Drug Distribution Flashcards
How do drugs move across the epithelium/endothelium?
Paracellular
Transcellular = pinocytosis, active transport and diffusion
Which barrier is more permeable for metabolism of substances?
Liver endothelium
Which barrier is more permeable for substances to be eliminated?
Renal endothelium in the glomerulus
Which barrier is less permeable to protect sensitive organs?
Blood-Brain barrier, to protect sensitive organs from circulating chemicals or pathogens.
What is pKa?
The hydrogen ion concentration (pH) at which:
50% of the drug is ionised
50% is un-ionised
What is the solubility of Unionised drugs?
They are lipid soluble, so diffuse across the membrane.
What are plasma proteins?
Plasma proteins are major transporters of endogenous lipids and steroid hormones.
What is protein binding?
In the blood, drugs can bind to plasma proteins. Drugs can exist in bound and unbound forms, this is a reversible reaction.
What is the importance of protein binding?
Some proteins are too large to pass through epithelia/endothelial
Only free drugs can bind their site of action (receptors/enzymes)
What are the implications on bound proteins?
They remain in the blood
Unable to exert their pharmacological effect
Cannot be metabolised or excreted
Becomes ‘stored in reservoirs’ and can impact volume of distribution
Which drug type can reach equilibrium across different compartments?
Unbound drugs can reach an equilibrium across different compartments.
Bound drugs can’t.
Which proteins can act as a reservoir?
Bound proteins.
What effect does protein binding have on a drug’s half life?
Heavily protein Bound drugs have a longer half life.
What factors affect protein binding?
drug factors
Affinity of drug to protein binding sites
Drug concentration
Plasma protein concentration
Which protein plasma is the most important for drug binding?
Albumin
What is the solubility of ionised drugs?
They are Insoluble so don’t diffuse across the membrane.
Why is there a change in the curve when a drug is given at a higher dose?
Plasma proteins become saturated.
Most drugs are given at doses that wouldn’t cause plasma proteins saturation
Where is tissue binding?
Fat
Bone
Muscle
Which drug can travel more easily across a cell membrane?
Highly lipophilic drugs
How do bisphosphonates work?
By binding to calcium in bones and inhibits resorption.
How is osteoporosis caused?
By increased resorption which causes thinning of the bones, increasing the risk of fractures.
What are two examples of bisphosphonates?
Alendronic acid - via tablet once a week
Zoledronic acid - via injection once a year
Where do highly lipophilic drugs bind?
To fat stores
Why would a drug wear off more quickly in an overweight patient?
Overweight patients have a greater ratio of lipid to other body tissue.
Calculating a dose according to weight doesn’t take this into account in the ratio.
Drugs that are highly lipid bound will distribute more freely in overweight patients than underweight patients .
What is the Volume of distribution?
definition
The apparent volume into which a drug disperses in order to produce the observed plasma concentration.
What is the equation for volume of distribution?
Vd= the total amount of drug in the body (g) / plasma concentration of the drug (g/L)
What is the extent of distribution of a drug throughout the body?
Plasma
Interstitial fluid
Intracellular fluid
Fat
What happens if a drug remains in the plasma?
Volume of drug distribution will be low
Drug dose can be low
What happens if a drug disperses to other fluids/tissues?
Volume of distribution will be high
Drug dose need needs to be high
What drug factors affect volume of distribution?
Plasma protein binding
Tissue binding
Physiochemical properties of drug: size, charge, pKa, lipid solubility, water solubility
What are patient factors that affect volume of distribution?
Age, sex, level of hydration, body muscle/ fat proportion
Water distribution
Why is volume of distribution useful?
It’s a guide for loading (initial) doses of drugs.
Volume of distribution of drugs, give examples of high and low values:
Heparin = 5L Gentamicin = 18L Chloroquine = 13,000L
