Exam 2: Toxicology DSA

Question 1

Learning Objectives 1

Describe the general features of adverse drug effects (time of appearance, predisposing factors, etc.) and understand their classification.

Answer 1

• Most unwanted effects arise during the first 10 days of treatment
• Predisposing factors: Age (< 1 year or >60 yo), Female sex, Positive past or recent history, Serious kidney or liver diseases
• Mechanisms: Pharmacological ( 70-80% of cases), Cytotoxic (5-15%), Immunological (5-15%)
• ADE are classified according to:
  
  • the frequency of their appearance
  • their severity
    
    • Mild = no new tx needed
    • Moderate = Δ of tx
    • Severe = discontinued use of tx and specific tx of ADR)
  • their underlying mechanisms (related to the drugs main MOA or secondary to a drugs metabolites)

Question 2

Learning Objectives 2

Define the term side effect and explain the mechanisms responsible for the side effects of a drug.

Answer 2

• Definition:
  
  • Unwanted, non-deleterious effects appearing after administration of standard therapeutic doses and related to the pharmacological properties of the drug.
• Factors to remember are:
  
  • In a single patient side effects are dose-dependent, they increase by increasing the dose.
  • The seriousness of side effects of drugs is usually low (otherwise the drug would be withdrawn from the marked) and the effects often decrease or even disappear in time because of tolerance.
• Mechanism of Side Effects:
  
  • Drugs are intended to modulate the function of a specific receptor (the intended receptor) in a particular tissue (the intended tissue).
    
    • On-target adverse effects in the intended tissue could be
• *caused by** a supra-therapeutic dose of the drug or by chronic activation or inhibition of the intended receptor by drug or its metabolite.
  * The same on-target effects could occur in a second tissue (the unintended tissue); in addition, the intended receptor could mediate an adverse effect because the drug is acting in a tissue for which it was not designed.
  * Off-target effects occur when the drug and/or its metabolites modulate the function of a target (the unintended receptor) for which it was not intended.

Question 3

Learning Objectives 3

Describe the main features of drug side effects.

Answer 3

• Incidence:
  
  • In a variable percentage of patients
  • With most drugs
• Seriousness:
  
  • Generally low
• Effects:
  
  • Depend on eliciting drug
• Dose-response relationship:
  
  • Dose-dependent
• Mechanisms:
  
  • Drug receptor interaction
  • Unknown (in several cases)
• Therapeutic measures:
  
  • Change the dose or the administration schedule
  • Switch to another drug

Question 4

Learning Objectives 4

Differentiate between side effects and overdose toxicity of a drug.

Answer 4

• Side effects:
  
  • Unwanted, non-deleterious effects appearing after administration of standard therapeutic doses and related to the pharmacological properties of the drug.
• Overdose Toxicity:
  
  • Overdose toxicity is an adverse effect appearing after the administration of doses higher than therapeutic doses.
  • Overdose toxicity of drugs depends mainly on the administered dose.
  • Most deaths due to drugs in hospitalized patients are caused by overdose toxicity.

Question 5

Learning Objectives 5

Describe what is the therapeutic index and therapeutic window..

Answer 5

• Therapeutic Index:
  
  • The ratio between an harmful dose and an effective
    dose of a drug.
    
    • Examples: LD50/ ED50 ; TD50/ ED50; TD1/ED99
    • Gives information only about overdose toxicity but often it is not useful to foresee other adverse drug effects (e.g., penicillins have very high therapeutic indexes but can also provoke allergic reactions which can be serious).
• Therapeutic Window:
  
  • The range between the minimum therapeutic dose and the minimum toxic dose of a drug
    
    • The range of doses (plasma concentrations) which have a high probability of therapeutic success with a low probability of dose-related unwanted effects

Question 6

Learning Objectives 6

Define the terms LD₅₀, TD₅₀ and ED₅₀.

Answer 6

___D₅₀ = Median ___ Dose (dose that causes the same effect in 50% of subjects)

• LD₅₀ = Median Lethal Dose
• TD₅₀ = Median Toxic Dose
• ED₅₀ = Median Effective dose

Question 7

Learning Objectives 7

Explain the mechanisms that can underlie the overdose toxicity of a drug.

Answer 7

• Interaction with drug receptors.
  
  • The most frequent mechanism
  • Examples of toxic effects related to drug receptor interaction are:
    
    • The hemorrhage due to anticoagulants
    • Cardiac failure due to beta-blockers
    • Coma due to hypnotic drugs
    • Paralytic ileus due to anticholinergic drugs, etc.
• The toxic effect is cytotoxic
  
  • an unspecific cell damage produced by the drug or by highly reactive intermediates made during the biotransformation of the parent compound.
• Intermediates can form covalent or non-covalent bonds with biological macromolecules leading to cytotoxic effects (e.g. breakage of cell membrane, block of enzymatic reactions, etc.) that can cause cell death.
  
  • Examples of drug-induced cytotoxicity are:
    
    • the nephrotoxicity and ototoxicity due to aminoglycosides antibiotics
    • the hepatotoxicity due to isoniazid
    • the cardiotoxicity due to tricyclic antidepressants, etc.

Question 8

Learning Objectives 8

Describe the appropriate behavior of the physician in dealing with the overdose toxicity of a drug and identify specific pharmacological antagonists.

Answer 8

It depends of the seriousness of symptoms.

• If symptoms are not severe
  
  • a reduction of dosage is what is needed.
• In serious cases
  
  • Drug must be withdrawn immediately and the therapy will aim at
    
    • the prevention of further absorption
    • enhancement of elimination of the drug
    • counteracting the main symptoms of toxicity.
• When the overdose toxicity is related to the specific effects of the drug
  
  • the use of pharmacological antagonists (if available) represents the most effective therapy.
  • See table attached below for examples of specific antidotes (do not memorize doses!!). I also made a seperate deck to study with the antidotes from his word document!

Question 9

Learning Objectives 9

Describe the main features of overdose toxicity of a drug.

Answer 9

• Incidence
  
  • In all subjects (if the dose is high enough)
  • With most drugs
• Seriousness
  
  • Can be very high
• Effects
  
  • Depend on eliciting drug
• Dose-response relationship
  
  • Dose-dependent
• Mechanisms
  
  • Drug receptor interaction
  • Cellular damage
• Therapeutic measures
  
  • Reduce the dosage
  • Use antagonists (if available)

Question 10

Learning Objectives 10

Define the term drug idiosyncrasy.

Answer 10

• Definition:
  
  • A genetically determined, abnormal reactivity to a drug.
    
    • An unusual response can be named idiosyncratic only if its genetic origin is known (or highly probable).
    • If an immunological mechanism underlies a given drug effect, then this is not an idiosyncratic response, it is instead defined an allergic response

Question 11

Learning Objectives 11

Define the term pharmacogenetics.

Answer 11

• The branch of pharmacology which studies the genetic basis for variation in drug response
• Individual variability is an important factor influencing the magnitude of a pharmacological effect of a drug.

Question 12

Learning Objectives 12

Identify a scenario where one can find a U-Shaped dose response curve.

Answer 12

• U-Shaped dose-response curve can occur for:
  
  • Essential metals and vitamins.
    
    • Vitamins and essential metals are essential for life and their lack
    • Adverse responses (plotted on the vertical axis)

This distribution is often Gaussian in shape.
Sometimes in some subjects, the biological response to a given drug is completely unusual,
either because it is qualitatively different from the effects usually observed or because it is
quantitatively outside (above or below) of the range that includes most responses and the
distribution is more like a U letter shape

Question 13

Learning Objectives 13

Explain the mechanisms that can underlie drug idiosyncrasy.

Answer 13

• The mechanisms of idiosyncratic drug reactions are many and often linked to genetic polymorphism of drug metabolizing enzymes.
  
  • Drug metabolism is highly inheritable and genetic factors account for most of the variation in metabolic rates of many drugs.
  • If the genetically induced polymorphism of drug metabolizing enzymes leads to a nonfunctional enzyme, a drug-induced disorder is more likely to occur.
• Drug receptor interaction (usually)

Question 14

Learning Objectives 14

List the most common instances of drug idiosyncrasy.

Answer 14

Question 15

Learning Objectives 15

Describe the appropriate behavior of the physician in dealing with drug idiosyncrasy.

Answer 15

• It depends on the illness that has occurred.
  
  • When an excess of drug is involved
    
    • The drug must be immediately withdrawn
    • When possible an antagonist should be given
  • When a decreased sensitivity to the drug has caused the syndrome a different therapeutic approach is mandatory.
    
    • For example in the vitamin D-dependent rickets type I,
      which is due to the inherited inability of the kidney to transform vitamin D into its active metabolite (25-dihydroxy-vit D3), the administration of this active form represents the treatment of choice.
• Because idiosyncrasy is linked to the genetic trait of a subject
  
  • Prophylaxis is of primary importance
  • a detailed personal and family history, before administering a drug known for its idiosyncratic potential, represents the best way to minimize the risk of an idiosyncratic reaction.

Question 16

Learning Objectives 16

Describe the main features of a drug idiosyncrasy.

Answer 16

• Definition
  
  • A genetically determined, abnormal reactivity to a drug.
• Incidence
  
  • Generally low
  • Only in genetically abnormal subjects
  • Only with certain drugs
• Seriousness
  
  • Can be high
• Effects
  
  • Depends on eliciting drug
• Dose-response relationship
  
  • Dose-dependent (usually)
• Mechanisms
  
  • Drug Receptor interaction (usually)
• Therapeutic measures
  
  • Stop the drug
  • Use antagonists (if available)

Question 17

Learning Objectives 17

Define the term drug allergy.

Answer 17

• Definition:
  
  • An unwanted drug effect resulting from previous sensitization to the same drug or a closely related one

Question 18

Learning Objectives 18

List the most common types of allergic reaction to drugs.

Answer 18

Question 19

Learning Objectives 19

Explain the mechanisms underlying drug allergy.

Answer 19

• In order to induce an allergic response the drug must have immunogenic properties, and it must behave as an antigen.
  
  • This property is mainly linked to the molecular weight (MW) of
    the drug since it has been shown that only molecules with a MW greater than about 6000 can be immunogenic.
• Therefore a drug may cause an allergic reaction only if:
  
  • 1) It has a MW higher than 6000 or
  • 2) It can function as hapten, which is capable of binding firmly (usually with covalent bonds) to a protein to form a product that has immunogenic properties.
    
    • Because most drugs have a MW lower than 1000 this second case occurs most frequently.

Question 20

Learning Objectives 20

Describe the appropriate behavior of the physician in dealing with drug allergy.

Answer 20

• It is related to the seriousness of the disease.
  
  • Mild symptoms
    
    • usually disappear when the drug is withdrawn.
  • In more serious cases
    
    • the administration of corticosteroids and antihistamines is advisable.
  • A lethal allergic drug reaction
    
    • can show up very rapidly (sometimes in two or three minutes) and it must be treated immediately.
    • Epinephrine administered subcutaneously (or even intravenously) is the best drug.

Question 21

Learning Objectives 21

Describe the main features of drug allergy.

Answer 21

• Definition:
  
  • An unwanted drug effect resulting from previous sensitization to the same drug or a closely related one
• Incidence
  
  • Generally low (~ 10% of all adverse drug reactions).
  • With many drugs.
  • The relative frequency of drug allergy is related to:
    
    • a) the structure of the drug
    • b) the route and number of administration
    • c) the associated illness
    • d) the individual predisposition
• Seriousness
  
  • Can be very high
• Effects
  
  • Independent of eliciting drug
• Dose-response relationship
  
  • Absent, in most cases
• Mechanisms
  
  • Immunological
• Therapeutic measures
  
  • Stop the drug
  • use anti-allergic drugs

Question 22

Learning Objectives 22

Define the term teratogen and teratogenesis.

Answer 22

• Teratogenic effects
  
  • Provoked by the drug in the fetus only.
• A teratogen
  
  • defined as any agent that (when administered during pregnancy) is able to cause an abnormal development of the fetus or the appearance of malformations
  • To be considered a teratogen the candidate drug must:
    
    • a) cause a characteristic set of malformations
    • b) exert its effect at a particular stage of fetal-development
    • c) show a dose-dependent incidence
• vs. Toxic effects
  
  • which are the same effects that a drug also causes also in adults
    
    • if given in too high of doses

Question 23

Learning Objectives 23

Describe the major features of prenatal toxicity of drugs.

Answer 23

Question 24

Learning Objectives 24

Explain the most likely mechanisms underlying drug teratogenesis.

Answer 24

• They are complex and probably multifactorial, but they can be schematically subdivided into two categories:
  
  1. The drug (or more often a highly reactive intermediate such as an epoxide) forms covalent bindings with functionally relevant macromolecules (DNA, RNA, enzymes, etc.), provoking alterations in cellular growth and differentiation.
     
     • This is the most frequent teratogenic mechanism.
     • Fetal DNA is most often the target molecule.
     • More than 90% of chemicals with carcinogenic actions are also teratogens.
  2. The drug binds to its cellular receptors but the biological response is abnormal
     
     • for instance the cleft palate due to high doses of corticosteroids is dependent upon reversible binding of the hormone to its receptor.

Question 25

Learning Objectives 25

List the FDA categories for prenatal risk of drugs.

Answer 25

Question 26

Learning Objectives 26

List the principal drugs proven or highly suspected to be teratogen in humans.

Answer 26

Question 27

Learning Objectives 27

Describe the main features of drug carcinogenesis.

Answer 27

• The effects of carcinogens are in general dose-dependent, additive and irreversible.
• There is always a long latent period between exposure to the agent that cause tumors and the detection of cancer
  
  • (an extreme example of carcinogenesis “in utero” is the development of vaginal cancer in women aged 15-20 whose mothers had used diethylstilbestrol during pregnancy).
• Most cancer causing chemicals probably are not carcinogenic in the form in which they enter the body, but are metabolically activated into reactive intermediates that are toxic and carcinogenic (epoxides, nitrosamines, etc.).
• many carcinogenic substances are also mutagenic
  
  • i.e. able to produce heritable alteration in cellular DNA

Question 28

Learning Objectives 28

List the principal drugs proven or highly suspected to be carcinogenic in humans.

Answer 28