Advanced pharmacology concepts

PHARMACODYNAMICS (how a drug exerts it effect on the body)

Dose-response

• With increasing dose of an agonist, the response increase until it reaches a maximum
• In the presence of an antagonist, higher does of agonist are required to achieve the same effect

Therapeutic (Effective), Toxic, Lethal dose

• For a population, the dose required to achieve a therapeutic effect can vary considerably (in a normal distribution)
• Similarly, the toxic and lethal doses varies
• ED50, TD50, LD50 represents the dose at which 50% of the population obtains an effective, toxic or lethal effect respectively
• If the dose range for a therapeutic and toxic dose overlaps significantly, the drug has a narrow therapeutic index (TI)
• Drugs with a low TI may need regular monitoring of levels to prevent toxicity
  
  * EC50 versus ED50: EC50 is the dose required for an individual to experience 50% of the maximum effect. ED50 is the dose for 50% of the population to obtain the therapeutic effect.

Antagonism

• Pharmacodynamic antagonism (via the receptor) e.g. Heroin (agonist) and Naloxone (antagonist) compete for the opiate receptor
• Physiologic antagonism (via two different physiological system) e.g. Glucagon (stimulates the heart) and Beta blockers (depress the heart) via different receptors
• Chemical antagonism (by binding the drug before it reached the receptor) e.g. Digoxin Fab Fragments

Other pharmacodynamic concepts

Hypereffective

• Individuals who exhibit exaggerated effect to an average dose

Hypo-effective

• Individuals who exhibit a reduced effect to an average dose

Down-regulation (and tolerance)

• The impact of chronic stimulation of a receptor by an agonist e.g. heroin
• Reduced population of receptors on the cell
• Results in higher dose of drug required over time to maintain equivalent effect (related to the clinical observation of 'tolerance'

Up-regulation (and rebound effect)

• The impact of chronic blockade of a receptor by an antagonist
• Increased population of available receptors on the cell
• Results in lower dose of agonist to produce equivalent effect
• Results in observation of 'rebound phenomenon' with an opposite exaggerated effect e.g. acute hypertension after ceasing beta blockers

Tachyphylaxis

• The clinical observation that some drugs rapidly loses their effectiveness over time
• Requires increasing dose to maintain effect
• Due to exhaustion of secondary messenger or metabolic pathways

PHARMACODYNAMICS (what happens to the drug after it is administered)

Other important concepts

First pass metabolism

• Drugs administered orally will then enter the portal circulation where they pass through the liver before reaching the systemic circulation
• This reduces the bioavailablity (see below) of the drug

Enzyme induction

• Drug metabolised by the liver may result in an increase of those specific metabolic enzymes over time.
• May require an increase in dose of that drug or other drugs use that metabolic pathway.

Enzyme inhibition

• Drugs metabolised by the liver can occupy specific metabolic pathways that prevent other drugs from using that pathway (a form of competitive antagonism).
• Dose reduction of other drugs may be required.

Phase I reaction

• A metabolic pathway that usually inactivates a drug

Phase II reaction

• A metabolic pathway that binds (conjugates) the drug so it becomes more water soluble so it can be excreted by the kidney

1st order kinetics (typical)

• The observation that drug levels fall in exponential fashion i.e. high drug levels fall faster than low drug levels

Zero order kinetics (sometimes)

Multi-compartmental model

• Recognises that different tissues in the body have different sizes, lipid composition and blood flow.
• Affects how rapidly or extensively drugs move into each of these compartments
• Results in plasma levels changing in a complex pattern

Drug barriers

• Certain tissues in the body are relatively resistant to the entry of many drugs
• Examples - Blood-brain, blood-testis, blood-placenta
• But may allow passage if the barrier is damaged or diseased

Some important terms

• Bioavailability = proportion of drug that enters the systemic circulation if it is not administered directly into the circulation
• Protein binding = proportion of drug that remain bound to plasma proteins (and therefore unable to exerts its effect)
• Volume of distribution = the apparent body water volume based on its final plasma concentration and drug administred
• Clearance = the amount of blood that is removed of drug per unit time. Combines the effects of metabolism and excretion
• Half life = the time it takes for plasma drug levels to halve its concentration (see first order kinetics)

Drug interactions - a summary

• Antagonism
• Enzyme induction
• Enzyme inhibition
• Synergism (combined effects of similarly acting drugs)
• Washout (residual effects of ceased drug affects new drug)

Dosing schedules are based on combination of

• Drug half life
• Therapeutic window
• Clinical duration of action

Maintenance dose

• Dose and frequency required to maintain target steady state plasma concentration
• Usually takes 5 half lives after commencing maintenance dose before target concentration is reached
• Is affected by rate of metabolism and excetion of a drug

Loading dose

• Dose required to immediately bring plasma concentration to target level
• Only required if rapid clinical effect is desired
• Is affected by volume of distribution of drug