Pharmacodynamics

PH3110 Unit 4

What graph can show the Michealis Menten theory of PD?

non Log Concentration vs Effect

What is the Emax?

The maximum concentration that will show no more effect

Why isn’t PD dependant on time?

Because the effect would be the same if it was in absorption phase or elimination phase

Why do we measure drug concentration in blood and not tissue?

• invasive

• concentration in blood is proportional to concentration in tissue

Why aren’t blood concentrations measured in multiple active species?

Because if blood concentration is measured, there will be a high concentration of prodrug which means less active species that determines a lower effect.

Why aren’t blood concentrations measured for single dose therapies?

Because after dose is administered, homeostasis takes over

Why is methotrexate dosed weekly?

To shut down DNA synthesis in rapid dividing cells and not normal cells

Why aren’t blood concentrations taken for drugs that are dosed weekly?

Because the concentration and effect relationship is broken

Why aren’t blood concentrations taken for drugs that enforce tolerance?

because the same concentration in the blood can produce a different effect over time

What is acute tolerance?

a rapid decrease in response after repeated exposure in a short time

Give an example of where frequent dosing causes tolerance?

Nicotine that is dosed frequently has a larger peak concentration. The body counteracts by desensitising receptors so has less effect.

Give an example of where fast administration causes tolerance?

Fast of Nifedipine can cause a quick rise to steady state, causing an increase in heart rate but little change in blood pressure because the body is responding fast to the drop in blood pressure (homeostasis)

Give an example of undesirable tolerance?

Nitroglycerin 24 hour patch causes tolerance to patients need to remove it overnight

Give an example of beneficial tolerance

Protriptyline at the start causes side effects but has a therapeutic effect after weeks so start at low dose and titrate

What is the difference in drug concentration between well perfused and poorly perfused tissues?

Well perfused tissues will rise in drug concentration at a similar rate to blood. Poorly perfused tissues will have a slower rise in drug concentration but will end up having a higher concentration of drug

Why are obese patients difficult to wake after anaesthesia?

because they are lipophilic drugs that deposit in fat as it acts as a reservoir.

What does it mean when a drug is perfusion rate limited?

The drug will be absorbed as fast as it can get into tissue.

What does it mean when a drug is permeability rate limited?

The drug will be absorbed as fast as it can cross the membrane/ barrier

What is hysteresis?

When there is a delay in the effect from the concentration, causing a loop when plotted on a conc - effect graph

What is counter-clockwise hysteresis?

during absorption, the concentration rises fast but the effect is catching up so there is a lower effect than expected.

during elimination, the concentration drops but the effect is catching up so there is a higher effect than expected

How does distribution half life link to equilibrium?

One half life will equal 50% equilibrium. The lower the half life, fast equilibrium is reached

What factors affect equilibrium? Which controls the speed of distribution and which controls the extent of distribution?

1. blood flow - speed

2. tissue affinity (Kp) - extent

What state of blood flow allows faster equilibrium?

High blood flow

What Kp value allows more distribution?

A lower Kp means the drug has less affinity for the tissue so will leave.

What would be the outcome if the same drug was given to target different tissues?

The drugs would have the same affinity so would reach the same concentration but because the tissues have different blood flow, it may take different times to reach equilibrium.

What would be the outcome if two different drugs were given to the same target tissue?

The drugs will have different affinities for the tissue but the same blood flow so they will have different equilibrium constants and will reach these at different times.

What are the worst conditions for drug distribution?

Poor perfusion and high drug affinity

What plasma protein do acidic drugs bind to?

Albumin

What plasma protein do basic drugs bind to?

Glycoproteins

What plasma proteins do lipophilic drugs bind to?

Lipoproteins

What do ionised drugs bind to in tissue?

Phospholipids

What do unionised drugs bind to in tissue?

Adipose tissue

What does gamma represent in the sigmoid Emax model?

Steepness of gradient

What does low gamma indicate in terms of dose?

Gradual curve so a large dose change is needed for a small effect

What does high gamma indicate in terms of dose?

steep curve so a small dose change causes a large effect