Drug Toxicity: PHA3320

• Course is Principles of Drug Action (PHA3320)
• Study notes are for Introduction to Drug Toxicity
• Winter 2025, Q3

Suggested Reading

• Golan: Chapter 06
• Katzung: Chapter 56
• Goodman and Gillman's The Pharmacological Basis of Therapeutics, Chapter 03, pages 73–81
• Rang & Dale's Pharmacology, Chapter 57, pages 692-702

Learning Objectives

• Define drug toxicity and describe the various types of toxicities
• Explain "On-" vs. "Off-Target" effects and relative to specific tissues
• Explain how drugs can induce immune responses
• Outline how immune responses contributes to immuno-toxicities
• Compare and contrast mechanisms of specific organ and tissue toxicities in the context of adverse drug effects
• Define haptens, carcinogens, and teratogens
• Describe how haptens, carcinogens, and teratogens each contribute to toxicity
• Describe the mechanism of acetaminophen induced hepatotoxicity

Introduction to Drug Toxicity

• Paracelsus, 1493-1541: "What is there that is not poison? All things are poison and nothing (is) without poison. Solely the dose determines that a thing is not a poison"
• Paracelsus was the first to publish documents claiming dose determines if a substance is therapeutic or toxic.

Drug Toxic Effects

• Drug toxic effects are any unintended pharmacologic effect(s) due to drug exposure.
• Also known as "side effects", "adverse effects", "adverse events"
• Drug toxic effects exist on a spectrum of severity
• Factors that may influence drug toxicity include patient factors like age, genetics, comorbidity, and allergies
• Drug factors that influence drug toxicity include dose, mechanism of action, and pharmacokinetics (ADME)

Quantal Dose Response Curves

• Drug toxicity is estimated by quantal dose response curves that look at cumulative percent exhibiting
• Therapeutic effect is measured by ED50
• Toxic effect is measured by TD50
• Lethal effect is measured by LD50

Therapeutic Window

• The therapeutic window describes a drug's range of efficacious doses without producing an adverse (toxic) effect in a given population
• Therapeutic index (TI) is the measure of the therapeutic window: TI = TD50/ED50
• A narrow (small TI) suggests a high risk of toxicity at therapeutic concentrations and usually requires patient monitoring
• A wide (large TI) suggests a low risk of toxicity at therapeutic concentrations, mostly observed in overdose cases

Adverse Drug Effects

• Over the counter drugs (OTC) can contribute to "adverse drug effects"
• Prescription drugs can contribute to "adverse drug effects"
• Herbal supplements can contribute to "adverse drug effects"
• Natural products can contribute to "adverse drug effects"
• Food/Drink can contribute to "adverse drug effects"

"On-Target" and "Off-Target" Effects

• Toxic effects may result from drug interaction with intended or unintended tissue.
• Intended tissue: Intended receptor or Untended receptor
• Unintended Tissue: Intended receptor or Untended receptor
• Many drugs can produce both on-target and off-target effects.

On Target Adverse Effects

• "On-target” (mechanism based) adverse effects.
• Also known as "Class" effects.
• Exaggeration of the desired pharmacologic action as a result of changes in exposure or sensitivity to the drug
• Usually dose dependent and due to:
  • Concomitant use of drugs with similar MOA/PK
  • Dosing error
  • Alteration of PK
  • Receptor changes (upregulation)

On-Target Effect Example

• Diphenhydramine: (Benadryl)
  • H₁ antagonist – intended for blocking peripheral histamine action (anti-allergy)
  • Crosses the BBB and antagonizes H₁ receptors causes somnolence (drowsiness)
• Local anesthetics: e.g. lidocaine, bupivacaine:
  • Na+ channel blockers – intended for blocking Na+ channels near site of injection.
  • Blockade of Na+ channel in CNS may promote tremors, seizures, and death.
• Haloperidol: Dopamine receptor (D2) antagonist: antipsychotic – blockade of D2 receptors in pituitary leads to increase in prolactin secretion which can lead to galactorrhea, sexual dysfunction, amenorrhea, and osteoporosis

Off-Target Adverse Effects

• Involves interaction with the "wrong" receptor(s)
• Unintended activation or inhibition of different receptor subtypes
• Most drugs often bind to more than 1 target (non-specific binding)
• Can be evaluated using knock out animals lacking the intended target

Off-Target Effects Examples

• Terfenadine
  • First non-sedating 2nd generation H1 antagonist
  • There was increased death due to arrhythmias among people taking terfenadine
  • Terfenadine binds cardiac IK, K+ channels which causes QTc prolongation -QT prolongation causes a cardiac arrhythmia called Torsades de pointes (TdP) -All new drugs are now evaluated for activity at this channel and clinically for this effect
• Thalidomide (Kevadon)
  • R-enantiomer is an effective sedative while S -enantiomer is a potent teratogen
  • Racemic mixture used for treating morning sickness and caused >10000 birth defects (phocomelia) across the world -Enantiomers can have differing pharmacological properties and are treated like different drugs by the FDA e.g. omeprazole and esomeprazole (proton pump inhibitors)
• Non-selective beta blockers (propranolol)
  • Primarily used for the effects on the heart's ẞ1-receptors which produces a positive chronotropic effect (increases heart rate)
  • Can cause bronchoconstriction due to effect on lung smooth muscle (β2)
  • Contraindicated in asthmatics
• B2 drugs can influence ẞ1 receptors too: Elevated dose of inhaled ẞ2 agonist used for asthma may increase heart rate

Idiosyncratic Drug Reactions (IDRs)

• Unpredictable, relatively rare, and often life threatening
• Occurs in a very small fraction of patients for unknown reasons
• Usually undetectable during preclinical and clinical trials unless the incidence is high
• Can affect many organs but often targets the skin, liver, and/or bone marrow If serious such as permanent organ damage, death...
  • Often lead to withdrawal of drug (Why?) Because susceptible patient populations cannot be Identified
• Most but not all IDRs are immune mediated and caused by reactive chemical species

Reactive Intermediates & Toxicity

• Most drugs not directly chemically reactive
• Some form reactive electrophilic metabolites and free radicals
• Formation generally occurs in phase 1 metabolism
• These are generally deactivated in phase II
• Short lived with half life < 1min, usually undetectable in blood or urine
• Except as phase II conjugates Saturation, absence, or impairment of detoxifying systems causes toxicity
• Free radicals generally abstract a hydrogen atom from another molecule, leading to a chain reaction causes oxidative stress

Organ & Tissue Toxicity

• Harmful immune response & immunotoxicity
• Hepatotoxicity
• Renal toxicity
• Neurotoxicity
• Skeletal muscle toxicity
• Cardio toxicity
• Pulmonary toxicity
• Carcinogenesis
• Teratogenicity

Harmful Immune Response & Immunotoxicity

• Immune (hypersensitivity) reactions (type I-IV)
• Autoimmunity
  • Occurs when an organism's immune system attacks its own cells/tissues
  • Methyldopa can cause hemolytic anemia by triggering an immune response against the Rhesus proteins
  • Hydralazine and isoniazid can induce a lupus like symptom by inducing antibodies against myeloperoxidase
• Mimics features of immune response
  • Features the “red man syndrome" with Vancomycin, ciprofloxacin
  • Direct drug effect on mast cells can cause degranulation that results in the releases of immune mediators and cytokines such as histamine
• Skin rashes
• Occur with a number of drugs although exact mechanism not fully understood but involves immune components
• Stevens-Johnson Syndrome (SJS) is life threatening
• Toxic epidermal necrolysis (TEN) is life threatening
• Sulfa drugs (cotrimoxazole, sulfasalazine), Penicillins (ampiciliin and amoxicillin), Anti-epileptics (phenytoin, carbamazepine, phenobarbital) can all induce a harmful immune response
• Immunotoxicity
  • Compromised immune function leading to secondary effects include Increased risk of infections -Cancer chemotherapy, immunosuppressant drugs, monoclonal antibodies(mabs)

Types of Hypersensitivity Reactions

• Immune system detects foreign substance(s)
• Drugs can act as immunogens and require prior exposure -Repeat exposure can cause fever, hypotension, and organ damage
• Peptidic or protein drugs are large molecules that can act as direct immunogens
• Most drugs with M.W < 600 are not direct immunogens
• But can act as haptens that bind and modify proteins often covalently
• Modified protein can then trigger the immune system

Hypersensitivity Reactions

• Type I – Immediate type (anaphylaxis)
  • Characterized by IgE production after exposure to the antigen (protein drug or hapten modified protein) -Subsequent exposure to the antigen causes mast cell degranulation
• Mast cells release histamine and other inflammatory mediators causing Wheal and flare reaction (skin), rhinitis, conjunctivitis and bronchoconstriction, e.g. streptokinase, penicillins
• Type II – Antibody-mediated hypersensitivity
  • Characterized as “antibody-dependent cellular cytotoxicity” (ADCC)
  • Drug binds to cells (usually RBCs) which is recognized by antibodies (IgG) causing cell lysis (hemolysis)via several mechanisms, e.g. penicillin and quinidine
• Type III – Immune complex mediated hypersensitivity
  • Characterized by Immune complex mediated hypersensitivity
  • Involves and can result in the formation of antibodies (usually IgG and IgM) against soluble antigens
  • Antigen antibody complexes are subsequently deposited in tissues which result in serum sickness and/or inflammatory reactions -e.g. buproprion and cefaclor
• Type IV – Delayed type hypersensitivity that results from the activation of TH1 and cytotoxic T cells usually presents as contact dermatitis
  • A hapten binds to a protein and the hapten-bound protein is phagocytosed by antigen presenting cells (APC). The APCs presents the antigen to T-cells, thereby activating a population of T-cells
  • T-cell activation leads to release of inflammatory factors -e.g. poison ivy, latex, and sulfamethoxazole

Summary of Hypersensitivity Reactions

Hepatotoxicity

• Is the most frequent reason for drug withdrawal (from the market)
• When 1/10,000 to 1/100,000 patients are affected, a drug can be withdrawn
• Most cases of acute hepatitis after drug therapy are idiosyncratic

• 600 known drugs and chemicals and >30 withdrawn drugs cause Hepatotoxicity

• Hepatotoxicity can be determined through liver function tests, LFTs such as Transaminase testing including aspartate aminotransferase, alanine aminotransferase, bilirubin, and PT/INR

Drug Induced Hepatotoxicity

• Liver is the major site of drug metabolism
• Some metabolites are highly reactive and can cause damage
• Acetaminophen causes 50% of acute liver failure
• It undergoes primarily phase II at therapeutic doses
• At toxic doses, it causes increased CYP oxidation causing reactive metabolite NAPQI formation
  • NAPQI then attacks cellular and mitochondrial proteins causing Destruction of hepatocytes
• Glutathione can attenuate some effects
• Treatment is intravenous N-acetyl cysteine antidote

Drug Induced Hepatoicity, Acetaminophen (APAP)

• APAP -Alternatives for benzoquinone imine (NAPQI) -Deactivation by GSH, or toxicity by reacting w/ protein

Risk Factors in Hepatotoxicity

Drug-Induced Renal Toxicity

• Kidneys are a major route of excretion for most drugs and metabolites
• Some antibiotics, NSAIDs, anti-neoplastics, ACE inhibitors, etc. can cause renal toxicity
• Amphotericin B is a polyene antifungal and can cause renal toxicity
  • It binds to ergosterol in the fungal cell membrane and creates pores which causes cell death -It also binds to sterols in the membrane of renal tubular cells
  • It has a low therapeutic index due to similar mechanism of antifungal and toxic effects
  • Renal toxicity, from Amphotericin B, is very common but usually reversible if damage is not severe

Drug-Induced Neural Toxicity

• Often associated with cancer chemotherapy in vinca alkaloids, paclitaxel, cisplatin, (others).
• Generally causes peripheral nerves (peripheral neuropathy) but can also affect CNS
• Platinum compounds have direct toxic effects on neurons
• Vinca alkaloids and Taxanes cause Microtubule disruption which results in:
  • Altered axonal transport
  • Neuronal cell death -Sensory and motor neuropathy

Drug-Induced Skeletal Muscle Toxicity (myopathy)

• Associated with statins, corticosteroids (dexamethasone, prednisolone, hydrocortisone), zidovudine
• Statins cause myopathy due to inhibition of geranyl-geranylation of muscle proteins
• Post translational modification that helps to anchor protein to the membrane
• It results in Mild muscle pain and weakness
• Also can cause Rhabdomyolysis (rare) in severe cases: -Characterized as Severe muscle aches/weakness, dark colored urine -Occurs in 1.5/100000 cases, risk increases with use of fibrates

Drug-Induced Cardiovascular Toxicity

• Three major mechanisms of cardiotoxicity: -Many drugs interact w/ K+ channels in heart & prolong QTc interval causing arrhythmia, MI, and stroke -Direct toxicity to myocytes anthracyclines like doxorubicin: -Causes heart failure and arrhythmias with Cardiac toxicity being dose limiting, -The lifetime exposure limit (example: 550mg/m²) -Toxicity to heart valves e.g. fenfluramine causes Proliferation of valvular myofibroblast due to activation of 5-HT2B receptors
  • May result in Promotes AV Valvular insufficiency and death
  • Drugs that prolong QTc interval or affect 5-HT2B receptors are usually avoided by pharma

Drug-Induced Pulmonary Toxicity

• Range in pulmonary toxicity includes
• Mild asthma exacerbation from beta blockers
• Chronic airway fibrosis and remodeling from (bleomycin, amiodarone)
• Lungs have large regenerative capacity, but repeated cycles of damage to epithelium leads to deposition of collagen in alveoli, resulting in fibrosis and loss of function
• Amiodarone & bleomycin should be avoided in patients with preexisting lung disease

Carcinogenesis Due to Drug Therapy

• Drugs that can cause cancer are called carcinogens -Initiators damage DNA and interfere with DNA replication or repair mechanisms -Most initiators are reactive species that covalently modify the structure of DNA and lead to mutation -Promoters facilitate proliferation of cells carrying precancerous mutations
• Drugs w/ potential for DNA damage are usually avoided, but DNA damage is on-target adverse effect for some anticancer agents -The alkylating agents (nitrosoureas, cyclophosphamide, etc.) -10-20% of acute myeloid leukemia is due to these drugs

Teratogenesis Due to Drug Therapy

• Teratogen: a drug that can induce developmental defects in the fetus
• Some drugs taken during pregnancy can be teratogenic to the fetus
• Fetal exposure is determined by mother ADME and ability to cross placenta -Lipophilic drugs are generally more likely to cross the placenta barrier
• Drug may be safe for mother but harmful to fetus
• Phase of fetal development at time of exposure determines teratogenic effect -Organogenesis occurs between 3 - 8 weeks (most vulnerable and profound effects) -Exposure before 3 weeks – death and spontaneous abortion -Exposure after 8 weeks – growth and maturation of organ

Teratogenesis Due to Isotretinoin

Treats acne, activates nuclear retinoid receptor (RAR) and retinoid X-receptor (RXR)

• These receptors regulate key transcriptional events during development
• Alteration to transcription causes abnormal fetal development
• Women are required to sign FDA mandated informed consent through IPLEDGE