MSE-3022 L1 Intro

Introduction to MSC 3,022: Pharmacology and Drug Development



Key Terminologies in Pharmacology

  • Pharmacokinetics (PK):

    • Definition: how the body affects a drug, including absorption, distribution, metabolism, and excretion (ADME).

  • Pharmacodynamics (PD):

    • Definition: how a drug affects the body, delving into interactions that induce biological effects.


5 reasons for medications

  • Treatment

  • prevention

  • alleviate symptoms

  • help deficiencies

  • disease modyfying agents (target immune system)


5 Pharmacodynamic actions

  • Action on receptors (agonist & antagonists)

    • Agonist - fully binds to receptor, turns it on. triggers response from cell

    • Partial agonist - slightly turns it on.

    • Antagonist - inhibits or prevents agonists binding to receptor.

  • Actions on enzymes

    • Speeds up reactions

    • Enzyme inhibitors drugs - effects specific enzyme pathway using paticular enzymes (e.g. NSAIDs block cyclo-oxygenase. Ibuprofen - COX 1 & 2, Celecoxib - COX 2)

  • Action on membrane ionic channels

    • Interfere with ion movement (charged atoms) across cell membranes (e.g. calcium channel blockers to lower heart rate if its too high, smooth muscle relaxes)

  • non-specific drug action (physiochemical)

    • not exactly receptor action

    • antacids (neutrilise stomach pH

    • Astringent (rectally to reduce haemorrhoids)

    • Osmotic laxatives (draw water into bowel from bloodstream)

    • Emollients (topical), moisturise skin by reducing water loss

  • Immune therapies (biologics)

    • New. Probably the future.

    • Develops monoclonal anitbodies by targeting cytokines and immune system cells

    • E.G. infliximab → TNF-a (tumor necrosis factor alpha protien secreted as in immune response) causes inflamation to fight infection. overproduction = chronic ongoing inflammation → crohns disease. Biologics bind to TNF-a.


Receptor pathway

  • Free agonist → receptor binding (changes structure) → signal transduction → secondary messenger → Signal amplification → Biological effect.

  • Can combine antibiotics with transport inhibitors to make sure the antibiotic stays in the bacteria


Types of receptors (goes in to more detail in other lecures?)

  • G-protein-coupled receptors (GPCR) (e.g. dopamine & serotonin receptors)

  • Channel-linked receptors (e.g. nicotinic acetylcholine recepor)

  • Kinase-linked receptors (e.g. insulin receptors)

  • DNA-linked receptors (e.g. steroid receptors)

  • Voltage-sensitive ion channels (e.g. Na+ channels blocked by anaestheticis such as lidocaine)

  • Enzymes (e.g. Cyclo-oxygenase inhibited by aspirin)

  • Transporter proteins (e.g. Serotonin reuptake transporter inhibited by fluoxetine).


Drug doses

  • High potency = lower dosage

  • Therapeutic window = window over which you can give different concentrations of a drug and they will be effective without causing toxicity (difference bwteen mid point of the drug effect curve and the adverse effect curve).

  • some drugs given orally over IV because toxic concentration can be hard to control

Pharmacokinetics Concepts Explained

  • ADME (Absorption, Distribution, Metabolism, Excretion):

    • Absorption: How drugs enter the bloodstream. (e.g. oral, IV, dermally)

    • Distribution: Volume of distribution which indicates how the drug spreads across different tissues. (important for different drugs that may prefer fats or water)

    • Metabolism: Transformation of the drug via enzymes (primarily CYP450 enzymes).

    • Excretion: Removal of drug metabolites, primarily through the kidneys.


ADME pathway example

  • medicine taken orally passes into GI system

  • Leaves GI via blood system, goes into liver via hepatic portal,

  • then the right side of the heart, then to lungs, back to left side of heart

  • Distrubuted across body

  • eventually metabolised by the liver, becoming more polar

  • Filtered by kidneys (not all drugs e.g. iron tablets not excreted by kidneys)

  • Excreted


absorption graphs

  • Tmax = time it takes to get to Cmax

  • Half life of the drug = amount of time it takes for the concentration of the drug to reduce by 50% in the body (starting fro Cmax)

  • AUC (area under curve) - total exposure to drug that the body recieves

  • Therapeutic range = between minimum toxic conc. (MTC) and minimum effective conc. (MEC)

  • We measure absorption via plasma conc.


Bioavailability

  • how much of the drug is ultimatly abosorbed/ used by the body

  • some drug lost during absorption process

  • Bioavailability of IV administered is assumed to be 100%

  • varies between patients

  • factors: time in GI tract, formulation of drug (modified release)


Drug distribution

  • extracellular fluid (fatty tissue)

  • intracellular fluid

  • CSF

  • foetus

  • synovial fluid

  • portion will always be bound to protiens (e.g. plasma). albumin is key binding protein

  • bound = no biological effect

  • binding depends on chemical properties and patient characteristics (e.g. elderly patients & liver disease = less albumin)

Volume of distribution

  • Total amount of drug in the body (dose given)/the conc. of drug in the plasma at a given time

  • higher Vd = more drug moved from plasma into tissues

  • useful to calculate doses required

Metabolism

  • drug is chemically altered in the body by liver

  • family of 300 cytochrome enzymes

  • made more hydrophilic as pass through liver (better watter affinity = easier for kidneys to filter)

  • drug converted to metabolite via many rounds in the liver, become less active

  • some drugs (e.g. aspirin, or codine → morphine) taken in inactive form, become active once metabolised (prodrug)

Metabolism phases

  • phase 1

    • oxidation, reduction, hydrolysis, hydroxylation

    • conversion into more polar inactive compounds

    • mostly by cytochrome P450 (varies in patients)

  • Phase 2

    • Conjugation

    • enzymes involed with coupling drugs with another molecule (e.g. UDP-GT) to make more water soluble, good for kidney excretion

  • system can become saturated (Vmax) (e.g. alcohol), so takes long time to metabolise (hangover) - goes from first order of kinetics to zero order (half life becomes inconsistant) - more easy to overdose. only able to metabolise about 10g alcohol/hour

Excretion

  • eliminated from body without further chemical change

  • Renal - glomerular filtration, proximal tubule (active secretion) & distal tubule (passive re-absorption)

  • clearance rates calculated using conc. of drug in plasma, conc. in urine and volume of urine being produced

Conclusion and Final Remarks

  • steady state - time taken to achieve steady blood of the drug, balance of absorption and elimination is reached (approx 5 half lives)