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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
What is Pharmacology?
Definition of a Drug
Definition of a Medicine
Protein Targets for Drug Binding
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
Nitric Oxide (NO)
Angiotensin (AT) receptor system
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
Remission-Induction Therapy
Aims to eliminate >99% leukemia cells; restore normal blood cell formation.
Consolidation Therapy
Strengthens remission; specific agents vary by risk factors and CNS status.
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.