Pharmacology and Toxicology Overview

Pharmacology and Toxicology

• This subject covers the study of drugs and their effects on living organisms.
• It includes the principles of both pharmacology and toxicology.
• Pharmacology focuses on the effects of drugs and chemicals on living organisms.
• Toxicology focuses on the harmful and adverse effects of chemicals, substances, physical agents on living organisms and the environment.
• Drugs can be natural or synthetic chemical substances that affect a biological system.

Importance of Pharmacology

• Understanding biochemical and physiological aspects of drug effects.
• Determining the effectiveness and safety of drugs.
• Helping in the diagnosis, prevention, and treatment of diseases.

Drug-Receptor Interactions

• Concerns the ability of a drug to affect a receptor.
• Probability or strength of the drug occupying a receptor at any time – Drug's affinity.
• Degree to which a drug or ligand activates the receptors and its resulting effect on cellular response – Intrinsic efficacy.

Effect of a Drug Depends on

• Disease states – Chronic kidney diseases affects dramatically the drug pharmacology.
• Number of Receptors – Differentially expressing receptors mediate biological responses of different levels.
• Drug dosage – Increase in amount increases drug effect until saturation of receptor.
• Drug potency/affinity – More potent drug – faster binding to receptor and slower releasing from receptor.
• Drug efficacy – Ability of drug to block or activate the receptor.

Dose-Response Relationship

• The most important concept in pharmacodynamics is the dose-response relationship.
• Describes the dependence of the effect of a drug from its concentration at its receptor.
• Pharmacodynamics describes the course of action of drugs leading to a physiological effect in a specific site in the body.

Four Main Pharmacokinetic Processes

• The components of pharmacokinetics include Absorption, distribution, metabolism and excretion (ADME).
• Used for explaining the various characteristics of different drugs in the body.
• Pharmacokinetic processes are influenced by patient factors like sex, age, genetics, and diseases, along with drug properties like protein binding, molecule size, and chemical characteristics.

Mechanisms of Absorption of Drugs from the Gastrointestinal (GI) Tract

• Passive diffusion is the vast majority of drugs absorbed by this mechanism.
• Driving force is the concentration gradient across a membrane separating two body compartments.
• Drug moves from an area of high concentration to an area of lower concentration.

Facilitated Diffusion

• Specialized transmembrane carrier proteins allow passage of drugs into the interior of cells.
• Does not require energy.
• Facilitates the passage of large molecules.
• Can be inhibited by compounds competing for the carriers.

Bioavailability

• Rate and extent that an administered drug reaches the systemic circulation.
• Determining bioavailability is important for calculating the drug dosages for non-intravenous routes of administration.
• Example: 100 mg of drug given orally, 60 mg absorbed unchanged, bioavailability is 0.6 or 60%.

Drug Distribution – Volume of Distribution

• Acid-base characteristics of drugs influence their distribution.
• Drugs may bind to proteins throughout the body, creating a bound and unbound phase equilibrium.
• Basic molecules interact strongly with negatively charged phospholipid head groups located on phospholipid membranes, leading to higher volume of distribution compared to acidic molecules.
• Lipophilic molecules are more likely to leave the bloodstream and distribute to areas with high lipid density (e.g., adipose tissue), having a higher volume of distribution than hydrophilic molecules which remain more in the bloodstream and have a lower volume of distribution.

Different Routes of Drug Administration

• Enteral route of medication, involves the digestive or alimentary tract, for example, rectal route which is rapid and effective absorption via the highly vascularised rectal mucosa. Partial bypass of the first-pass metabolism. Also Intravenous injection (IV route), with upper extremities being the commonly preferred site, is the most frequent parenteral route. Bypasses the first-pass metabolism, easy access, and lower incidence of thrombophlebitis and thrombosis in the upper limbs.
• Parenteral route of medication – Intramuscular injection (IM) administered in different body muscles, and commonly given in the upper outer quadrant of the buttock. The subcutaneous route (SC) which involves injection into the layer of skin below dermis and epidermis, is absorbed at a slow-sustained rate, and can be given in various sites including the upper arm's outer area and abdomen.

Drug Calculations

• Ratio and Proportion Method, Desired Over Have or Formula Method, Dimensional Analysis Method.
• Three primary methods for the calculation of medications dosages.

What is Lorazepam?

• Used to relieve anxiety and treat insomnia caused by anxiety.
• A class of medications called benzodiazepines.
• Commonly used to treat alcoholism and alcohol withdrawal symptoms.
• Available in tablet form, liquid form, and for injection.
• Helps to decrease withdrawal symptoms and reduce cravings to drink.

Dimensional Analysis Method

• Uses conversion factors of equivalency.
• No need to memorize specific formulas.
• Start with a unit of measure.
• Construct the equation with available information.
• Place information with the same unit as the previous denominator into the numerator.
• Repeat cancelling out unnecessary units until needed.
• Determine the numeric answer with the needed correct unit of measure.
• Example: Calculating the desired dose of digoxin.

What is the difference between antibiotics and antimicrobial drugs?

• Antimicrobials: A group of agents aiming to reduce the possibility of infection and sepsis.
• Antibiotics: Derived from molds or synthesized; a group of agents aiming to kill bacteria (bactericidal) or preventing their multiplication (bacteriostatic).

Basis of Antibiotics Action

• Various antibiotics act by interfering with cell wall synthesis, plasma membrane integrity, nucleic acid synthesis, ribosomal functions, and metabolic pathways of bacteria (such as folate synthesis).

β-Lactam Antibiotics

• Examples: Penicillin, cephalosporin, carbapenem, etc.
• All antibiotics contain a β-lactam ring.
• Work by inhibiting the last step in bacterial cell wall peptidoglycan synthesis.

Mode of Action for Bacitracin

• Bacitracin is a complex polypeptide produced by Bacillus subtilis (Gram-positive bacilli, catalase-positive, non-pathogenic bacterium) .
• Inhibits peptidoglycan synthesis in a step of bacterial cell wall synthesis.
• Peptidoglycan is an envelope surrounding the cytoplasmic membrane of most bacterial species.

Antibiotics Act by Interfering with Plasma Membrane Function

• Polymyxins (e.g., polymyxin B, colistin): Disrupts the outer cell membrane, binds and neutralizes lipopolysaccharides, inhibits respiration in Gram-negative bacteria, bind to bacterial membranes.
• Leading to rapid depolarization and inhibiting DNA, RNA and protein synthesis.
• Daptomycin treats infections caused by Gram-positive bacteria (e.g., MRSA, VRE).

Antibiotics Act by Interfering with Ribosomes Function

• Major classes of protein synthesis-inhibiting antibacterials: Chloramphenicol, macrolides, and lincosamides.
• Bind to the 50S ribosomal subunit to inhibit peptide bond formation and stop protein synthesis.
• Aminoglycosides: Bind to the 30S ribosomal subunit impairing proofreading and thus resulting in faulty proteins.
• Tetracyclines bind to 30S ribosomal subunit preventing the binding of tRNAs thereby inhibiting protein synthesis.

Antibiotics Act by Affecting DNA and RNA Synthesis

• DNA synthesis inhibitors: Ciprofloxacin, Levofloxacin, Moxifloxacin (fluoroquinolones).
• RNA synthesis inhibitors: Rifamycin.

What is Rifamycin?

• Antibiotics that act by affecting RNA synthesis of bacteria.
• Particularly effective against mycobacteria (tuberculosis, leprosy, mycobacterium avium complex (MAC) infections.
• Common side effects include constipation and headache.
• Synthesized either artificially or naturally from the bacterium Amycolatopsis rifamycinica.
• Includes the "classic" rifamycin drugs as well as the Rifamycin derivatives rifampicin, rifaximin, rifabutin, rifapentine, and rifalazil.

Antibiotics Act by Interfering with Metabolic Pathways

• Folic acid synthesis inhibitors: Sulfonamides, sulfones, trimethoprim.
• Mycolic acid synthesis inhibitors: Isoniazid.

Side Effects of Topical Antifungal Agents

• Possible side effects include burning, stinging, swelling, irritation, redness.

Routes of Administration for Antivirals

• Most antivirals are oral drugs.
• Other common routes include topical (skin creams), eye drops, small-particle aerosol, and intravenous (IV) medication.

Drugs for Common Viral Skin Infections

• Oral herpes: Acyclovir, penciclovir, famciclovir, valacyclovir
• Papillomas (warts): Topical salicylic acid, cantharidin.

Agenda - Cancer Treatments

• Cancer basics, Traditional chemotherapy, Hormonal therapy, Targeted therapy, Immunotherapy, Cell Therapy, Clinical Application

Toxicology of Chinese Medicinal Herbs

• TCM drugs use different parts of plants—leaves, roots, stems, flowers, seeds.
• Herbs often combined in formulas given as teas, capsules, liquid extracts, granules, powders.
• Preparation of TCM includes reducing or eliminating toxic effects, enhancing efficacy, changing performance, modifying properties for storage/preparation, and creating pure medicinal materials, modified and flavored.

Side Effects and Risks of Herbs

• Reports of products being contaminated with drugs, toxins, or heavy metals are often seen.
• In general, Chinese medicines should be administered at least 1–2 hours before or after western medicines to minimize possible interactions.

Herb-Drug Interaction

• Two main approaches to understanding herb-drug interaction: Pharmacokinetic interaction and Pharmacodynamic interaction.
• Pharmacokinetic interaction is the interference with the body's process of dealing with a drug, including absorption, distribution, metabolism, excretion.
• Pharmacodynamic interaction impacts the drug's action on the body, changing the relationship between drug concentration and resultant effect.

Principles of Inflammation and the Immune System

• This section explores inflammation, highlighting its role in the innate immune response and the body's defense mechanisms.
• The immune system's components (cells and organs), its functions (fighting infections, maintaining health), and its responses to various stimuli (like toxic compounds, pathogens), are all discussed in relation to the inflammatory processes.
• Barrier defenses are highlighted as important parts of the immune system, such as those in the oral cavity, stomach, nasal cavity, mucosal surfaces and in skin.
• The hallmark of the innate immune response is how effective inflammation is when fighting pathogens, toxic compounds, and damaged cells.
• The hallmark of innate immune response is inflammation. Inflammation is the response of the immune system to harmful stimuli. Examples of such harmful stimuli include toxic compounds, irradiation, pathogens, and damaged cells. The inflammatory response is a crucial defense mechanism that helps maintain health, it acts by removing the injurious stimuli, and initiates a healing process.

Antirheumatoid Drugs

• Agents used in the therapy of inflammatory arthritis, predominantly rheumatoid arthritis.
• Rheumatoid arthritis is a disease in which the immune system attacks healthy cells, causing inflammation (painful swelling) in affected parts of the body.

Diagnosis of Rheumatoid Arthritis

• Medical history, signs, symptoms—Physical examination of joints.
• Blood tests - White blood cell count, C-reactive Protein, Rheumatoid Factor, etc.
• X-ray to assess severity of joint destruction.
• Ultrasound to detect active inflammation, fluid buildup, and bone erosion.
• MRI scan for better viewing of joints and swelling.

Drugs for Treatment of Rheumatoid Arthritis

• NSAIDs: Nonsteroidal anti-inflammatory drugs for pain relief and reduction of inflammation.
• Steroids: Corticosteroids reduce inflammation, pain, and slow joint damage.
• Conventional DMARDs (disease-modifying antirheumatic drugs): Methotrexate, etc.
• Other drugs as advised by the doctor.

Systemic Lupus Erythematosus (SLE)

• Long-lasting (chronic) autoimmune disease in which the immune system mistakenly attacks healthy cells, causing inflammation.
• Affects many parts of the body (joints, skin, lungs, heart, kidneys, brain, etc.).
• Women are diagnosed about nine times more often than men.
• Most often happens to people between ages 15 and 45.

Drugs for Treatment of SLE

• NSAIDs to relieve pain and reduce inflammation.
• Antimalarials, such as hydroxychloroquine, to affect the immune system and help reduce lupus symptoms.
• Steroids—Corticosteroids—reduce inflammation.
• Immunosuppressants—Suppress the immune system.
• Other drugs, as advised by a doctor.

Multiple Sclerosis (MS)

• Chronic autoimmune disorder affecting the central nervous system.
• The body attacks its own myelin sheaths, resulting in unpredictable symptoms.
• Symptoms can range from mild to severe; some patients may lose their ability to walk, write, speak, or see clearly.
• MS affects people differently.

What Causes Multiple Sclerosis (MS)?

• Multiple possible causes, including autoimmune disorders, environmental factors, infectious agents (viruses), and genetic factors.
• MS is not commonly a hereditary disorder, but some genetic variations may increase the risk.

Principles of Toxicology I & II

• Major drug toxicities are grouped into five categories based on mechanism, such as on-target, hypersensitivity, off-target, biological activation, and idiosyncratic.
• Example of classifications in the context of drug toxicity are included.

Example of Drug Synergism

• Aspirin and caffeine: Combination provides greater efficacy and pain relief than either drug alone.

Drug-Food Interaction

• Food affects medications, improving or worsening their effects, causing new side effects, affecting how the body processes food.

Coca-Cola and NSAIDs

• A significant increase in plasma ibuprofen concentration when taken together (increased extent of absorption).
• Daily dosage and frequency of NSAIDs, like ibuprofen, needs close observation if taken with Coca-Cola.

Green Vegetables and Warfarin

• Spinach is rich in vitamin K, and vitamin K helps with blood clotting.
• Warfarin inhibits vitamin K. Eating spinach alongside warfarin may reduce warfarin's effectiveness.

Milk and Tetracyclines

• Milk interferes with the absorption of tetracyclines by forming insoluble substances.
• It results in the reduction of tetracyclines' bioavailability.

Matured Cheese and Phenelzine

• Mature cheese contains tyramine.
• Consuming mature cheese with phenelzine may raise blood pressure to dangerously high levels, resulting in severe health complications.

Grapefruit and Statins

• Grapefruit juice contains furanocoumarins, increasing statin potency and consequently the risk of side effects like leg pain and muscle weakness.

Mechanisms of Drug Toxicity

• Major drug toxicities are categorized based on their underlying mechanism: on-target (e.g., statins, penicillins), hypersensitivity and immunological (e.g., penicillins), off-target (e.g., terfenadine), biological activation (e.g., acetaminophen), idiosyncratic (e.g., halothane).

Mitochondrial Toxicity

• Inhibition of protein complexes, membrane transporters, Krebs cycle enzymes, and fatty acid metabolism, DNA replication.
• Oxidative stress or mitochondrial permeability transition pore can cause damage to lipids, DNA, and proteins, leading to cell death and apoptosis.

Cell Cycle Mediated Toxicity

• Cell cycle has four phases: GI, S, G2, and M.
• Drugs can affect cell cycle and cause toxicity if they affect any stages.

Apoptosis

• Mitochondria play a key role in apoptosis.
• Induction of mitochondrial outer membrane permeabilization, releasing pro-apoptotic factors, which leads to caspase activation and DNA fragmentation, causing cell death.

Organ and Tissue Toxicity

• Drugs can cause toxicity in various organs (liver, kidneys, hematopoietic system, gastrointestinal tract).
• Cardiovascular, Nervous, and respiratory systems.

What Drugs are Renal Toxic?

• Certain antimicrobial drugs (aminoglycosides, antifungals, beta-lactams, quinolones, rifampin, vancomycin) can lead to drug-induced acute renal failure.

Symptoms of Neurotoxicity

• Dysfunction relating to nervous system includes confusion, poor concentration, memory loss, personality changes, loss of sensation, and muscle weakness.

This quiz delves into the key concepts of pharmacology and toxicology, focusing on the effects of drugs on living organisms. Explore the mechanisms of drug-receptor interactions, along with the significance of understanding drug effectiveness and safety in medical practice. Test your knowledge on the principles that govern these vital fields.