Pharmacology Basics Quiz

Course Information

• Course Name: PHM 10303 Pharmacokinetics
• Course Description: Principles of ADME
• Instructor: Dr. Azyyati Mohd Suhaimi, Faculty of Pharmacy UniSZA
• Adapted from: Dr. Shazia Jamshed, Uni of Alberta, MIT Open Course

Course Structure

• Test 1: 10%
• Test 2: 10%
• Practical Report 1: 10%
• Practical Report 2: 10%

Definitions

• Drug: A chemical or substance that causes changes in the structure or function of living organisms.
• Medicine: The vehicle for administering a drug (active ingredient) to a human or animal (e.g., tablet, capsule, injection, ointment, inhaler, suppository).
• Pharmacokinetics: The study of the kinetics of absorption, distribution, metabolism, and excretion (ADME) of drugs and their corresponding pharmacological, therapeutic, or toxic responses in humans and animals.
• Pharmacology: The science of drug actions and uses.
• Pharmacodynamics: The mechanisms of action (what the drug does to the body).
• Toxicity: The manifestation of harmful effects of a drug after exposure to high levels (intoxication or poisoning).
• Therapeutics: The use of drugs for intended clinical benefits (e.g., curing a disease or relieving symptoms).

Therapeutic Prescribing

• The primary goal of drug therapy is to achieve the desired beneficial effects with minimal adverse effects.
• Drug choice depends on the mechanism of action (pharmacodynamics).
• Drug dose, route, and formulation are determined by pharmacokinetics (how the body handles the drug).

Pharmacology

• Pharmacology deals with the actions of drugs on the body (pharmacodynamics) and the fate of drugs in the body (pharmacokinetics).
• For a drug to work, it must enter the body and be distributed to its site of action, often a macromolecular receptor in target tissue.
• Drug effects are typically temporary due to the body's detoxification and elimination systems.

Relationship between Pharmacokinetics and Pharmacodynamics

• Pharmacokinetics describes how the body acts on the drug (absorption, distribution, metabolism, excretion).
• Pharmacodynamics describes how the drug acts on the body (receptor binding, biological effects).

Pharmacodynamics Basic Principles

• Mechanism of action: Specific molecular processes by which drugs work (e.g., enzyme inhibition, receptor stimulation).
• Mode of action: General description of the type of drug action (e.g., analgesics, supplements).
• Site of action: Specific organs, tissues, or cells affected by the drug (e.g., sensory neurons, myocardium, bronchi).

Mechanism of Action

• The fundamental principle of pharmacodynamics is drug-receptor interactions.
• Specific receptors in the body allow for drug interactions.
• Drugs must have the correct molecular shape to interact with a particular receptor; the analogy often used is "lock and key."

Example: Morphine

• A naturally occurring substance found in opium poppies.
• Part of a family of natural substances known as opiates or opioids (also includes codeine).
• Some synthetic derivatives are available (e.g., heroin, methadone, pethidine).
• Used therapeutically and recreationally throughout history.

Opioid Receptors

• In the 1970s, pharmacologists identified endogenous opioids (e.g., enkephalins, endorphins).
• These have a role in pain perception, mood, and other physiological functions.
• Opioid receptors are found in key areas of the body (e.g., brain, spinal cord, gut, eye).
• Only substances with a similar chemical structure to morphine can attach to opioid receptors (key-lock analogy).
• These substances are called opioid agonists; when they attach, they trigger responses.

Effects of Opioids (Morphine)

• Relief of pain (analgesia).
• Mood elevation (euphoria).
• Sedation.
• Pupil constriction (miosis).
• Reduced gut motility (constipation).
• Cough suppression (anti-tussive).
• Tolerance and dependence with repeated doses.
• Respiratory depression leading to death in overdose.

Mixed Effects of Opioids

• Because of the variety of opioid receptors, separating desirable and undesirable effects of opioids (e.g., morphine, codeine) is challenging.
• For example, patients receiving opioids for chronic pain often experience constipation.

Agonists and Antagonists

• Agonists: Drugs that stimulate receptors (e.g., salbutamol).
• Antagonists: Drugs that block receptors (e.g., metoprolol).

Pharmacokinetics - ADME

• Absorption: The process by which a drug proceeds from the site of administration to the measurement site (bloodstream) in the body.
• Distribution: The process by which a drug is transported within the body to its site of action.
• Metabolism: The process by which the body chemically alters a drug to facilitate excretion.
• Excretion: The process by which the body removes a drug or its metabolites.

ADME - Simplified

• Absorption- Where do and how many MDNS get in?
• Distribution- Where do and how many MDNS go?
• Metabolism- How many MDNS turn into?
• Excretion- How many MDNS are excreted?

Routes of Drug Administration

• Parenteral (injection, intravenous, intramuscular, topical)
• Enteral (oral, rectal, respiratory)

Absorption

• The process by which a drug moves from the administration site to its measurement site (bloodstream) within the body.
• Necessary for a therapeutic effect.
• Most drugs are absorbed through the gastrointestinal tract, with bloodstream absorption occurring following intravenous administration.
• Factors influencing absorption include membrane transport.

Mechanisms of Drug Absorption

• Simple diffusion (passive diffusion)
• Active transport
• Facilitated diffusion
• Pinocytosis (endocytosis)

Absorption (Simple Diffusion)

• Drugs diffuse across a cell membrane from high to low concentration.
• Rate depends on factors such as lipid solubility, size, ionization state, and surface area of absorption. -Lipid-soluble drugs usually absorb more rapidly.
• Smaller molecules diffuse more readily.
• Involves passive passage, no energy required.
• Water-soluble drugs may need channels or pores in the cell membrane.

Simple Diffusion-Ionization

• Most drugs exist in both ionized and unionized forms.
• Unionized form = lipid soluble.
• Ionized form = water soluble.
• The proportion of each form depends on pH and pKa (dissociation constant) of the drug.

Simple Diffusion pKa Factors

• pKa = pH at which the concentrations of ionized and unionized forms are equal.
• pH of the medium affects ionization of drugs.
• Weak acids = best absorbed in stomach.
• Weak bases = best absorbed in intestine.

Facilitated Diffusion

• A type of passive transport.
• No energy required.
• Uses transport proteins for diffusion of solutes across the plasma membrane.
• The solute moves down the concentration gradient.

Active Transport

• Selective energy expenditure
• Transport against a concentration gradient.
• For substances structurally similar to endogenous substances (e.g., ions, vitamins, sugars, amino acids).
• Usually occurs across small intestine through specific sites.

Passive vs. Active Transport

• Passive transport moves along a concentration gradient (from high to low).
• Active transport moves against a concentration gradient (from low to high), requiring energy.
• Facilitated diffusion is a type of passive transport using carrier proteins.

Pinocytosis (Endocytosis)

• Fluid or particles are engulfed by a cell membrane.
• Membrane invaginates, encloses fluid/particles, forming a vesicle.
• Vesicle detaches and moves to the cell's interior.
• Energy expenditure is required.
• In drug transport, it is important for protein drugs and other large molecules.

Bioavailability

• The fraction of an administered dose reaching the systemic circulation.
• Drugs given intravenously have 100% bioavailability.
• Drugs administered in other ways have bioavailability values less than 1.
• Bioavailability is influenced by factors like the drug formulation and physiological variables in the body.
• Bioavailability is determined by comparing the area under the plasma drug concentration-time curve (AUC) following non-intravenous and intravenous administration.

Factors Affecting Bioavailability

• Formulation factors: Excipients, particle size, crystalline or amorphous form of the drug.
• Physiological factors: Gastric emptying, intestinal motility, changes in GIT pH, nature of intestinal wall.

Distribution

• Process of drug movement to body tissues after entering systemic circulation.
• Affected by factors like partitioning across membranes, binding to tissue components, binding to blood components (RBC, plasma proteins), and physiological volumes.
• Total body water (intra, interstitial, and intracellular fluid compartments) influences distribution.

Apparent Volume of Distribution(Vd)

• The theoretical volume in which the total drug amount in the body would distribute to give the measured plasma concentration.
• Influenced by factors like blood flow rate, capillary structure, and protein binding.

Protein Binding

• Many drugs bind to plasma proteins in the bloodstream.
• This limits drug distribution.
• Key binding proteins include albumin, alpha-1-acid glycoprotein, and lipoproteins.

Blood-Brain Barrier (BBB)

• Brain capillaries have tight junctions that limit the passage of water-soluble substances.
• Lipophilic, positively-charged molecules with low molecular weight can cross the BBB.

Elimination

• The irreversible removal of parent drugs from the body.
• Two main processes:
  • Drug metabolism (biotransformation).
  • Excretion.

Drug Metabolism

• The liver is the primary site of drug metabolism.
• Drugs are chemically modified to facilitate excretion.
• Enzymes (e.g., CYPs) catalyze oxidation, reduction, hydrolysis, hydration, conjugation, or isomerization metabolic reactions.

Drug Metabolism: Phases

• Phase I: Converts parent compounds into more polar metabolites. This can be achieved by adding or unmasking functional groups.
• Phase II: The main detoxification step; involves conjugation reactions with endogenous substances.

Cytochrome P450 (CYP)

• The most important enzyme system for phase I metabolism.
• A microsomal superfamily of isoenzymes.
• Involved in the oxidation of many drugs.
• Activity is influenced by drugs and other substances, causing drug interactions.

Renal Excretion

• Kidneys are the primary organs for drug excretion.
• Filtered substance, nearly all water, and most electrolytes are passively and actively reabsorbed in the renal tubes.
• However, most polar substances and drug metabolites are excreted via the kidneys.
• Tubular secretion can enhance elimination.

Summary

• ADME and the factors influencing each process are crucial for understanding drug action.

Drug R&D

• The process of developing new drugs can take 10-15 years and only about 10% are successful for commercialization.
• R&D costs typically range from $800 million to $1 billion.

Why Drugs Fail

• Pharmacokinetic issues.
• Animal toxicity.
• Miscellaneous factors.
• Adverse effects in humans.
• Commercial reasons.
• Lack of efficacy are some major reasons why drugs fail.

Importance of Pharmacokinetic Studies

• Toxic drugs may accumulate.
• Useful drugs may lack therapeutic benefit due to the dose not being sufficient.

Test your knowledge of pharmacology concepts with this quiz. It covers essential topics such as endogenous opioids, drug therapy, and pharmacokinetics. Perfect for students or anyone interested in the field of medicine.