Introduction to Pharmacology and Toxicology

Introduction to Pharmacology and Toxicology

• Pharmacology is the scientific study of the effects of drugs and chemicals on living organisms.
• A drug is a natural or synthetic chemical substance that affects a biological system.

Importance of Pharmacology

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

Toxicology

• Toxicology is the field of science that studies the harmful and adverse effects of chemicals, substances, physical agents, or situations on living organisms and the environment.

Drug-Receptor Interactions

• Focuses on a drug's ability to affect a given receptor, its probability of occupying a receptor, its affinity, and the degree to which it activates the receptors, leading to a cellular response (intrinsic efficacy).

Effect of a Drug Depends On

• Disease states can drastically affect drug pharmacology and kinetics.
• The number of receptors and their expression levels influence biological responses.
• Drug dosage increases the drug's effect until receptor saturation.
• Drug potency/affinity- affects binding to and releasing from receptors.
• Drug efficacy is the drug's ability to block or activate a receptor.

Dose-Response Relationship

• A crucial concept in pharmacodynamics.
• It describes the effect of a drug's concentration at the receptor.
• Describes the course of action of drugs leading to a physiological effect at a specific site in the body.

Four Main Pharmacokinetic Processes

• Absorption, distribution, metabolism, and excretion (ADME)
• Explaining the characteristics of different drugs in the body.
• Pharmacokinetic processes can be influenced by factors such as patient characteristics (sex, age, genetics, and underlying diseases) and drug properties (protein binding, molecule size, and chemical characteristics).

Mechanisms of Absorption of Drugs from the Gastrointestinal Tract

• Passive diffusion is the most common mechanism, involving movement of drug from high to low concentration across a membrane.
• It does not require a carrier protein.
• Other factors affecting drug absorption include route-specific factors.

Mechanisms of Facilitated Absorption

• Specialized transmembrane proteins (carriers) aid drug passage into cells.
• Does not require energy.
• Facilitated by large molecules.
• Can be inhibited if compounds compete with the carriers.

Bioavailability

• Its the rate and extent that an administered drug reaches the systemic circulation.
• Important consideration, especially with non-intravenous routes of administration to calculate proper drug dosages.

Drug Distribution - Volume of Distribution

• Acid-base characteristics, such as the propensity to bind proteins, affect volume of distribution.
• Basic molecules interact with negatively charged phospholipid head groups (in membranes), leading to a higher Vd compared to acidic molecules.
• Lipophilic molecules are more likely to leave the blood and enter high lipid density tissues (e.g., adipose tissue)
• Hydrophilic molecules remain more in the blood stream.

Different Routes of Drug Administration

• Enteral (e.g., oral, rectal) - often involves first-pass metabolism
• Parenteral (e.g., intravenous, intramuscular, subcutaneous) – bypasses first-pass metabolism.

Drug Calculations

• Ratio and Proportion Method
• Desired Over Have or Formula Method
• Dimensional Analysis method

What is Lorazepam?

• A benzodiazepine used to treat anxiety and insomnia, often used to treat alcohol withdrawal symptoms.
• Available in tablets and liquid forms for injection.

Dimensional Analysis Method

• Uses conversion factors for equivalent units.
• Avoids memorizing specific formulas by building equations with available information and correctly placing units in numerator and denominator.

Step 3: Clinical Research Studies - Phase 3

• 300 to 3,000 volunteers/Study participants.
• Purpose: Determine efficacy, monitor safety (adverse reactions).
• Phase usually lasts 1-4 years.

Step 3: Clinical Research Studies - Phase 4

• Purpose: Further evaluate safety and efficacy.
• Large number of participants.

FDA IND Review Team

• Specialists in different areas (Project Manager, Medical Officer, Pharmacologist, Pharmacokineticist, Chemist, Microbiologist, Statistician).
• Purpose: Evaluate protocol, safety, and efficacy of the drugs.

Pharmacology and Toxicology: Principles of Neuropharmacology

• Drugs that Alter Axonal Conduction - Local Anesthetics
• Works by decreasing axonal conduction, suppressing nerve transmission.
• Used for localized pain relief
• Important but limited indications.

Monoamines Neurotransmitters

• Includes Serotonin & Dopamine.
• Serotonin - regulates mood, patterns, appetite, etc.
• Dopamine - pleasure chemical, released in response to rewards.
• Involved in mood, alertness, focus, memory, motivation, sleep.

What is ADHD?

• Attention-Deficit/Hyperactivity Disorder.
• Common mental disorder among children.
• Symptoms include inattention, impulsivity, and hyperactivity.

Central Nervous System Pharmacology

• Sub-classifications (Narcotic Analgesics, Non-narcotic Agents, The cholinergic agents, Adrenergic agents and CNS stimulants)
• Different pathways of action (sigma & mu receptors, neurotransmitters, etc).

Central Nervous System Pharmacology (Continue)

• Anticonvulsants - either affect sodium evacuation or GABA levels.
• Sedatives and Hypnotics - decrease thalamus and cortex activity to promote sleep.
• Anti-depressants- affect norepinephrine and serotonin levels: may increase or block their utilization.

Central Nervous System Pharmacology (Continue)

• Antipsychotics - block dopamine receptors, reduce responsiveness of medulla.
• Anxiolytics - alter responses in limbic center, increase GABA levels.

Analgesics - Non-Opioid Analgesics

• Three major classes: Salicylates (aspirin), para-aminophenol (Tylenol), and NSAIDs (Ibuprofen).
• Inhibit prostaglandin synthesis.
• Indications: Pain, Fever
• Side Effects: GI problems, Headache, Dizziness
• Examples: Aspirin, Acetaminophen, Ibuprofen, Naproxen sodium

Glaucoma

• A common condition causing damage to the optic nerve.
• Fluid buildup in the front part of the eye increases pressure.
• Could lead to loss of vision.

Narcolepsy

• A long-term brain condition causing issues with sleep-wake cycles.
• May lead to significant daytime sleepiness.

Anti-Convulsants

• Mechanism: Decrease neuronal firing using several different mechanisms.
• Indications: Seizures
• Side Effects: Nystagmus, Drowsiness, Hypotension, Respiratory depression
• Examples: Hydantoins (ethotoin, felbamate, phenytoin), Barbiturates (phenobarbital, mephobarbital, primidone), Benzodiazepines (clonazepam, clorazepate, diazepam).

Principles of Cardiovascular Pharmacology

• Types of heart medications, pharmacology of blood vessels, Drugs for hyperlipidemia.
• Anticoagulants and antiplatelet agents.

Common Symptoms of Myocardial Ischemia - Angina

• Not a disease but a symptom of other conditions, such as chest pressure or pain.
• Develops when a part of the heart isn't receiving enough oxygen.

Anti-Ischemic Drug Therapy

• Decrease myocardial oxygen consumption by lowering heart rate and blood pressure, reducing myocardial contractility, or ventricular preload.
• Increase myocardial oxygen supply by vasodilation of coronary vessels.

Anti-Ischemic Drug Therapy - Nitroglycerin

• A vasodilator to provide relief from angina pectoris (chest pain).
• Can give quick relief from an attack of angina pectoris.

Common Calcium Channel Blockers - Nimodipine

• Lipid soluble, penetrates the blood-brain barrier, effective against vascular spasm after intracerebral bleeding.

Two Main Types of Calcium Channel Blockers

• Dihydropyridines and Nondihydropyridines.
• Dihydropyridines target blood vessels causing them to relax.
• Nondihydropyridines target heart muscles and blood vessels and are effective at treating heart rhythm problems.

Most Commonly Prescribed Diuretics

• Thiazides are the most commonly prescribed diuretics.
• Not only decrease fluids, but they also cause the blood vessels to relax.
• Avoid if you have severe dehydration, anuria, electrolyte abnormalities, or known hypersensitivity.

Angiotensin Receptor Blockers (ARBs)

• Used for treatment of high blood pressure and heart failure.
• Prescribed in chronic kidney disease and after a heart attack

What is Chronic and Acute Heart Failure?

• Chronic heart failure- a long term condition affecting the heart's ability to pump blood effectively.
• Acute heart failure- a sudden condition where the heart cannot pump blood sufficiently posing a significant threat to life.

Principles of Endocrine Pharmacology

• Different parts of glands
• Examples of exocrine glands: sweat glands, salivary glands, mammary glands.
• Examples of endocrine glands: adrenal gland, pituitary gland, thyroid gland.

Overactive Thyroid (Hyperthyroidism)

• Thyroid gland produces excess hormones.
• Symptoms: Weight loss, nervousness, irregular pulse, irritability, sleep disturbances, etc.

Medications for Treating Hyperthyroidism

• Methimazole & Propylthiouracil
• First-line treatment for hyperthyroidism, particularly in pregnant women.
• Works quickly and is associated with lower risk of birth defects

Medications for Treating Hypothyroidism

• Replacing missing thyroid hormones (e.g., Levothyroxine).
• Regular blood tests are needed to monitor dosage.

Pharmacology of Bone Mineral Homeostasis

• Active vitamin D metabolites- affect calcium and phosphate homeostasis in bone and gut.
• Parathyroid hormone - affects calcium reabsorption in bone, gut and kidney.
• Parathyroid hormone and vitamin D affect urinary excretion of calcium.

Medication for Hyperparathyroidism - Cinacalcet

• Decrease parathyroid hormone & serum calcium levels.
• First-line treatment for hyperparathyroidism, especially if surgery is not possible.

Progestins

• Help other hormones function properly.
• Regulate the menstrual cycle, preventing unusual stopping or excessive bleeding (amenorrhea).
• Prevent anemia and uterine cancer.
• Combined with estrogen for contraceptives.

Estrogen Receptor Modulators

• Used in treatments for osteoporosis, and post-menopausal symptoms, and breast cancer.
• These drugs block estrogen receptors and prevent tumor growth.

Medication Specifically for the Male Reproductive System

• Androgens, such as testosterone.
• Important for secondary sexual characteristics (e.g., facial/body hair growth, voice change)
• Influences muscle and bone development, metabolism.

Diabetes Type 1 and Type 2

• Type 1 diabetes - a lifelong condition where the body doesn't produce insulin (immune system destroys insulin-producing cells).
• Type 2 diabetes - The body doesn't produce enough insulin, or the body's cells don't respond properly to insulin.

Insulin

• Main medicine for type 1 diabetes.
• Administered by injection or insulin pump.

Insulin Pen and Pump

• Insulin pen - an alternative to insulin vials & syringes (convenient, easy-to-use method of insulin administration.)
• Insulin pump - delivers continuous supply of insulin underneath the skin, suitable for those needing ongoing insulin regulation.

Steps for Using Insulin Pen

• Follow steps carefully for safe and correct insulin injection.

Body Sites for Injecting Insulin

• Injecting insulin safely into different body areas in order to avoid irritation.

Drugs for Treating Asthma

• Inhalers (devices containing medicine for inhaling).
• Relievers (short-acting bronchodilators) and Preventers (steroid inhalers) – relieve asthma symptoms.

Preventers (steroid inhalers)

• Reduce inflammation in the airways improving breathing.
• Taken twice daily.
• Take 7-14 days to build effectiveness.

Chronic Obstructive Pulmonary Disease (COPD) & Risk Factors

• COPD risk factors: Smoking, secondhand smoke, family history of related conditions, lung irritants, past respiratory infections.

Steroid Inhalers for COPD and Steroid Tablets for COPD

• Used to decrease inflammation in the airways.
• Steroid inhalers are usually given twice daily for treating COPD and prevent flare-ups (exacerbations).
• Short courses of steroid tablets (often 5 days) can be prescribed.
• Side effects of frequent steroid use include weight gain, mood swings, and weakened bones.

Antibiotics

• First-choice antibiotic: Doxycycline (treatment lasts 4 days)
• Alternatives: Amoxicillin, Clarithromycin, and Erythromycin

How to Test for Theophylline

• Monitor theophylline blood levels using a trough level (measured just prior to the next dose) to determine lowest expected blood concentration level

Method of Analysis of Theophylline

• High-performance liquid chromatography (HPLC) with ultraviolet detection (272 nm) is a reliable lab method.

Principles of Gastrointestinal Pharmacology

• Motility or movement of GI tract is controlled by muscle structures.
• Circular muscle narrows/restricts the lumen while the longitudinal muscle shortens the intestine.

Pathologies of the Gastrointestinal Tract (GI Tract)

• Impairment of one or more GI functions (e.g., absorption, secretion, motility).
• Divided into functional (e.g., dyspepsia, IBS) and organic (e.g., peptic ulcer, GERD, IBD) types

###Difference Between Organic and Functional GI Disorders

• Functional: changes in GI function without significant anatomical damage;
• Organic: noticeable physiological/anatomical changes in organs/tissues.

Common Causes of Peptic Ulcer Disease

• Infection with Helicobacter pylori.
• Use of NSAIDs.
• Other less common causes include smoking or stress from other health conditions.

Factors Increasing the Risk of Developing Peptic Ulcers

• Alcohol use, smoking, uncontrolled stress, and poor eating habits.

Drugs for Gastrointestinal Disease - Nonprescription Medicines

• Antacids (e.g., Mylanta) - neutralize stomach acid.
• Potential side effect: diarrhea/kidney complications from overuse
• Proton Pump Inhibitors (e.g., lansoprazole, omeprazole, esomeprazole) - block acid production helping damaged esophagus tissue heal—stronger acid blockers than H2 blockers.

General Side Effects of H-2 Blockers

• Generally safe.
• Pregnant women should check with doctor.
• H2 blockers can interact with other medications.
• Can affect absorption of some vitamins.

How Do Antiemetic Medications Work?

• Block signals in the brain associated with nausea and vomiting.
• Interrupt chemical messengers to the "vomiting center" of the brain.
• Types of chemical messengers: Histamine, dopamine, serotonin, neurokinins.

Different Antiemetic Drugs

• Antagonists for serotonin, dopamine, histamine and neurokinins.
• Some antiemetics are more effective for specific conditions (e.g., chemotherapy-induced vomiting/nausea)
• Antihistamines are a first-line choice for nausea and vomiting in pregnancy.

Adsorbents Used in Treatment of Diarrhea

• Bind and inactivate bacterial toxins, non-specific action.
• May reduce digestive enzymes, nutrients, and drug absorption.
• May not be effective in controlling fluid loss, so dehydration prevention can be needed.
• Examples: Kaolin, pectin, activated charcoal.

Gas with Loose Stools

• Can be due to conditions such as diverticulitis.
• Can result from increased bacteria in the small intestine.
• Related to diet, low fiber intake, lack of physical activity, obesity, etc.

Bristol Stool Chart

• 7 types of stools
• Types 1-3 are more likely to indicate constipation.

How Do Different Laxatives Work?

• Bulk-forming, emollient stool softeners, and osmotic laxatives promote bowel movements in different ways.

Mineral Oil Enema for Constipation

• Mineral Oil Enema coats the stool, preventing water absorption and lubrication, facilitating bowel movement in those experiencing difficulty passing stools (i.e. those who suffer from hemorrhoids or childbirth recovery).

Antimicrobial Pharmacology

• Antimicrobials aim to reduce infection risk or sepsis.
• Antibiotics (derived from molds or synthetically produced) either kill bacteria(bactericidal) or stop their multiplication(bacteriostatic).

Basis of Antibiotics Action

• Various antibiotics interfere with cell wall synthesis, plasma membrane integrity, nucleic acid synthesis, ribosome function, metabolic pathways.

β-Lactam Antibiotics

• Contain a beta-lactam ring.
• Works by inhibiting the last step in bacterial cell wall peptidoglycan synthesis.

Mode of Action for Bacitracin

• Inhibits peptidoglycan synthesis in bacterial cell walls.
• Produced by Bacillus subtilis.

Antibiotics Act Byinterfering With Plasma Membrane Function

• Polymyxins (e.g., Polymyxin B, Colistin) disrupt the outer cell membrane of Gram-negative bacteria; bind and neutralize lipopolysaccharide & inhibit respiration Leading to rapid membrane depolarization & DNA, RNA and protein synthesis inhibition.

Antibiotics Act by Interfering With Ribosome Function

• Chloramphenicol, macrolides, and lincosamides prevent peptide bond formation for protein synthesis
• Aminoglycosides impair proofreading and produce faulty proteins
• Tetracyclines block tRNA binding, thus stopping protein synthesis

Antibiotics Act By Affecting DNA and RNA of Bacteria

• Fluoroquinolones affect DNA synthesis.
• Rifamycin affects RNA synthesis.

What is Rifamycin?

• Synthesized by a bacterium (Amycolatopsis rifamycinica), affects RNA Bacterial synthesis .
• Treats tuberculosis, leprosy, and M. avium complex infections.
• Common side effects: constipation and headache

Antibiotics Act By Interfering With Metabolic Pathways of Bacteria

• Sulfonamides & Trimethoprim affect folic acid synthesis
• Isoniazid affects mycolic acid synthesis

Side Effects of Topical Antifungal Agents

• Potential side effects: Burning, stinging, swelling, irritation, redness.

Routes of Administration for Antivirals

• Most antivirals are oral drugs.
• Other common administration routes include topical, eye drops, small-particle aerosols, intravenous, etc.

Drugs for Common Viral Skin Infections

• Treating viral skin infections such as oral herpes & papillomas (warts) - antiviral medications (e.g., topical salicylic acids, cannabinoids).

Agenda: Cancer Treatment

• Overview on Traditional Chemotherapy, Hormonal Therapy, Targeted Therapy, Immunotherapy, Cell Therapy and Clinical Applications.

Toxicology of Chinese Medicinal Herbs

• Herbs are used in combination (e.g., as teas, capsules, extracts, granules, powders).

Preparation of Traditional Chinese Medicine (TCM)

• Methods for reducing toxic effects and improving efficacy, facilitating storage, and preparing pure ingredients.

Side Effects and Risks of Herbs

• Potential contamination with other substances/drugs or toxins could increase risks of adverse/serious side effects from herbs;
• Important to consider separating time intervals when taking TCM herbs compared to other drugs to avoid drug-drug interactions.
• Herbs may interact with other medications and some people may be more sensitive for certain herbs.

Herb-Drug Interaction

• Pharmacokinetic interactions: affect drug absorption, distribution, metabolism and excretion.
• Pharmacodynamic interactions: affect drug action on the body causing a change in the relationship between drug concentration and drug action.

Principles of Inflammation and Immune Pharmacology

• Overview on the cells involved, innate/adaptive response, barrier defenses, types of inflammation, etc.
• Agents used in the therapy of inflammatory arthritis (e.g., rheumatoid arthritis) and conditions such as Systemic Lupus Erythematosus (SLE) and multiple sclerosis (MS)

What is the Immune System?

• Network of cells and organs that work together to defend against pathogens and other harmful stimuli.
• Includes white blood cells, lymphatic tissues and organs.

The Immune System

• Two mechanisms: innate & adaptive response.
• Innate - rapid & non-specific; adaptive - slow & specific.

Barrier Defenses in Our Body

• Defenses that prevent entry of pathogens.
• Oral cavity- salivary glands (e.g., lysozyme); stomach- low pH; mucosal surfaces- epithelial cells, normal flora; skin - keratinized cells, low pH, washing action.

What is Inflammation

• A hallmark of innate immune response in response to harmful stimuli (e.g. infectious agents, toxic substances or cell damage).
• A defense mechanism for removing harmful stimuli to trigger a healing process.

Anti-Rheumatoid Drugs

• Agents for inflammatory arthritis, predominantly Rheumatoid Arthritis (RA).
• Immune system is overactive leading to inflammation in multiple joints.

Diagnosis of Rheumatoid Arthritis

• Medical history, physical examination, blood tests (e.g., blood count, CRP, RF), X-ray, ultrasound and MRI.

Drugs for Treatment of Rheumatoid Arthritis

• NSAIDs - pain relief and inflammation reduction.
• Steroids - reduce inflammation, pain, and slow joint damage.
• Conventional DMARDs – Methotrexate and others for long-term management.
• Other medications as advised by physicians.

Systemic Lupus Erythematosus (SLE)

• Chronic, systemic autoimmune disease.
• Characterised by inflammation and organ involvement, mainly affecting women.

Drugs for Treatment of SLE

• Nonsteroidal anti-inflammatory drugs (NSAIDs), antimalarials (e.g., hydroxychloroquine), corticosteroids, immunosuppressants, conventional DMARDs.

Multiple Sclerosis (MS)

• Chronic, autoimmune disorder that affects the central nervous system.
• Characterized by unpredictable course and varied symptoms.
• The symptoms vary from patient to patient, sometimes affecting mobility, writing, speech, vision, etc.

What happens in Multiple Sclerosis (MS)?

• Immune system attacks myelin (protective coating on nerve fibers).
• Myelin damage results in sclerosis (formation of scar tissue) and lesions. -Causes loss of electrical impulse conduction between nerve fibers and brain resulting in unpredictable symptoms.

What Causes Multiple Sclerosis (MS)?

• Many possible causes, including autoimmune disorders, environmental factors, infectious agents, and genetic factors;
• Often not considered a hereditary disease though certain genetic variations increase risk.

Example of Drug Synergism

• Aspirin and Caffeine
• Combination gives increased efficacy and pain relief compared to separate usage

Drug-Food Interaction

• Food can alter how drugs work, making them either more or less effective (or causing new side effects), which may alter how the body uses the food/nutrients.

Coca-Cola and NSAIDs

• Consuming Coca-Cola with NSAIDs like ibuprofen significantly increases its plasma concentration.

Green Vegetables and Warfarin

• Vitamin K found in some leafy greens can affect blood clotting and negatively interact with warfarin which is a blood thinner and anticoagulant.

Milk and Tetracyclines

• Dietary calcium in milk can form insoluble compounds with tetracycline antibiotics causing a reduction of bioavailability and effectiveness.

Mature Cheese and Phenelzine

• Eating certain ripened cheeses (high in tyramine) while taking phenelzine (antidepressant) can increase blood pressure.

Grapefruit and Statins

• Grapefruit juice may increase the potency of some statins (cholesterol drugs).
• This may increase risk of side effects.

Mechanisms of Drug Toxicity

• On-target (drugs acting on intended target location).
• Off-target (drugs acting on other target locations).
• Biological activation (drugs undergoing changes to produce toxicity effects).
• Idiosyncratic (unique reactions specific to individual patients).

Classifications in the Contexts of Drug Toxicity

• Different ways drugs lead to toxicity, including on target, off target, biological activation, & idiosyncratic actions, and examples of drugs involved in each category.

Mitochondrial Toxicity

• Five Complexes (I, II, III, IV, V) are involved in ATP production in mitochondria.
• Some drugs can inhibit the complexes, leading to impaired ATP synthesis.
• Drugs can also inhibit mitochondrial membrane transporters causing osmotic swelling and reduced ATP productions.

Mitochondrial Toxicity- Inhibition of Krebs Cycle Enzymes and Fatty Acid Metabolism

• Fluroacetate or tetracyclins can inhibit Krebs or fatty acid oxidation enzymes in mitochondria.

Mitochondrial Toxicity- Inhibition of Mitochondrial DNA Replication and mtDNA-encoded Protein Synthesis

• Some drugs can inhibit mtDNA replication or mtDNA-encoded protein synthesis.

Mitochondrial Toxicity - Oxidative Stress

• Oxidative stress is often caused by an imbalance of free radicals & antioxidants, resulting in cell damage or even apoptosis.

Mitochondrial Toxicity - Mitochondrial Permeability Transition Pore

• Some drugs can induce irreversible opening of mitochondrial permeability transition pores, leading to water influx(swelling) resulting in drug induced mitochondrial toxicity.

Targets of Oxidative Stress

• Oxidative stress can damage various parts of cells, including lipids, DNA, proteins.

Cell Cycle Mediated Toxicity

• Drugs can affect various steps of the cell cycle, which could lead to toxicity

Apoptosis

• Mitochondria play a crucial role in apoptosis initiation & enhancing death signaling.
• This involves disrupting the outer membrane and releasing pro-apoptotic factors.

Organ and Tissue Toxicity

• Drugs could cause harm to various organs like liver, kidneys, hematopoietic system, skin, GI tract, nervous system, cardiovascular system, lungs, and eyes.

What Drugs Are Renal Toxic?

• Antibacterial drugs like aminoglycosides, antifungals (e.g. amphotericin B), beta-lactams, quinolones, Rifampin, Vancomycin can lead to acute kidney damage.

Symptoms of Neurotoxicity

• Symptoms related to compromised nervous system function (possible causes: confusion, lack of focus, memory problems, personality alterations, loss of sensation/feeling, muscle weakness).

This quiz covers the foundational concepts of pharmacology and toxicology, including the effects of drugs on living organisms and the importance of these fields in medical science. You'll explore drug-receptor interactions, the significance of drug effectiveness, and the impacts of chemicals on health and the environment.