PHARM

• Pharmacodynamics


  what the drug does to the body
• Pharmacokinetics


  what the body does to the drug
• Pharmacokinetics A.D.M.E

  A-absorption (How does it get in)

  D-distribution (Where does it go)

  M-metabolism (How is it broken down)

  E-excretion (How does it leave)
• Potency


  the strength of something such as a drug or alcoholic beverage.
• Efficacy


  the ability to produce a desired or intended result
• Potency vs Efficacy

  potency: amount of drug necessary to produce desired effect

  efficacy: ability of drug to achieve desired effect
• Drug selectivity


  a drug is selective if it affects only one type of cell or tissue and produces a specific physiologic response
• Adverse side effects

  Harmful or undesirable effect of a medication or intervention
• Concentration response


  Relationship exists between the concentration of a drug at its site of action and its therapeutic or toxic effects.

  
  

  Just because a drug is in the system doesn't mean it's enough to be therapeutic-- drug level needs to reach a certain concentration to be therapeutic
• dose response


  correlation between the amount of a drug given and its effects
• Drug half life


  the time required for the elimination process to reduce the concentration of the drug to 50% what it was at initial administration
• Drug Agonist


  a drug that will bind to a receptor on a cell and trigger a response by the cell, generally mimicking the response or action of a naturally occurring substance
• Drug Antagonist


  a drug that blocks another drug from combining with a receptor
• Therapeutic Index


  A ration of the blood concentration at which a drug causes death (in animal) or toxicity (human) to the amount that causes a therapeutic effect.
• Question


  Answer
• Drug Absorption


  process by which a drug moves from its site of administration to the systemic circulation.
• Explain what it means that the body is compartmentalised

  drugs need to cross lipid membrane to move from one compartment

  to another compartment
• Transcellular

  Move across a cell

  - lipophilic

  - passic diffusion/facilitation diffusion/active
• Paracellular


  Through tight junction

  - low molecular weight and hydrophilic
• Administration routes

  Oral and Intravenous (veins)
• Factors affecting oral absorption

  i and ii and iii

  i- Molecular Size

  >oral absorption decreases as molecular weight ‚Üë

  ii- Solubility

  >hydrophilicity and lipophilicity affect passive diffusion at membranes

  iii- Ionisation
• Two ways to estimate drug solubility

  LogP - partition coefficient

  Polar surface area and topological psa
• LogP

  Two layer solvents - organic and water then add drug and mix then allow layers to equilibrate. Then you measure drug concentration in both layers.

  If more in solvent then lipophilic/ if more in water then hydrophilic
• logP Values of oral drugs

  less than 5
• Prodrugs


  medications that turn into an active form once they enter the body.
• PSA

  Polar surface area

  sum of surface of polar atoms (N/O) in a molecule and attached to H
• PSA predict

  Intestinal absorption and blood-brain barrier crossing
• Topological PSA

  Calc the sum of tabulated surface contributions of polar fragments (computational method)
• Factor affect oral - ionisation and pH dependant ionisation


  many drugs classified as weak acids and based

  
  

  pH-dependent ionisation of functional groups

  - pKa is the pH at which drug molecules are 50% ionised

  - only unionised drug molecules can diffuse passively across lipid membranes
• Lipinski rule (not really important)


  < 5 H-bond donors (-OH and -NH)

  < 10 H-bond acceptors (-O and -N)

  molecular weight < 500

  the calculated logP < 5
• Biological factors that affect oral absorption

  o pH

  o ingested food

  o gut mobility

  o intestinal enzymes

  o transporters
• Early detection of aspirin overdose treated with activated charcoal to decrease aspirin absorption. Why?

  Charcoal has pores that allow drug molecules to be attached to activated charcoal. AC is not absorbed and will be excreted or removed through faeces -> decreasing absorption of aspirin
• Transporters in

  Intestine (absorb)

  Liver (metabolise)

  Kidney (excretion)

  or

  Organs with barrier function

  - brain - placenta
• Placenta transporters


  protect fetus or developing embryo from harmful symbiotic like alcohol
• MDR1

  (multidrug resistance protein 1) or P-gp (P-glycoprotein)
• MRP2


  (multidrug resistance-associated protein 2)
• BCRP


  (breast cancer resistance protein)
• 3 types of ATP binding cassette transporters

  MDR1

  MRP2

  BCRP
• In Vitro predict oral absorption with which cells

  Caco-2 cells
• Caco-2 Cells


  * og derived from a human colon adenocarcinoma

  * an in vitro system to predict intestinal permeability and efflux liability

  - grow as a monolayer and differentiate on reaching confluence into intestinal epithelial cells

  - express multiple key drug transporters, including MDR1, BCRP and MRP2