Pharmocology Review

Principles of Drug Action

Objectives and Aims

  • Understand the following key components of pharmacology:

    • Definition of Pharmacology

    • What constitutes a drug and a medicine

    • Protein targets for drug binding

    • Mechanisms of drug action

      • Agonists (full, partial, inverse, biased)

      • Antagonists (competitive, irreversible)

Lecture Outline

  1. What is Pharmacology?

  2. Definition of a Drug

  3. Definition of a Medicine

  4. Protein Targets for Drug Binding

  5. Mechanisms of How Drugs Act

    • Agonists

    • Antagonists

Definitions

Pharmacology

  • Study of drug effects on living systems (Rang and Dale, 2012).

  • Key organization: Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists.

Drug

  • Chemical substance of known structure (not a nutrient) that produces a biological effect upon administration.

  • Types of drugs:

    • Synthetic chemicals (e.g., β-blockers)

    • Natural compounds (e.g., morphine)

    • Genetically engineered products (e.g., insulin).

Medicine

  • A drug administered for therapeutic purposes.

  • Examples of drug classes and indications:

    • β-blockers -> coronary artery disease, hypertension

    • ACE inhibitors -> hypertension, heart failure

    • Statins -> hypercholesterolemia

    • NSAIDs -> pain relief, inflammation.

Mechanisms of Drug Action

Protein Targets for Drug Binding

  • Main types of regulatory proteins:

    • Receptors (e.g., β-adrenoceptors)

    • Enzymes (e.g., ACE)

    • Carrier molecules (transporters)

    • Ion channels (e.g., L-type Ca²+ channels).

  • Drug effects result from binding and dissociation from these targets.

Agonists and Antagonists

  • Agonists: activate receptors (e.g., full agonists like isoprenaline).

  • Antagonists: block receptors (e.g., competitive antagonists like propranolol).

Affinity and Efficacy

  • Affinity: Measure of how well a drug binds to a receptor.

  • Efficacy: Ability of a drug to produce a response upon binding.

    • Full agonist efficacy = 1

    • Partial agonist efficacy > 0, < 1

    • Antagonist efficacy = 0.

Competitive Antagonism

  • Competitive antagonists can be overcome by increasing agonist concentrations.

  • Example: Propranolol shifts the isoprenaline effect to the right on concentration-effect curves.

Irreversible Antagonism

  • Can form a covalent bond with receptors, permanently reducing available receptors.

GPCR Overview

  • GPCRs: Largest class of membrane proteins in the human genome.

  • Often called "7TM" receptors, indicating seven transmembrane domains.

  • Not all 7TM receptors signal through G-proteins.

GPCR Structure

  • Common architecture includes:

    • Single polypeptide with an extracellular N-terminus

    • Intracellular C-terminus

    • Seven hydrophobic transmembrane domains (TM1-TM7)

    • Three extracellular loops (ECL1-ECL3)

    • Three intracellular loops (ICL1-ICL3)

Classification of GPCRs

  • Class A (Rhodopsin-like):

    • Receptors for small molecules, neurotransmitters, peptides, hormones, including olfactory and visual pigments.

  • Class B (Secretin receptor family):

    • Responds to polypeptide hormones (e.g., glucagon, secretin).

  • Class C (Metabotropic glutamate):

    • Includes glutamate receptors and calcium-sensing receptors.

  • Adhesion and Frizzled families: Unique classes with distinct signaling properties.

G-Proteins

  • G-Proteins are membrane-resident proteins that recognize activated GPCRs.

  • They consist of three subunits: α (alpha), β (beta), and γ (gamma).

  • Active through their association with guanine nucleotides (GTP, GDP).

  • In an inactive state, they exist as an αβγ trimer.

Receptor-G-Protein Interaction

  • GPCR activated by ligand (e.g., noradrenaline) undergoes a conformational change.

  • GDP dissociates from the α subunit, GTP binds, leading to G-protein dissociation into active α and βγ subunits.

  • These active subunits diffuse in the membrane to interact with target enzymes or ion channels.

Signaling Pathway

  • Human Heart Example: β1,2 AR Activation:

    • Noradrenaline binds to β1- and β2-adrenoceptors.

    • Gs protein activation leads to adenylate cyclase (Ac) production of cAMP, resulting in increased heart rate (tachycardia) and positive inotropic effects.

Termination of Signaling

  • Signaling ends with GTP hydrolysis to GDP by GTPase activity of the α-subunit.

  • Active α-GTP unit dissociates from the effector, and the mechanism amplifies signaling results.

    • A single agonist-receptor complex activates multiple G-proteins, enhancing the production of second messengers (e.g., cAMP).

Lecture Outline

  1. Nitric Oxide (NO)

  2. Angiotensin (AT) receptor system

  3. Endothelin (ET) receptor system

Control of Vascular Smooth Muscle Tone

  • Vascular smooth muscle tone controlled by mediators:

    • ↑ or ↓ tone by substances secreted from:

      • Sympathetic nerves (e.g., noradrenaline)

      • Vascular endothelium (e.g., nitric oxide, prostanoids, endothelin)

      • Circulating hormones (e.g., adrenaline, Angiotensin II)

Nitric Oxide (NO)

  • Considered the "Molecule of the Year" in 1992.

  • Acts as a biological messenger in mammals affecting:

    • Neuroscience

    • Physiology

    • Immunology

Discovery of NO

  • Loss of relaxing response in rabbit aorta preparations indicates the role of NO.

  • Nobel Prize in Physiology 1998 awarded for discoveries concerning NO as a signaling molecule.

Synthesis of NO

  • Synthesized from l-arginine by nitric oxide synthase (NOS).

  • Three isoforms of NOS:

    • Neuronal (nNOS)

    • Endothelial (eNOS)

    • Inducible (iNOS)

Effects of Nitric Oxide

  • Involved in relaxation of smooth muscle by activating cyclic GMP pathway.

  • Changes in intracellular calcium levels lead to relaxation.

Therapeutic Approaches

  • NO administered as a gas for:

    • Dilating blood vessels in ventilated alveoli

    • Treating pulmonary hypertension

  • NO donors like Glyceryl Trinitrate and Isosorbide Mononitrate are powerful vasodilators used for angina.

Renin-Angiotensin System

  • Regulates:

    • Arterial blood pressure

    • Renal function

  • Plays a critical role in conditions like hypertension and heart failure.

Pathway Overview

  • Circulating angiotensinogen cleaved by renin to produce angiotensin I.

  • Angiotensin I converted to active angiotensin II by ACE.

  • Angiotensin II binds to AT1 and AT2 receptors affecting vascular tone and blood pressure.

Receptor Effects

  • AT1 Receptors:

    • Found in multiple tissues (vascular smooth muscle, liver, heart).

  • AT2 Receptors:

    • Fetal tissue abundance, counter-regulates AT1 activities.

Therapeutic Targets

  • Angiotensin converting enzyme inhibitors (ACEIs) and AT1 receptor blockers as treatment for hypertension and heart failure.

Endothelin (ET)

  • Identified in 1988 as a potent vasoconstrictor.

  • Ends with three isoforms: ET-1, ET-2, ET-3, mediated by ETA and ETB receptors.

Receptor Functions

  • ETA is primarily for vasoconstriction.

  • ETB receptors release NO and PGI2, facilitating smooth muscle relaxation.

Pharmacological Management of Pulmonary Arterial Hypertension

  • Bosentan improves exercise endurance and survival in pulmonary arterial hypertension patients by blocking ET receptors.

Heart Failure

  • Definition and etiology.

  • Systole and diastole dynamics.

  • Neurohormonal response and remodeling.

  • Pharmacological management strategies.

  • Stages of heart failure:

    • β-blockers (antagonists)

    • ACE inhibitors/AT1 receptor antagonists

    • Neprilysin inhibitors

    • Aldosterone inhibitors

    • Digoxin

    • Ivabradine

    • Inotropes

Chronic Heart Failure

Definition

  • A complex clinical syndrome characterized by symptoms such as dyspnea and fatigue, indicating compromised ventricular function during physical activity.

Incidence and Prognosis

  • 1-3% incidence in developed countries, rising to 10% in patients aged 75 and older.

  • ~50% mortality rate within 5 years; significant risk of sudden death from arrhythmias.

Aetiology

  • Common causes:

    • Coronary artery disease

    • Hypertension

    • Diabetes

    • Cardiomyopathies

    • Valve disease

    • Lifestyle factors (alcohol misuse, etc.)

Heart Failure Dynamics

Systole and Diastole

  • Systole: the heart contracts and ejects blood.

  • Diastole: the heart relaxes, allowing filling with blood. Atrial contraction precedes ventricular contraction.

Ejection Fraction

  • Left Ventricular Ejection Fraction (LVEF): percentage of blood ejected with each contraction.

  • LVEF = (EDV-ESV)/EDV.

Types of Heart Failure

  • HFrEF (Heart Failure with Reduced Ejection Fraction): LVEF ≤ 40%.

  • HFpEF (Heart Failure with Preserved Ejection Fraction): LVEF > 40%.

Neurohormonal Response

  • Markers: Elevated BNP, ANP, NT-proBNP; increased noradrenaline and adrenaline.

  • Effects: Thyroid activation, hypertrophy, fluid retention, fibrosis.

Cardiac Remodeling

  • Structural alterations in response to hemodynamic load or injury.

    • Physiological: Adaptations to exercise or pregnancy.

    • Pathological: Response to overload or injury leading to maladaptive changes.

Management of Heart Failure

Guidelines and Stages

  • Stage A: Risk factor modification (hypertension, diabetes).

  • Stage B: Asymptomatic structural changes; treatment with β-blockers and ACE inhibitors.

  • Stage C: Symptoms present; management includes diuretics, ACE inhibitors, β-blockers, etc.

  • Stage D: Advanced therapies (mechanical support, transplantation).

Pharmacological Interventions

  • β-blockers: Improve survival rates, reverse remodeling, antiarrhythmic effects.

  • ACE inhibitors: E.g., Enalapril; shown to improve survival in systolic heart failure.

  • ARNI (Angiotensin receptor-neprilysin inhibitors): E.g., Valsartan/sacubitril; enhances cardiac function and reduces hospitalizations.

  • Aldosterone antagonists: E.g., Spironolactone; reduces morbidity and mortality.

Digoxin and Inotropes

  • Digoxin: Increases contractility; no mortality benefit but reduces hospitalizations.

  • Inotropic agents: Short-term agents for refractory heart failure; e.g., Milrinone, Dobutamine.

Decompensated Heart Failure

  • Acute worsening, characterized by increased dyspnea, fatigue, and fluid overload.

Conclusion

  • Heart failure remains a complex condition requiring multidisciplinary management and pharmacological intervention to improve patient outcomes.

Physiology of Respiration

Control of Breathing

  • Controlled by spontaneous rhythmic discharges from the medulla.

  • Regulated by CO2 and O2 levels with some voluntary control.

Regulation of Airway Musculature

  • Irritant receptors and C fibers respond to:

    • Cold air

    • Inflammatory mediators (cytokines, interleukins)

    • External chemicals (ammonia, cigarette smoke)

  • Efferent pathways include:

    • Parasympathetic nerves (acetylcholine release)

    • Sympathetic nerves (beta2-adrenoceptor activation)

    • Non-adrenergic non-cholinergic (NANC) inhibitory nerves (NO release).

Mechanisms of Action

  • Parasympathetic nerves: Constrict bronchial smooth muscle; increase secretions through M3 receptors.

  • Sympathetic nerves: Dilate tracheobronchial blood vessels; decrease secretions through beta2-adrenoceptors.

  • NANC nerves: Relax bronchial smooth muscle via NO and vasoactive intestinal peptide.

Clinical Presentation of Asthma

  • Over 2 million Australians affected.

  • Symptoms include:

    • Intermittent wheezing

    • Shortness of breath

    • Difficulty exhaling

    • Chest tightness

    • Coughing.

Characteristics of Asthma

  • Airway inflammation.

  • Bronchial hyper-reactivity.

  • Reversible airway obstruction.

Inflammation in Asthma

  • Associated with inflammatory cells (eosinophils, basophils, mast cells, lymphocytes).

  • Activated T-helper type 2 (Th2) cells release cytokines (IL-4, IL-5).

  • Chronic inflammation can lead to:

    • Epithelial shedding

    • Mucous hypersecretion

    • Airway remodeling (fibrosis, hyperplasia).

Therapeutics for Asthma

Medication Classes

  • Bronchodilators:

    • Short-acting (SABAs) like Salbutamol, Terbutaline (symptom relief).

    • Long-acting (LABAs) like Salmeterol, Eformoterol (maintenance).

  • Anti-inflammatory agents:

    • Corticosteroids (e.g., Beclomethasone, Budesonide).

    • Leukotriene receptor antagonists (Montelukast).

    • Cromoglycate and Nedocromil (mast cell stabilizers).

Mechanisms of Action

  • Corticosteroids suppress cytokine formation and upregulate beta2-adrenoceptors.

  • LABAs relax bronchial smooth muscle and inhibit inflammatory mediator release.

  • Leukotriene antagonists prevent bronchoconstriction and mucus secretion.

Advanced Therapies

  • Omalizumab: Binds to IgE to prevent allergic reactions.

  • Theophyllines: Inhibit phosphodiesterases for bronchodilation.

  • Adenosine: High levels in asthmatics causing bronchoconstriction, enhances mast cell activation.

Gastrointestinal Tract Overview

  • Functions:

    • Absorption and digestion of food

    • Endocrine secretion of hormones

    • Pharmacological significance of oral administration (tablets, capsules)

Control Mechanisms in Gastrointestinal Tract

Neuronal Control

  • Vagal pathways from the autonomic nervous system

    • Parasympathetic (M3 receptors) increases muscle tone and peristalsis

    • Sympathetic (B1 adrenoceptors) decreases muscle tone

  • Enteric nervous system operates through:

    • Myenteric plexus (Auerbach's plexus)

    • Submucous plexus (Meissner's plexus)

Hormonal Control

  • Endocrine and paracrine secretions from:

    • Gastrin: Stimulates acid secretion

    • Cholecystokinin (CCK): Aids digestion

    • Histamine: Increases acid secretion through H2 receptors

Gastric Acid Regulation

  • Stomach secretes ~2.5L of gastric juice daily for:

    • Proteolytic digestion

    • Iron absorption

    • Pathogen killing

  • Major components:

    • Hydrochloric acid and pepsin

    • Proton pump (H+/K+-ATPase) as therapeutic target

Common Gastrointestinal Disorders

Dyspepsia and Heartburn

  • Triggered by foods or eating habits

  • Treated with:

    • Antacids

    • Proton pump inhibitors

Peptic Ulcers

  • Caused by:

    • Imbalance in mucosal defense and aggressive factors (e.g. Helicobacter pylori)

  • Treatment: Antibiotics and proton pump inhibitors

Gastroesophageal Reflux Disease (GORD)

  • Causes: Weakened lower esophageal sphincter

  • Symptoms: Heartburn, regurgitation

  • Treatment: Antacids, proton pump inhibitors

Anti-emetic Medications

Mechanisms of Vomiting

  • Triggered by:

    • Toxins, irritants, medications

  • Reflex arc includes:

    • Chemoreceptive trigger zone (CTZ) in medulla

    • Vagal afferent inputs

Types of Anti-emetics

  • 5-HT3-receptor antagonists (e.g. Ondansetron): For chemotherapy-induced nausea

  • D2 receptor antagonists (e.g. Metoclopramide): Used less due to reduced efficacy

  • NK1 receptor antagonists (e.g. Aprepitant): Control chemotherapy-induced vomiting

Treatments for Diarrhea and Constipation

Diarrhea

  • Usually self-limiting; causes include:

    • Enteric infections, malabsorption, inflammatory bowel disease

  • Treatment with opioids (e.g. Loperamide) to decrease motility

Constipation

  • Defined as <3 stools per week

  • Treatments vary:

    • Bulk-forming laxatives (e.g. Psyllium husk)

    • Faecal softening agents (e.g. Docusate)

    • Stimulants (e.g. Bisacodyl)

    • Osmotic laxatives (e.g. Glycerol) for bowel stimulation

Opioid-Induced Constipation

  • Managed with Methylnaltrexone

    • Opioid antagonist that does not cross blood-brain barrier, preserving analgesic effects.

Drug Metabolism Overview

  • Involves two major phases: Phase I and Phase II reactions.

    • Phase I Reactions: Functionalization reactions (oxidation, hydroxylation, etc.).

    • Phase II Reactions: Conjugation reactions (glucuronidation, acetylation, etc.).

  • Key functions: Convert drugs (xenobiotics) into more hydrophilic metabolites for elimination.

Phase I Reactions

  • Key Enzymes: Cytochrome P450s (CYPs).

  • Purpose: Introduce functional groups to drugs (e.g., -OH, -COOH).

  • Examples:

    • Hydroxylation of drugs (e.g., Metoprolol, Carvedilol).

    • Activation of certain prodrugs (e.g., irinotecan).

  • Metabolism routes often lead to drug inactivation.

Phase II Reactions

  • Main Enzymes: UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), N-acetyltransferases (NATs).

  • Purpose: Attach a hydrophilic moiety to the drug or metabolite.

  • Results in higher molecular weight and water solubility, aiding in drug excretion.

  • Specific conjugation outputs include glucuronide, sulfate, acetyl, and methyl derivatives.

Drug Metabolism Sites

  • Primary site for Phase I and II reactions: Liver.

  • Other sites: Plasma, lungs, gastrointestinal tract.

  • First-Pass Metabolism: Oral drugs undergo metabolism before systemic circulation, impacting bioavailability.

Importance of Drug Binding

  • CYP enzymes bind to drugs, influencing their metabolism and therapeutic effects.

  • Drug interactions can occur due to competition for CYP enzymes (e.g., Grapefruit juice and CYP3A4).

Clinical Relevance

  • Paracetamol (Acetaminophen): Primarily metabolized via glucuronidation and sulfation.

    • Overdose risks leading to hepatotoxicity via N-acetyl-p-benzoquinone imine (NAPQI).

    • Management includes N-acetylcysteine to replenish glutathione.

  • Methylation: Catalyzed by methyltransferases like COMT and TPMT, affecting drugs like 6-mercaptopurine.

Summary of Key Enzymes and Pathways

  • Phase I:

    • CYP3A4: Most abundant; metabolizes 30-50% of clinically used drugs.

    • Phase II:

      • UGT: Major role in glucuronidation.

      • SULT: Major role in sulfation.

      • NAT: Involves N-acetylation reactions.

Conclusion

  • Understanding drug metabolism is crucial for predicting drug behavior in the body, interactions, and clinical outcomes.

Introduction to Pharmacogenomics

  • Pharmacogenomics examines how genetic makeup affects drug response.

  • Aims to develop personalized medicine.

Objectives and Aims

  • Understand pharmacogenomics principles and variability in drug responses.

  • Awareness of pharmacogenomic tools.

  • Examples include β-adrenoceptors and CYP2D6.

Variable Drug Responses

  • Statistics: 90% of drugs respond variably (30-50% of individuals).

  • Impact on Populations: Large inter-individual variability is observed in drug classes (e.g., ACE inhibitors, SSRIs, anticancer drugs).

Factors Affecting Drug Response

Endogenous Factors

  • Physiological: weight, age, gender, ethnicity.

  • Pathophysiological: diseases (e.g., heart failure).

Exogenous Factors

  • Environmental: smoking, diet.

Genetic Variability in Drug Response

  • Genetic differences affect drug pharmacokinetics: absorption, distribution, metabolism.

  • Key enzymes include CYP2D6, CYP2C9, UGT1A1, impacting responsiveness.

Current Status of Pharmacogenomics

  • Genetic polymorphisms significantly influence drug effects and toxicity.

  • Growing interest in genes encoding transporters, receptors.

Types of Genetic Variants

  • SNPs: Most common genetic variation associated with changes in phenotype.

  • VNTRs: Variable repeats impacting gene expression.

  • Indels: Insertions/deletions causing changes in gene function.

  • CNV: Variability in gene copies among individuals.

Pharmacogenomic Study Approaches

Candidate Gene Studies

  • Focus on specific genes linked to drug response.

Genome-Wide Association Studies (GWAS)

  • Allows comprehensive analysis of genetic variants across populations.

Methods of Genotyping

  • Techniques include DNA sequencing, RFLP, real-time PCR, and microarrays.

CYP450 Variability

  • Key drug metabolizing enzymes that significantly impact drug efficacy and safety.

  • Genetic variability defines phenotypes: ultrarapid, extensive, intermediate, and poor metabolizers.

CYP2D6 Polymorphisms

  • Involved in metabolism of numerous commonly prescribed drugs.

  • Variations lead to serious clinical implications, impacting drug therapy outcomes.

Clinical Implications of CYP2D6

  • Various case studies (Tamoxifen, Codeine, Perhexiline) highlight the importance of pharmacogenomics in therapy.

  • Tailored dosing strategies based on metabolizer phenotype can enhance therapeutic outcomes and minimize adverse effects.

Pharmacogenomics and Antidepressants

Overview of Pharmacogenomics

  • Focuses on how drug metabolizing enzymes affect antidepressant effectiveness.

  • Key enzymes: CYP2D6 and CYP2C19.

  • Crystal structure studies of CYP2D6 (Rowland et al., 2006).

Objectives and Importance

  • Understanding CYP2D6 polymorphisms and their clinical impacts on antidepressants.

  • Enhance knowledge on pharmacogenomics and antidepressant drugs (CYP2D6, CYP2C19).

Clinical Efficacy of Antidepressants

  • Randomized controlled trials indicate:

    • Only 35-45% of patients return to premorbid functioning after 6-8 weeks of standard antidepressant doses (Kirchheiner et al., 2004).

CYP2D6 and Antidepressant Dosing

  • Recommended dosing considers population and subpopulation differences:

    • 7-10% Caucasians are poor metabolizers, 40% are intermediate, and 50% are extensive metabolizers.

    • Average dose calculations:

      • Formula: Dave = 0.1DPM + 0.4DIM + 0.5DEM.

Sites of Action for Antidepressants

  • Tricyclic antidepressants (TCAs) and their mechanisms, focusing on NET and SERT activities:

    • Examples: imipramine, desipramine, amitriptyline, nortriptyline.

Metabolism of Tricyclic Antidepressants

  • Key metabolic pathways in the liver include:

    • N-demethylation and ring hydroxylation processes retaining biological activity.

Genetic Variability in CYP Enzymes

Metabolizer Classifications

  • Ultrarapid Metabolizers (UM): > 2 active genes.

  • Extensive Metabolizers (EM): 2 functional genes.

  • Intermediate Metabolizers (IM): One functional and one defective allele.

  • Poor Metabolizers (PM): No functional enzymes (defects or deletions).

CYP2D6 Genetic Polymorphisms

  • Various mutations affect enzyme activity:

    • *1 (Wild-type): Normal activity.

    • *3, *4, *5 (Inactive): Variable frequencies in populations.

    • *2xn (Increased activity): Gene duplications observed.

CYP2C19 and its Role in Antidepressants

  • Catalyzes selective 4-hydroxylation of S-mephenytoin.

  • Polymorphisms include:

    • *2A and *3A: Resulting in no enzyme activity (poor metabolizers).

Population Data on CYP2C19

  • Poor metabolizer frequencies:

    • 13-23% in Asian populations.

    • 2-5% in Caucasians.

Other Factors Influencing Antidepressant Response

  • Variability may arise from:

    • 5-HT receptors.

    • NET (SLC6A2) and adrenergic receptors.

  • Limited available information on these influences.

Pharmacogenomics in Oncology

Objectives and Aims

  • Understand pharmacogenomics in cancer via acute lymphoblastic leukaemia (ALL).

  • Explore thiopurine methyltransferase (TPMT) and its effect on 6-mercaptopurine.

General Overview

  • Anticancer drugs are toxic with a low therapeutic index.

  • Pharmacogenomics enhances cancer chemotherapy:

    • Increases efficacy

    • Reduces toxicity.

  • Optimizes treatment for ALL through individualized approaches.

Acute Lymphoblastic Leukaemia (ALL)

  • ALL is a heterogeneous disease affecting lymphoid progenitor cells in bone marrow and blood:

    • Subdivided by immunologic properties (T-cell vs B-cell).

    • Mainly affects children (peak age 2-5 years).

  • Advancements in treatment over decades:

    • Survival rates improved from ~10% in the 1960s to ~80% in the 1990s due to better chemotherapy and identification of high-risk patients.

Treatment Protocols for ALL

  1. Remission-Induction Therapy

    • Aims to eliminate >99% leukemia cells; restore normal blood cell formation.

  2. Consolidation Therapy

    • Strengthens remission; specific agents vary by risk factors and CNS status.

  3. Continuation Treatment

    • Focuses on eradicating residual leukemia and CNS treatment.

Role of TPMT in ALL Treatment

  • 6-Mercaptopurine (6-MP)

    • Widely used for ALL, requires metabolism to achieve cytotoxicity.

    • Inactivation pathways involve TPMT and xanthine oxidase.

  • TPMT Polymorphisms

    • Variants impact enzyme activity levels, influencing drug response and toxicity:

      • Wild-type (high activity) vs. Variants (intermediate/low activity).

      • Dose adjustments needed to prevent toxicity (e.g., significant reductions for homozygous variants).

Implications of TPMT Variations

  • High TPMT activity may lead to higher leukemic relapse rates; may require higher drug dosages.

  • TPMT deficiency increases risk of toxicities from drug accumulation.

  • Patients with adjusted dosages based on TPMT genotype show better overall treatment quality and efficacy.

Other Considerations

  • Non-genetic factors also affect drug responses:

    • Drug-drug interactions

    • Environmental factors

    • Age, sex, and organ function.

  • Overall pharmacogenomics assists in optimizing individual patient therapy in ALL.