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