Pharmacology

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Pharmacology

ADVERSE REACTIONS

CHAPTER THREE

OBJECTIVES

• Define and explain the adverse reactions to drugs.

• Explain the different types of adverse reactions that can occur such as toxicity, allergic reactions, side effects and idiosyncratic responses.

• Describe common signs and symptoms of an adverse drug reaction.

• Summarize dental hygiene considerations that apply to drug action, handling and adverse reactions.

Adverse Reactions

• Drugs cause good (therapeutic effect) and bad effects (adverse effect) and this is because drugs act on many tissues at the same time.

• Adverse effects can happen at usual therapeutic doses.

CLASSIFICATIONS OF ADVERSE REACTION

1.TOXIC REACTION: The amount of the desired effect is excessive; dose related

Predictable Dose-related Acts on target organs Extension of the drug’s pharmacologic effects• E.G include: hypoglycemia with an oral hypoglycemic agent or insulin

* Drug allergies are not examples

of dose-related

response –WHY?

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2. SIDE EFFECT: Occurs when a drug acts on a non target organ, producing

an undesirable effect Is dose related reaction NOT part of the desired therapeutic outcome

Predictable Dose-related Acts on nontarget organs

E.G include: stomachache, headache, nausea, vomiting, local effects

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3. IDIOSYNCRATIC REACTION:• Genetically related abnormal response• This is a reaction that is neither a side effect nor an

allergic reaction.

• Some are genetically determined abnormal reactions.• Some are due to an immunologic mechanism.

• E.G: Eskimos metabolize certain drugs faster than other populations; therefore, a larger dose of those drugs would be needed in that population

4. DRUG ALLERGY:• Immunologic response to drug• Can be mild as a rash or severe as

anaphylaxis • Neither predictable or dose-related

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Specific reactions:1. Hives2. Urticaria (rash, itching)3. Inability to breath4. Anaphylaxis

5. INTERFERENCE WITH NATURAL DEFENSE MECHANISMS:

The drug reduces body’s ability to fight infection(eg. adrenocorticosteroids);

Drugs that interfere with the body’s defenses can cause more infections

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EG: Treatment for Allergic Reaction

• Mild Reaction – antihistamine

• Anaphylactic reaction – epinephrine subcutaneously

• True allergy vs. Side effect

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Remember

When using a drug - The beneficial effect must be weighed against its potential for adverse reactions

1. Exaggerated Effect on Target Tissues

An extension of the therapeutic effect caused by: overreaction of the sensitive patient

OR a dose that is too large for the patient.

In cases of systemic diseases such as kidney or liver disease, the disease may interfere with the metabolism or excretion of the drug therefore, the action of the drug may be enhanced or prolonged.

Clinical Manifestations of Adverse Reactions

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2. Effect on Non-target tissues

Caused by a non-therapeutic action of the drug.

Reactions can occur at usual doses but appear more often at higher doses

A reduction in the dose of the drug will usually reverse the adverse reaction.

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3. Effect on Fetal Development (Teratogenic Effect)

TERATOGENIC- comes from the Greek prefix terato-meaning “monster” and the suffix-genic; meaning “producing” a malformed fetus.

There is a relationship between drugs and congenital abnormalities. eg. thalidomide an OTC drug was found to cause short arms and legs

in the exposed fetus. Used as a sedative/hypnotic & also used to treat leprosy.

These drugs in dentistry are considered the ‘safest’ :penicillin and erythromycin, acetaminophen (Tylenol), and the local anesthetic lidocaine (Xylocaine).

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• Early in pregnancy (first trimester) the organs in the fetus are forming, which is considered the most critical time for teratogenicity.

• Drugs taken during the 2nd and 3rd trimester stages may affect the newborn, but the fetus is fully developed. – Fetal organogenesis has already occurred, therefore

critical stages in fetal development have passed.

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Effect on Fetal Development (Teratogenic Effect)

4. Local Effect

Local tissue irritation– Occasionally, injectable drugs can

produce irritation, pain, and tissue necrosis at the site of injection

– Topically applied agents can produce irritation at the site of application

– Drugs taken orally can produce gastrointestinal symptoms such as nausea

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5. Drug Interaction

• A drug interaction can occur when the effect of one drug is altered by another drug– Interactions may result in toxicity or lack of

efficacy– Interactions may also produce beneficial effects

• The likelihood that a drug interactions would occur increases with the number of drugs a patient is taking

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6.Hypersensitivity (Allergic Reaction)

Occurs when the immune system of an individual responds to the drug administered or applied

Neither dose dependent nor predictable Intensity increases with subsequent

exposures May be life-threatening

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• Drug allergy can be divided into 4 types of reactions, depending on the type of antibody produced or the cell mediating the reaction:

– Type I: Immediate– Type II: Cytotoxic/Cytolytic– Type III: Immune

complex/Arthus/Serum sickness– Type IV: Delayed Hypersensitivity

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Hypersensitivity (Allergic Reaction)

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TYPE I•Mediated by immunoglobulin E (IgE) antibodies

• When a drug antigen binds to IgE antibody, histamine, leukotrienes, and prostaglandins are released, producing vasodilation, edema, and inflammation

• Anaphylactic shock or immediate hypersensitivity reactions

HINT: STUDY ALL THE TYPES

OF ALLERGIC REACTION

S


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TYPE I

• The targets of this reaction are • Bronchioles, resulting in

anaphylactic shock• Respiratory system, resulting in

asthma• Skin, resulting in urticaria and

dermatitis


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TYPE I•Because these reactions can occur quickly after drug exposure, they are known as immediate hypersensitivity reactions

– Anaphylaxis is an acute, life-threatening allergic reaction characterized by hypotension, bronchospasm, laryngeal edema, and cardiac arrhythmias


TYPE II

•Complement-dependent reactions involving IgG or IgM antibodies

• The antigen-antibody complex is fixed to a circulating red blood cell, resulting in lysis

•hypersensitivity causes cytolytic reactions •EG: penicillin-induced hemolytic anemia.


TYPE III• Mediated by IgG• The drug antigen-antibody complex fixes complement

and deposits in the vascular endothelium• Manifested as serum sickness; • Includes urticarial skin eruptions, arthralgia (joint

pain), arthritis, fever…, with little or no lung involvement

• EG: Can be caused by penicillins



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TYPE IV

•Delayed hypersensitivity reaction•Generally manifested as skin eruptions•Mediated by sensitized T-lymphocytes and macrophages– Examples include allergic contact

dermatitis; poison ivy


7. Idiosyncrasy

Neither a side effect nor an allergic reaction May be genetically determined

Example: Primaquine-induced hemolytic anemia: Approximately 10% of male African Americans develop a severe hemolytic anemia when given the antimalarial drug primaquine. This is an example of a genetically determined abnormal reaction (idiosyncrasy).

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8. Interference With Natural Defense Mechanisms

• A drug’s effect on the body’s defense mechanisms can result in an adverse reaction– Long-term systemic administration of

corticosteroids can result in decreased resistance to infection

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Toxicologic Evaluation of Drugs

• LD50 – LETHAL DOSE:

– dose of a drug that kills 50% of experimental animals

• ED50 – MEDIAN EFFECTIVE DOSE:

– dose required to produce a specified intensity of effect in 50% of the animals


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Therapeutic Index (TI)- LD50/ ED50 >10 needed to produce a therapeutically useful drug

The therapeutic index is the ratio of the LD50 to ED50. The smaller the ratio is, the closer the LD50 is to the ED50 and therefore the closer a deadly dose is to the therapeutic dose.

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Therapeutic Index

Therefore, the lesser the therapeutic index is, the greater the toxicity will be.

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Toxicological Evaluation of Drugs

CALCULATING THE THERAPEUTIC INDEX (TI)- LD50/ ED50

EXAMPLE: In an assessment of drug action for a certain therapeutic agent,

results indicate that the ED50 is 20 mg/kg, and the LD50 is 400 mg/kg.

What is the therapeutic index for this agent? One must divide the LD50 value by the ED50 value. The LD50

value (400) divided by the ED50 value (20) equals 20. THEREFORE, in this example the TI is greater than 10 and is a

therapeutically useful drug

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Pharmacology

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