Lecture 35 - Pharmacokinetics 2 Flashcards
What type of drug is aspirin?
NSAID
Non-steroidal anti-inflammatory drug
Describe the function of aspirin in the body
- Binds covalently to COX –> inhibiting it
2. Prostoglandin synthesis halted
What are the effects of aspiring at the different doses?
50mg / day: blood thinner
350 mg / 4 hours: anti-inflammatory, analgesic
Describe the function of aspirin at low doses
- Acetylates COX in platelets
2. Platelets can no longer aggregate
What does COX normally do in platelets?
Makes a product that allows platelets to aggregate
Why can’t COX be replaced in platelets?
Platelets are proper cells, and they can’t make protein
All of an absorbed drug is subject to … on the way into the body
Hepatic metabolism
What does the liver do to drugs?
Inactivation
Activation
Increase solubility
What are the types of reactions performed by the liver on drugs?
Phase I:
- modifying functional groups
- CYPs: Cytochrome P450
Phase II:
- conjugation (attachment of sugars)
- increases water solubility
How are drugs excreted from the body?
Mainly kidney
Also can be secreted into bile
What is the functional unit of the kidney?
Describe its function
The nephron
Glomerulus Bowman's capsule PCT Loop of Henle DCT Collecting Duct Vasa recta Afferent and efferent arterioles
Which processes are taking place in the nephron?
Filtration
Secretion
Reabsorption
Describe the generalised process of filtration
Most stuff in the glomerular blood is pushed out through the fenestrated capillaries into the Bowman’s capsule
Which structures maintain the integrity and function of the glomerular tuft?
Podocytes
- Hold the membrane
- Make it like a collander
What is the main driving force for filtration?
Pressure
High pressure in the glomerulus, low pressure in the Bowman’s capsule
How much blood is filtered per day?
180 L
What is normal blood volume in the body?
5 L
Which molecules are filtered out of the blood?
Ions
Sugar
Water
Amino acids
What doesn’t get filtered?
Proteins
What percentage of the blood is filtered?
15-20%
Describe how structure relates to function in the PCT
Great SA: reabsorption
Mitochondria: active transport
How is stuff secreted into the nascent urine
Through transporters:
OCT: organic cation transporter
OAT: organic anion transporter
What is competition of secretion?
What is an example of this?
Penicillin and Probenecid
Two drugs might use the same transporter to be secreted into the nascent urine.
If both these drugs are present in the blood at the same time, they will compete for this receptor, and thus will have a longer half life in the body
Which molecules are actively reabsorbed by the nephron?
Glucose
Which molecules are passively reabsorbed by the kidney?
Lipid soluble molecules
How is aspiring overdose treated?
Forced alkaline diuresis
Bicarb + water
Aspiring trapped in the urine, will not be reabsorbed, because it is now charged.
Lots of urine will be made
Which processes in the kidney are saturable, which aren’t?
Filtration: non-saturable
Reabsorption:
- acitve: saturable
- passive: non-saturable
Secretion: saturable
Filtration is non-saturable. What does this mean?
It means that the more of the drug in the blood, the greater the concentration in the urine
What is bioavailability?
How is it calculated?
The amount of drug that makes it to the circulation
Bio. = in blood / administered
What happens to drugs that aren’t very bioavailable?
- Destroyed in the GIT
- Insoluble
- Hepatic first pass metabolism
In what circumstances is a drug 100% bioavailable?
Intravenous injection
What factors affect bioavailability?
I/ Absorption
- transit time
- emptying time
II/ Destruction
- enzyme polymorphisms
- disease
- competition
- enzyme inhibitors
What happens to the size of the dose as bioavailability decreases?
Dose increases
What is volume of distribution?
The theoretical amount of blood with the given concentration of the drug, required to have the same amount of the drug in the blood as the plasma
How is Vd calculated?
Vd = amount in body / plasma concentration
In litres
What does it mean if a drug has a very high volume of distribution?
It is being sequestered out of the blood into other body compartments
What is the lowest theoretical Vd?
In what circumstances would this occur?
Around 5L
If all the drug was in the plasma
ie bound to a protein in the plasma
What factors influence Vd?
Protein binding
Access to body compartments
Lipid solubility
How is clearance calculated?
What is the unit?
Clearance = metabolism + excretion / plasma concentration
Litres / min
How is half life calculated?
Vd x Clearance
Unit is 1/min
What affects clearance?
Liver function Renal function - Polymorphisms - Disease - Competition - Enzyme inhibitors
What is half life?
The time it take for drug plasma concentration to fall by half
Drugs that obey first order pharmacokinetics have what sort of half life?
Fixed
What affects half life?
Clearance
Vd
