Pharmacology: Introduction and Pharmacokinetics

• BMS161 (1) covers General Pharmacology, including Introduction and Pharmacokinetics: Absorption.
• The Course Foundations of Pharmacology covers Pharmacokinetics, Pharmacodynamics, Cholinergic & Adrenergic nervous systems, General Chemotherapy, Autacoids, Principles of cancer chemotherapy, and drug names.
• The course will teach practical skills such as finding knowledge, calculating doses, and finding drug information.
• Learning resources include Lippincott's Illustrated Reviews: Pharmacology (7th edition) by Whalen K, Finkel R and Panavelil TA (2018).
• Optional resources include Basic and Clinical Pharmacology (15th edition) by Bertram G. Katzung, Suzan B. Masters and Anthony J. Trevor (2020) and Rang and Dale's Pharmacology (8th edition) by H.P. Rang, M.M. Dale J.M. Ritter, R.J. Flower and G. Henderson (2016)
• A drug is a chemical substance used for treatment, diagnosis, or prevention of diseases.
• Drugs have chemical, nonproprietary (generic), and proprietary (brand) names; for example, Paracetamol (Acetaminophen) has brand names like Panadol®, Abimol®, and Pyral®.

Sources of Drugs

• Drugs can be sourced naturally from plants like atropine, morphine, peppermint, animals like insulin hormone, microorganisms like antibiotics such as penicillin, and minerals like iron and calcium.
• Drugs can be semi-synthetic or synthetic
• Synthetic drugs can be created through chemical synthesis, such as aspirin, or biological synthesis using recombinant DNA technology to produce human insulin and Erythropoietin.

Drug Development

• Drug approval involves animal studies and then clinical studies.
• Animal studies focus on pharmacologic profiles (actions on all organs) and safety tests related to toxicity, reproductive effects, carcinogenicity, mutagenicity, and addiction liability.
• Clinical studies occur over 3-7 years
• Phase I trials involve a small number of healthy volunteers to determine clinical dose ranges without blinding.
• Phase II trials use a small number of patients to assess safety and efficacy, often comparing the new drug to an older one in a single-blind study.
• Phase III trials involve a large number of patients in a double-blind study.
• Post-marketing pharmacovigilance is also essential.

Placebo Effects

• Placebo is an inert substance given to please the patient
• Placebo effects are reactions unrelated to a drug's pharmacologic effects.
• Placebos help distinguish between the pharmacodynamic and psychological effects of medication.
• Clinical trials employ Single vs Double-Blind Techniques

General Pharmacology Divisions

• Pharmacodynamics covers the mechanism of drug action and its biochemical and physiological effects, both therapeutic (intended) and side effects (unintended).
• Pharmacokinetics involves what the body does to the drug covering absorption, distribution, metabolism (biotransformation), and excretion (ADME).
• Pharmacokinetics studies effective dose kinetics that wasn't part of its initial design

Pharmacokinetics

• Absorption is the process drug enters blood from the administration site.
• Distribution is the movement of the drug to either its site of action or other organs via blood.
• Metabolism occurs mainly in the liver.
• Elimination, including clearance, primarily happens through excretion via the kidneys.

Drug Absorption Mechanisms

• Passive diffusion occurs with the concentration gradient and does not require ATP or a carrier.
• Facilitated diffusion occurs with the concentration gradient, involves a carrier, and doesn't need ATP.
• Active transport occurs with or against the concentration gradient, requires ATP and a carrier
• Active transport example is L-dopa transportation to the brain
• Endocytosis is the Vitamin B12 absorption mechanism
• Exocytosis is the release of neurotransmitters.

Carrier Transport System

• Saturability leads to limited absorption.
• Competition for carrier transport exists, such as amino acids competing with L-Dopa for brain transport

Factors Influencing Absorption (Passive Diffusion)

• pH can affect drug absorption.
• Blood flow impacts absorption with intestines greater than the stomach.
• Drug administration in shock is not preferred subcutaneously.
• Absorption of subcutaneous insulin can be increased by exercising.
• Intestines (200 m²) provide a 1000-fold greater surface area for absorption compared to the stomach; the lungs provide 70 m².
• Contact time influences absorption: diarrhea or food in the stomach decreases gastric emptying, slowing absorption.
• P-glycoprotein is a transmembrane transporter protein expressed in various tissues like the liver, kidneys, intestines, and brain.
• P-glycoprotein pumps drugs out of cells, reducing drug absorption in the intestine.
• P-glycoprotein is associated with multidrug resistance in cancer cells.

Effect of pH on Drug Absorption

• Dissociation Constant [pKa] is where 50% of the drug is ionized and 50% is unionized.
• Changes in pH of the medium will lead to changes in the ionization ratio
• The ionized form is hydrophilic (charged) and cannot cross membranes
• The unionized form is lipophilic (uncharged) and can cross membranes for absorption.
• Aspirin (weak acid with pKa 3.5) is mostly non-ionized in the empty stomach crossing cell membranes and causing inflammation and peptic ulceration.
• In Aspirin drug poisoning, alkalization of urine enhances renal drug elimination by increasing ionization and inhibiting tubular reabsorption.
• Acidification of urine (reducing urine pH below drug pKa) is helpful in basic drug poisoning like amphetamine.
• Drugs are more absorbed in the same media and excreted in opposite conditions

Bioavailability

• Bioavailability is the percentage of drug released from a formulation that reaches systemic circulation and becomes available for biological effect.
• Bioavailability is calculated by dividing the area under the blood concentration-time curve (AUC) after any route of administration by that after IV administration, for the same dose

Factors Influencing Bioavailability

• Factors related to dosage form (e.g., synthesis techniques and excipients) can affect disintegration of the dosage form into particles
• Factors related to the drug (molecular weight and solubility) can affect dissolution of the drug particles into molecules.
• Factors affecting drug stability in the GIT and GIT secretions can result in drug destruction.
• Food and co administered drugs interact with drugs.
• Gut pH & a drug's pKa, affect ionization of drug molecules into ions.
• Factors related to the absorptive system (e.g., GIT motility and presence of GIT disease) can modify the rate of crossing the absorptive surface.

First-Pass Effect (First-Pass Metabolism; Presystemic Elimination)

• First-pass effect is the metabolism of some drugs in a single passage through the liver, gut wall, or lungs before reaching the systemic circulation.
• Sites for first-pass effect are the liver, intestine (e.g., Estrogen), and lung (for inhaled drugs like nicotine).
• Hepatic first-pass effect is when drugs absorbed from the GIT are carried first in the portal circulation to the liver
• Drugs are extensively metabolized in their first pass e.g., nitroglycerin & propranolol.
• Factors reducing hepatic first-pass metabolism include a reduction in portal blood flow (portal hypertension, propranolol) and inhibition of hepatic metabolizing enzymes (liver failure and presence of enzyme inhibitors as Erythromycin)
• Reducing the hepatic first-pass effect will lead to increased bioavailability

Routes of administration

• Enteral which is through the digestive tract
• Parenteral which includes Intravenous, Intramuscular, Subcutaneous, Intradermal, Intrathecal, Epidural, Intra-arterial, Inhalation, and Intraarticular routes
• Topical includes application to the eye, skin, nose, and lung for systemic or local effects.