
of the balance between the drug’s adverse (toxic) effects
and its benefits
targeted tissue and toxicity considerations
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
also, an antagonist at D2 receptor in
striatal areas that cause motor
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
An adverse effect of simvastatin therapy is
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
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
Non -selective β agonists
activate β1 receptors and β2 receptors causing
off-target (β1 receptor) activation – can cause tachycardia and palpitations
when used to treat asthma
Non -selective β-blockers (antagonists)
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
The toxic product is usually removed by glutathione
Approximately 13g of acetamiophen intake
therapeutic goals of acetaminophen and antidote
keep plasma acetaminophen levels
prevent centrilobular hepatic
n-acetylcysteine is an antidote
that restores glutathione levels
Small molecule drugs (< 600 daltons)
form haptens that bind to proteins
(e.g., peptides, proteins) activate the immune system directly
Two toxic immune responses
- hypersensitivity reactions and autoimmune
(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.
Type II, III, and IV
ciprofloxacin- type IV (delayed type hypersensitivity reaction) -can be very severe in some patients
Can cause hemolytic anemia and thrombocytopenia
by eliciting an immune response to Rhesus antigens (Rh
–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
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.
hemolytic anemia idiosyncratic effects not related to drug metabolism
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.
We now know that G6PD deficiency is:
an X-linked recessive genetic trait that is related to the sickle-cell trait that protects from malaria
Effective Dose/response (ED50)
curve describes the therapeutic effect.
Toxic Dose/response (TD50)
curve describes any adverse effects.
Lethal Dose/response (LD50)
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
co-exposure of NG and viagra
additively increases cGMP levels and creates a risk of
Drug-Food Interactions acetaminophen
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
Chronic treatment with the D2 dopamine receptor antagonist drug
chlorpromazine can lead to a type of motor system toxicity known as
Long term hormone replacement therapy (with estrogen) for postmenopausal women
results in continued estrogen receptor pathway
stimulation that can lead to endometrial cancer.
A drug or its metabolites or both can interact
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.
toxic metabolites in lung through
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
The kidney has blood flow output and other shit
(25% of cardiac output)
concentrates many drugs and other xenobiotics for excretion
can further biotransform drugs into toxicmetabolites
transport chemicals into tubular cells
Examples of drugs that can cause renal failure:
(aminoglycoside antibiotics especially gentamicin),
NSAIDs, and angiotensin-converting enzyme (ACE)
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).
Thalidomide- upper and lower time, and other
--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
: 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
: '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
Fetal Warfarin Syndrome (FWS):
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.
Cancer causing drugs include the following:
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)
Drugs may interfere at 2 steps to cause cancer
Initiation(genotoxic drugs, radiation,
Promotion(drugs that release growth
Genotoxic mutations involve two types of genes.
(1) Proto-oncogenes encode proteins that encourage cell cycle progression.
(2) Tumor suppressor genes encode proteins that inhibit growth and cell cycle progression
Cancer chemotherapeutic cytotoxic alkylating agents
(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
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.
Voluntary Reporting of Adverse
Effects on the part of practicing physicians and other providers is part of the solution.