4 - Pharmacokinetics Flashcards
What does ADME stand for?
Absorption
Distribution
Metabolism
Excretion
What methods of drug administration are there?
Oral - ingestion, inhalation, (buccal [cheek], sublingual [tongue]) Dermal Subcutaneous Intramuscular Intraperitoneal Intravenous
A depot injection is an injection, usually subcutaneous, intradermal, or intramuscular, that deposits a drug in a localized mass, called a depot, from which it is gradually absorbed by surrounding tissue. Such injection allows the active compound to be released in a consistent way over a long period.
What determines the method of administration?
Whether the desired effect is systemic or local.
The route of administration is a critical determinant of the onset, duration, intensity and degree of localisation of drug action.
What do enteral and parenteral mean?
Enteral means via the GI tract - sublingual, buccal, oral, rectal
Parenteral means all other methods - intravenous, intramuscular (DEPOT THERAPY), subcutaneous, percutaneous, inhalation
What are the two main ways drugs move around the body?
- Bulk flow transfer i.e. bloodstream
2. Diffusional transfer i.e. short distance
Drugs cross both liquid and aqueous environments. Where are these environments found?
Liquid compartments - blood, lymph, EC/IC fluid
Lipid barriers - cell membranes
How do drugs cross barriers?
- Passive diffusion (lipid soluble) - pH PARTITION HYPOTHESIS
- Across aqueous pores/facilitated diffusion (least common as pores and therefore drug must be very small <0.5nm)
- Carrier proteins/active transport (water soluble)
- Pinocytosis (rare) - via liposomes
- Filtration (small water soluble molecules)
- Paracellular transport (around cells, often overlooked).
How many membranes does the average membrane have to cross in the body?
3, if orally ingested and the target is on the cell surface.
From the small intestine - capillary wall (in) - capillary wall (out) to EC fluid - drug target
What are most drugs which affects their ability to travel freely?
Either weak acids or bases which are either ionised or unionised depending on the local pH.
What is aspirin at physiological pH?
Weak acid
What is morphine at physiological pH?
Weak base
What is pKa?
The dissociation constant
N.B. It is CONSTANT, only pH and concentrations change.
Apply the pH partition hypothesis/Henderson-Hasselbalch equation to a weak base.
10^(pKa-pH) = [BH+]/[B]
Apply the pH partition hypothesis/Henderson-Hasselbalch equation to a weak acid.
10^(pKa-pH) = [AH]/[A-]
What is ‘ion trapping’?
Drugs can get localised within certain compartments. This changes the proportion of drug that will reach the target.
e.g. Aspirin diffuses easily out of the GI tract but it is more difficult for it to diffuse out of the blood
Give an example where ‘ion trapping’ trapping can be manipulated
Treatment with IV sodium carbonate increases the pH of urine and ionises a greater proportion of aspirin. This increases the rate of excretion. This is a common method used for acidic drugs e.g. overdose.
What factors influence drug distribution?
- Regional blood flow
- Extracellular binding (plasma proteins)
- Capillary permeability (tissue alterations - renal, hepatic, brain/CNS, placental)
- Localisation in tissues
What is the distribution of blood to different organs?
At rest: Liver 27% Kidneys 22% Brain 14% Heart 4%
Muscle 20% (during exercise)
What are the clinical implications of plasma protein binding?
If plasma protein bound, the drug cannot leave the bloodstream, reducing the amount which can reach the target e.g. warfarin 90%, aspirin 50-80%. This is especially a problem with acidic drugs.
In addition, if drugs are coadministered, they can displace each other from plasma proteins which can increase the amount reaching the target.
What are the types of capillary permeability?
Continuous - H20 gap filled junctions
Blood brain barrier - Tight junction
Fenestrated
Discontinuous
What are the clinical implications of tissue localisation for drug distribution?
If drugs are very fat soluble e.g. general anaesthetics
75% may be partitioned in adipose tissue and can be subsequently released.
What are the two major routes of drug excretion?
- The kidney
- The liver - via concentration into bile (v. large molecular weight conjugates)
+ Lungs – excreted via expired air, passive diffusion of volatile compounds
Other routes (usually of little quantitative importance) = gastrointestinal secretions, saliva, sweat, milk, genital secretions, integument.
Outline the process of drug excretion at the kidneys
20% of the blood is ultrafiltrated at the glomerulus, 80% passes by.
Only low molecular weight drugs can pass through here.
At the kidney and proximal tubules, basic and acidic drugs are actively secreted into the lumen dependent on available transporters.
Lipid soluble drugs will return to the bloodstream at the distal convoluted tubule and collecting duct.
N.B. This is why the goal of metabolism is to make drugs more water soluble.
Outline the process of drug excretion in the liver
There is a discontinuous structure in the liver, allows easy access to hepatocytes.
However water soluble metabolite produced by hepatocytes cannot get into the bile duct from the blood, requires an active transport system.
What is the ‘enterohepatic cycling’?
The water soluble metabolite is excreted via the bile into the gut where gut bacteria breaks down the conjugate, refreeing the free drug (cleaving the glucuronide conjugate).
The free drug is lipid soluble again and is reabsorbed into the intestinal capillaries and transported back to the liver via the hepatic portal vein.
At the liver the drug can also return to the systemic circulation.
This is known as ‘drug persistence’.
What can you predict?
The time course of drug action
What is bioavailability? (linked to absorption)
The proportion of administered drug that is available within the body to exert its pharmacological effect.
Measured via areas under concentration versus time curves.
What is ‘apparent volume of distribution’? (linked to distribution)
The volume in which a drug appears to be distributed e.g. fat soluble drugs can occupy a larger apparent volume as they can also enter adipose tissue - an indicator of the pattern of drug distribution
What is ‘biological half-life’? (linked to metabolism/excretion)
Time taken for the drug concentration to half (in blood).
What is ‘plasma clearance’? (linked to excretion)
The volume of blood (plasma) cleared of a drug in a unit time. Sum of total processes if more than one.
What is the therapeutic window?
The range of doses which can treat a disease effectively without having toxic effects.
What is first-pass metabolism?
A phenomenon of drug metabolism whereby the concentration of a drug, specifically when administered orally, is greatly reduced before it reaches the systemic circulation. Mostly due to the liver and the gut wall.
Mrs. Beryl is a 57-year-old with chronic hypertension and takes oral propranolol twice daily. Doctors recently found that her liver function tests have declined so immediately reduced the dosage of her medication. Which of the following is the best explanation for why her dosage was altered?
- Propranolol causes cirrhosis of the liver over time
- Absorption of propranolol increases in patients with liver failure
- Liver failure reduces first pass metabolism of propranolol
- Excretion of propranolol decreases in patients with liver failure
- The distribution of propranolol changes in patients with liver failure
- Liver failure reduces first pass metabolism of propranolol
What is depot therapy?
A depot injection is an injection, usually subcutaneous, intradermal, or intramuscular, that deposits a drug in a localized mass, called a depot, from which it is gradually absorbed by surrounding tissue. Such injection allows the active compound to be released in a consistent way over a long period.
Could the selective uptake of drugs into the lymphatic
system be used to any therapeutic advantage and, if so,
how could this be achieved?
The lymphatic route is able to avoid first-pass metabolism, thus acting as a bypass route for compounds with lower bioavailability, ie, those undergoing more hepatic metabolism.
The lymphatic route also provides an option for the delivery of therapeutic molecules, such as drugs to treat cancer and human immunodeficiency virus, which can travel through the lymphatic system.
How would it be achieved?
To what therapeutic advantage could enterohepatic cycling be put?
Increasing drug persistence and duration of action
Lower doses of drugs can be therapeutically effective because elimination is reduced by the ‘recycling’ of the drug.
N.B. For a small number of drugs that are very toxic to the intestine (e.g. irinotecan), these molecules which would not otherwise be very toxic can become so because of this process, and therefore inhibition of this step can be protective.
