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Pharmacology
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2. CHAPTER THREE
ADVERSE REACTIONS

3. 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.

4. 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.

5. CLASSIFICATIONS OF ADVERSE REACTION
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?
P.28

6. E.G include: stomachache, headache, nausea, vomiting, local effects
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 6

7. 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 7

8. Immunologic response to drug
DRUG ALLERGY:
Immunologic response to drug
Can be mild as a rash or severe as anaphylaxis
Neither predictable or dose-related
Specific reactions:
Hives
Urticaria (rash, itching)
Inability to breath
Anaphylaxis 8

9. 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 9

10. P29 – Fig. 3-1 10

11. EG: Treatment for Allergic Reaction
Mild Reaction – antihistamine
Anaphylactic reaction – epinephrine subcutaneously
True allergy vs. Side effect 11

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

13. Clinical Manifestations of Adverse Reactions
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. 13

14. Clinical Manifestations of Adverse Reactions
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. 14

15. Clinical Manifestations of Adverse Reactions
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). 15

16. Clinical Manifestations of Adverse Reactions
Effect on Fetal Development (Teratogenic Effect)
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. 16

17. Clinical Manifestations of Adverse Reactions
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 17

18. Clinical Manifestations of Adverse Reactions
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
on occasion these interactions may be sought in order to obtain an improved therapeutic effect. Examples of this include the use of codeine with paracetamol (acetaminophen) to increase its analgesic effect. OR have adverse reactions such as when taking Flagyl (antibiotic) do not drink alcohol – severe adverse reaction such as vomiting may occur at an increased rate 18

19. Clinical Manifestations of Adverse Reactions
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 19

20. Hypersensitivity (Allergic Reaction)
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 20

21. Mediated by immunoglobulin E (IgE) antibodies
HINT: STUDY ALL THE TYPES OF ALLERGIC REACTIONS
Hypersensitivity (Allergic Reaction)
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
P 31. study all the types (I-IV) for testing purposes 21

22. Hypersensitivity (Allergic Reaction)
TYPE I
The targets of this reaction are
Bronchioles, resulting in anaphylactic shock
Respiratory system, resulting in asthma
Skin, resulting in urticaria and dermatitis
P 31. study all the types (I-IV) for testing purposes 22

23. Hypersensitivity (Allergic Reaction)
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
P 31. study all the types (I-IV) for testing purposes 23

24. Hypersensitivity (Allergic Reaction)
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.
Lysis refers to the breaking down of a cell, often by viral, enzymic, or osmotic mechanisms that compromise its integrity.
Cytolytic: The dissolution or destruction of a cell.
Hemolytic anemia: is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels (intravascular hemolysis) or elsewhere in the human body (extravascular). It has numerous possible causes, ranging from relatively harmless to life-threatening. The general classification of hemolytic anemia is either inherited or acquired.

25. Manifested as serum sickness;
Clinical Manifestations of Adverse Reactions
Hypersensitivity (Allergic Reaction)
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
Vascular endothelial cells line the entire circulatory system, from the heart to the smallest capillaries.
Serum sickness is a reaction that is similar to an allergy. The immune system reacts to medications that contain injected proteins used to treat immune conditions
Arthralgia literally means joint pain - it is a symptom of injury, infection, illnesses (in particular arthritis) or an allergic reaction to medication.

26. Hypersensitivity (Allergic Reaction)
TYPE IV
Delayed hypersensitivity reaction
Generally manifested as skin eruptions
Mediated by sensitized T-lymphocytes and macrophages
Examples include allergic contact dermatitis; poison ivy
Macrophage: A type of white blood cell that ingests foreign material. Macrophages are key players in the immune response to foreign invaders of the body, such as infectious microorganisms.
T lymphocytes : belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity 26

27. Clinical Manifestations of Adverse Reactions
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). 27

28. Clinical Manifestations of Adverse Reactions
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 28

29. Toxicologic Evaluation of Drugs
LD50 – LETHAL DOSE:
dose of a drug that kills 50% of experimental animals

30. Toxicologic Evaluation of Drugs
ED50 – MEDIAN EFFECTIVE DOSE:
dose required to produce a specified intensity of effect in 50% of the animals
p31 30

31. Toxicologic Evaluation of Drugs
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. 31

32. Toxicological Evaluation of Drugs
Therapeutic Index
Therefore,
the lesser the therapeutic index is, the greater the toxicity will be. 32

33. Toxicologic 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 33