Pharmacokinetics 1 Flashcards
Pharmacokinetics
What the body does to the drug
State the 4 main processes of pharmacokinetics
(Liberation)
Absorption
Distribution
Metabolism
Excretion
Advantages of plasma used in transporting drugs
Easy convenient sampling pool, in which we can use to measure the amount of drug in the body
OR
A convenient way in which a drug is distributed in the body.
State some routes of drug administration
Oral
Sublingual
Inhalational
Topical
Transdermal
Intramuscular
Intravenous
Advantages and Disadvantages of the oral route
A: Convenient
D: First pass effect, many variables and barriers
Advantages and Disadvantages of the sublingual route
A: No first-pass effect
D: Inconvenient, small dose limit
Advantages and Disadvantages of the inhalational route
A: Fast, rapid delivery to blood
D: Requires special properties of drug (vaporised, atomised)
Advantages and Disadvantages of the topical route
A: Convenient, Localised
D: Only local
Advantages and Disadvantages of the transdermal route
A: Prolonged release
D: Skin very effective barrier
Advantages and Disadvantages of the intramuscular route
A: Rapid for aqueous, slow for oil
D: Painful, requires trained personnel
Advantages and Disadvantages of the intravenous route
A: Direct, total dose, rapid
D: Requires professional, infection risk, rapid response
First-pass effect
Any barrier between the drug being administered to your patient and it getting into the plasma.
Anything that metabolises/transforms/changes the drug due to the interaction of enzymes.
Bioavailability
The fraction of unchanged drug that reaches the systemic circulation.
Alun - bioavailability definition
How much of the administered dose you would expect to see get into the patients plasma.
IV injection bioavailability
100%
Bioavailability equation
(AUC oral / AUC IV) x 100%
State the 4 ways that small molecules can cross cell membranes
- Diffusing directly through the lipid
- Diffusing through aqueous pores
- Transmembrane carrier protein
- Pinocytosis
Feature of drug to : diffuse directly through the lipid
Drug should be:
- Uncharged
- Lipophilic enough
Feature of drug to : use a transmembrane carrier protein
Drug should be:
- Charged
- Hydrophilic
When is diffusion through aqueous pores used ?
More likely important for diffusion of gases.
Aqueous pores are VERY small.
When is pinocytosis used ?
Mostly macromolecules, not drugs.
(for larger molecules: proteins/peptides)
Describe hydrophilic drugs
Hydrophilic drugs are soluble in aqueous, polar media.
Cannot pass through the lipid bilayer
Describe lipophilic drugs
Lipophilic drugs are soluble in fats and non-polar solutions.
Describe polar media
Blood plasma
Cytosol
Interstitial fluid
Describe non-polar solutions
Interior of lipid bilayer and fat
Feature of drugs
Many drugs are weak acids or bases
- ionised:unionised ratio depends on pH
- ionised drugs have low lipid solubility
Gastric Acid pH
1-3
Large Intestine pH
8
Small intestine pH
5-6
Plasma pH
7.4
What drug properties affect absorption ?
Lipophilicity
Ionisation
When do barriers to absorption arise ?
Unless the drug is directly injected into systemic circulation.
Factors that affect distribution
Degree of drug ionisation
Lipid solubility
pH of compartments
Cardiac output and blood flow
Capillary permeability
Plasma protein binding
Compartment model - state some places drugs may go to
(from shortest to longest time)
Vessel Rich Group (VRG) - kidneys
Muscle
Adipose
Key feature of compartment model
Not all drugs will distribute evenly around the body
Some will go and accumulate in different locations.
The further away the drug gets from plasma and the more likely it is to accumulate in distant tissues, the harder it is to get rid of that drug from the body.
This is because the route out of the drug from the body is also via the plasma.
What are Bisphosphonates ?
Treatment given to reduce the burden of osteoporosis.
Work by killing off osteoclasts, (bone resorbing cells which degrade and remove bone from the body)
Mechanism of action of bisphosphonates
Phosphate groups have a high affinity for calcium, so the bisphosphonates will bind VERY strongly to bone where there is a high degree of calcium.
Key feature of bisphosphonates
Quickly distributed to the skeleton
Long time to remove drug as it binds so strongly to bone.
State the 2 types of bisphosphonate
Oral alendronate
IV zoledronate
Oral alendronate
Daily/weekly
IV zolendronate
Yearly
Why is zolendronate given by IV only ?
Any dietary source of calcium will be bound to by this.
It would bind to calcium in the GI tract and not get absorbed.
Protein binding
A drug must be free to distribute widely or bind to its receptor
State some drugs that bind to plasma proteins
Albumin
alpha-1 acid glycoprotein
Lipoproteins
Globulins
Albumin
A lot of drugs that will stay in high concentrations in the plasma will bind to albumin and stay there.
Importance of drugs binding to albumin
ONLY drugs which are unbound can interact with receptors / get from the plasma into other tissues.
So those bound to albumin cannot interact.
% unbound drugs
Fraction of unbound drugs can be as low as 1%
What does competition for binding sites cause ?
Can cause big increases in free drug concentrations.
Feature of warfarin and aspirin
98% of warfarin bound to albumin.
Aspirin has a high affinity for albumin…
So in the presence of aspirin competition occurs and whichever has the highest affinity for the site is likely to win.
Which has a higher affinity for albumin, aspirin or warfarin ?
Aspirin
Increased Aspirin levels results in:
Increased warfarin available in the plasma
Describe distribution between body fluid compartments
Permeability across tissue barriers
Binding within compartments
pH partition
Fat:Water partition
What does degree of distribution between compartments depend on ?
Tissue and Drug dependent factors
Where is body water distributed ?
Distributed into 4 main compartments
How can side-effects of some drugs be minimised ?
By limiting their distribution via the route of administration.
Muscarinic Ach receptor agonists
Pilocarpine
Bethanechol
Pilocarpine
Non-selective muscarinic agonist
Constricts pupils
Glaucoma - decrease IOP
Xerostomia - following head/neck radiotherapy
Bethanecol
Non-selective muscarinic agonist
Bladder and GI hypotonia
Structure of bethanechol
Quaternary ammonium
POLAR substance
not readily absorbed
Structure of pilocarpine
Tertiary amine
