[Study8] Adverse Drug Reactions - Part II

Immune-mediated Mechanisms of ADRs

Immunotoxicity

• The immune system is damaged or suppressed by a drug

• Intentional or unwanted

  • Drugs that kill cancer cells also kill bone marrow and lymphoid tissues

  • → Lead to secondary infections oncogenesis

Autoimmune reactions

• Attack patient’s own cells

Hypersensitivity/allergic reactions

• Immune system recognize something as foreign

• Requires prior exposure to drug/ allergen

  • The first exposure sensitizes the immune system; a later exposure can trigger the reaction

Hapten

Drugs <600 daltons are too small to directly trigger an immune response

Gell-Coombs Classification of Hypersensitivity

Type	Name	Main immune component	Key idea
I	Immediate/anaphylaxis	IgE	Fast, potentially life-threatening
II	Antibody-dependent cytotoxic	IgG/IgM	Antibodies attack target cells
III	Immune complex/serum sickness	IgG/IgM	Immune complexes deposit in tissues
IV	Delayed T-cell mediated	T cells	Delayed reaction

Type I — Immediate Hypersensitivity / Anaphylaxis

rapid allergic reaction

• IgE

• Occurs after re-exposure to allergen

• Binds to mast cells → degranulate

• release histamine, leukotreines, porstaglandins, cytokines

• Anaphylaxis cause skin, respiraotry, GI, CNS, cardiovascular problems

Type II — Antibody-dependent Cytotoxic Reaction

• IgG or IgM

• Binds to target cell (usually RBC)

• Antibody Recognize target

• Cell destruction occurs through cytotoxic T cells or complement

Type III — Immune Complex-mediated Reaction

• serum sickness

• IgG/ IgM

• Antigen-antibody complexes form

• complexes deposit in tissues

• Activates complement and inflammation

Type IV — Delayed T-cell-mediated Reaction

• T lymphocytes

• Delayed reaction 2-7 days after reexposure

• Haptens binds to body proteins

• T cells activated

• Inflammation/ cellular dmg occurs

Mechanisms of Idiosyncratic ADRs

Idiosyncratic = unpredictable reaction occurring in a small number of people

CYP450

Genetic differences in cytochrome P450 enzymes can change how quickly someone metabolizes a drug.

Idiosyncratic ADRs — Hyporeactive vs Hyperreactive

Hyporeactive

• The patient requires an unexpectedly high dose to produce the usual effect.

Hyperreactive

• The patient experiences the drug's effect at an unexpectedly low dose.

Example

Codeine is a pro-drug

• It is converted into morphine by CYP2D6

  • Poor metabolizer: doesn't convert enough codeine → little/no analgesic effect

  • Rapid metabolizer: converts codeine to morphine quickly → potentially severe toxicity, even at therapeutic doses

Mechanisms of Oncogenic ADRs

Oncogenesis = development of cancer

Cancer can occur when there is an imbalance between:

• Cell division

• Apoptosis

Primary oncogenic effects

Some drugs can:

• Damage DNA

• Interfere with DNA repair

• Promote proliferation of mutated cells

Proto-oncogene

• Normal gene that promotes cell division.

Oncogene

• A proto-oncogene that becomes permanently activated through mutation/amplification → promotes abnormal cell growth.

Tumor suppressor gene

Normally:

• Slows cell division

• Repairs DNA

• Initiates apoptosis

Mutation/inactivation → uncontrolled cell growth.

Secondary Oncogenic Effects

These are related to therapeutic immunosuppression

• Immunosuppression can allow latent oncogenic viruses to reactivate

Ex: Epstein-barr virus, HPV, Hep B, C etc

Mechanisms of Teratogenic ADRs

Teratogenesis = process causing structural or functional defects in a fetus.

Teratogen =

• Drug teratogenicity depends partly on whether the substance can cross the placenta. agent capable of causing these defects

Timing of Teratogen Exposure

Conception → Day 17

• Teratogen exposure can result in —Spontaneous abortion

Day 18 → Day 55

• This is organogenesis

• Teratogen exposure can cause —Developmental abnormalities

Day 55 → 3rd trimester

• This is primarily fetal growth

• Teratogen exposure can cause — Organ function

ADRs Affecting Skin (Mucosa)

Rash

• Skin eruption

Pruritus

• Itching

Urticaria

• Hives

• Acute <6 weeks

Angioedema

• Localized swelling of deep tissues

• 
  

Erythema Multiforme (EM)

An acute immune-mediated reaction affecting skin/mucosa

• Target/iris lesions

• Crusting of lips

Stevens-Johnson Syndrome (SJS) & Toxic Epidermal Necrolysis (TEN)

triggered by drugs/toxins

• Oral manifestations similar to EM

Oral Lichenoid Reactions

If an oral lichen-planus-like lesion is caused by an external drug → it's a lichenoid reaction, not true oral lichen planus.

Arthralgia

Joint pain

• Many drugs can cause it

Teratogenesis-related ADRs

• Enamel hypoplasia

• Tooth discoloration

• Diminished long-bone growth

Increased rates of

• Neural tube defects

• Cleft palate

• Other congenital abnormalities

Secondary ADRs Related to Therapeutic Immunosuppression

Immunosuppression can lead to secondary infections and malignancies

• Can cause oral ulcerative lesions

• Signs not as obvious with immunosuppressed patients

Fungal Infections

Candida

• White, raise, cottage cheese, can be scraped off leaving red/ hemorrhagic tissue underneath

Viral Infections

Herpes Simplex Virus (HSV)

• Painful ulcerations

• Lips/intraoral tissues

Herpes Zoster

• Reactivation of latent varicella-zoster virus

Epstein-Barr Virus (EBV)

• Oral hairy leukoplakia

• Laterla border of tongue'

• oncogenic virus (reactive = secondary malignancies)

Secondary Malignancies

Therapeutic immunosuppression can increase risk of:

• Squamous cell carcinoma

• Kaposi sarcoma

• Lymphomas

• Lymphoproliferative diseases

• Spindle-cell sarcoma

Withdrawal Syndrome

ADR caused by stopping or rapidly reducing a substance after prolonged use/high doses

• associated with alcohol, tobacco, cocaine, heroine etc

How to prevent ADRs

Benefits of drug should outweigh the risks

• Treat the actual dental problem rather than relying on medication

• Dont overprescribe

• Give patient instructions (how to take, when, how much) + followup