Pharmokinetics Flashcards
What would make the perfect drug?`
Stable form amenable to introduction into the body.
Pass into the body.
Reach its biological target.
Remain in the body long enough to achieve its therapeutic end.
Not produce harm while in the body.
Exit the body when its job is done.
What are the most important physical properties of a drugs with regards to absorption distribution, potency, and elimination?
Lipophicilty and Hydrophicility
What does a lipophilic drug mean?
be insoluble in aqueous media.
bind too strongly to plasma proteins.
distribute into lipid bilayers.
What does a hydrophilic drug mean?
inability to cross plasma membrane.
What does LogP do?
measure lipophilic/hydrophilic nature of a molecule
What is the equation for LogP?
Log ( [B]OCT / [B] water )
What class has high permeability and high solubility?
Class 1
ampiphilic
What class has low solubility but high permeability?
Class 2
lipophilic
What class has low permeability but high solubility?
Class 3
hydrophilic
How does ionisiation affect diffusion through a membrane?
un-ionised molecules pass through membrane
What is the Henderson-Hasselbalch equation?
pH = pKa + log10 ( [ionised form] / [non-ionised form] )
pKa = pH at which equal amounts of ionised and non-ionised forms exist
What is pH trapping?
Changes in pH result in ionisation of a molecule so it cannot pass back through the membrane
How does adding sodium bicarbonate affect pH trapping?
Changes pH of departments so ionised form combines with non-ionised form and moves back through the membrane
What is enteral administration?
Oral
Sublingual
Rectal
Inhalation
What is Topical administration?
Application to other epithelial surfaces
i.e. skin, cornea, vagina, nasal mucosa
What is parenteral administration?
Injection
subcutaneous intramuscular intravenous intrathecal
What affects the speed at which a drug is absorbed if it is taken orally?
GI motility
Splanchnic blood flow
Formulation of medicine
Physiochemical properties of drugs.
What is bioavailabilty?
Bioavailability (F) is the fraction of administered dose that reaches the systemic circulation.
Bioavailability does not represent the amount of drug reaching the molecular target!
Thinking of oral administration, incomplete bioavailability can arise from?
Incomplete absorption and loss in faeces.
1st pass metabolism.
What is the equation for total body H2O?
0.6 x body weight
What is volume of distribution?
volume of fluid required to contain the total amount of drug in the body (D) at the same concentration as that present in the plasma (Cp)
Vd = D/Cp
measured in Litres
Cannot be smaller than volume of intravascular plasma (3L ish)
Often Vd is normalised to body weight; the unit is then L/kg.
What are the factors of drug distribution?
- physiochemical factors:
size of drug molecule (larger molecules do not cross membranes well e.g. heparin)
pKa of drug (pH difference between plasma and tissue can lead to accumulation)
- Pharmacological properties of the drug
E.g. binding of molecule to particular plasma or tissue proteins that might allow specific uptake into tissue
- Blood flow in the organ/tissue
- Barriers of organ/tissue
What happens during phase 1 of metabolism?
What sort of reactions occur?
Changes drug into derivative by altering its structure via:
oxidation
hydrolisis
reduction
Which of the cytochrome P450 family are related to drug metabolism?
CYP1-4
What happens during phase 2 of metabolism?
Reactions involve the formation of a covalent bond.
Results in a H2O soluble conjugate (excretion).
Products of Phase 2 metabolism are predominantly INACTIVE, however in some cases activity is retained.
What is 1st pass metabolism?
Metabolism begins before drugs reach general circulation:
Liver
Lung
Intestinal lumen
Intestinal wall
Why is the metabolism of codeine different?
increases its activity
Why does grapefruit juice affect the metabolism of drugs?
contains furanocoumarins which inhibit CYP3A4 and CYP1A2 reducing the first pass effect of drugs metabolised by these in gut wall
so can lead to increased plasma levels which can be dangerous for drugs with low therapeutic index
What are poor metabolisers defficient in?
People deficient in CYP2D6, called “poor metabolisers”, have inherited a non-functional gene from each parent, and have no CYP2D6 activity.
What are intermediate metabolisers?
“Intermediate metabolisers” have inherited one non-functional gene; they have some CYP2D6 activity, but it is lower than normal.
What are Ultra-rapid metabolisers?
There are some people who have higher than normal CYP2D6 activity, and they are called “ultra-rapid metabolisers”.
What are extensive metabolisers?
Most people have at least one functional gene, and they have normal CYP2D6 activity.
What are the different routes of excretion?
fluids
solids
gases
Which method of excretion is important for low MW polar compounds?
fluids
Which method of excretion is important for high MW compounds?
solids
Which method of excretion is important for volatile compounds?
gases
What is the equation for total renal excretion?
glomerular filtrate + tubular secretion - reabsorption
Which drugs enter the bile duct?
drugs with gluronic acid
because they are too polar and remain in the gut
What could a zero order elimination kinetic imply about a drug?
toxic
