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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
- 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
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
- metabolite formation
- The toxic product is usually removed by glutathione
- Approximately 13g of acetamiophen intake
- depletes glutathione
therapeutic goals of acetaminophen and antidote
- keep plasma acetaminophen levels
- below line
- 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
- –antihypertensive agent
- 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
- severe hypotension.
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