Drug Absorption and Distribution Flashcards
In pharmacokinetics (what the body does to a drug) there are 4 parameters:
- Absorption
From site of administration into the blood - Distribution
Drug can reversibly leave the bloodstream and distribute into the interstitial and intracellular fluids of tissues - Metabolism
Body inactivates the drug through enzymatic modification - Excretion
Drug is eliminated from the body in urine, bile or faeces
Mention the 6 different routes of drug administration
1.Oral
- Parenteral (injection)
Intravenous (IV)
Intramuscular (IM)
Subcutaneous (SC) - Inhalation
- Topical
creams, ointments, transdermal patches - Sublingual
(e. g. nitroglycerin) - Rectal
ORAL route -
mostly absorption occurs primarily in the ileum
Advantages:
safe
convenient
economical
Disadvantages irritant drugs cause sickness not possible in vomiting patients patient compliance necessary some drugs (e.g. proteins) destroyed by gut acid/flora intestinal absorption can be erratic
Explain 5 factors affecting gastrointestinal absorption.
These factors impact on a drugs BIOAVAILABILITY –> the proportion of the administered dose which enters the systemic circulation
- Gut motility
(Increase GM, decrease A) - Gut pH
poor absorption of strong acids and bases - Physico-chemical interactions eg with food, other drugs
- Competition for carriers/transporters
- Particle size and formulation:
pharmaceutical preparations are formulated to produce the desired absorption characteristics
Define Absorption across physiological barriers
Absorption is the passage of drug from the site of administration to the plasma
main site of absorption of oral drugs is the small intestine
The most important ways in which drugs cross cell membranes are
- passive diffusion through lipid (SD)
- diffusion through aqueous channel (FD)
- carrier mediated transport (AT)
- important for all routes of administration except i.v.
- drug must cross cell membranes and be absorbed into bloodstream
Absorption across physiological barriers
- PASSIVE DIFFUSION
- lipid solubility –> rate of absorption
- non-polar/ un-ionised substances dissolve in lipid
- ionised species have low lipid solubility
- many drugs are weak acids or bases and therefore exist in both ionised and un-ionised forms
- ratio of ionised : un-ionised determined by pH
Drug absorption – pH and pKa.
The proportion of a drug that is ionised depends on the pH of the solution and the pKa of drug. How?
Many drugs are weak acids (proton donator) or bases (proton acceptor)
pKa = measure of the strength of an acid/base
When pH of solution=pKa of drug, 50% of drug is ionised
50% of drug is ionised when ____________
When pH of solution=pKa of drug,
Acidic drug in acid solution is
LESS IONIZED - neutral
Basic drug in acid solution is
mostly ionized = base H+
Basic drug in basic solution is
LESS IONIZED - neutral
Acidic drug in basic solution is
mostly ionized = acid-
pH - pKa
relations to Approx % ionisation of acids vs of base
if pH - pka = -3 ---->Ai=0.1, Bi = 99.9 -2 ------>-Ai=1, Bi = 99 -1 ---->Ai=10, Bi = 90 0 ---->Ai=50, Bi = 50 1 ---->Ai=90, Bi = 10 2 ---->Ai=99., Bi = 1 3 ---->Ai=99.9, Bi = 0.1
see table and practice drawing it
pH partitioning =
= acidic drugs accumulate in basic fluid compartments and visa versa
eg.
Aspirin is a weak acid. It has a pKa of ~3.5
→ In the stomach, it is mostly un-ionised (neutral), therefore can pass through the lipid membrane, into the plasma, but it gets trapped in the plasma as it becomes ionized.
Explain the distribution of drugs across body compartments
Once in the systemic circulation (following absorption or i.v. injection) drugs must be distributed to their target organ/tissue.
Drug distribution is the reversible transfer of drug from one location to another within the body.
For most drugs this occurs as passive diffusion of the un-ionised form across cell membranes until equilibrium is reached.
Distribution is a reversible process – drugs travel from the systemic circulation to the tissue as the concentration in the blood increases, and from the tissues into the blood when the blood concentration decreases.
Tissues that are well perfused e.g. lung liver get the drug ____________.
rapidly. Poorly perfused tissues such as fat, muscle and skin the distribution rate into these tissues is slower
Factors affecting distribution
can affect in two ways:
1. RATE OF DISTRIBUTION
2. EXTENT OF DISTRIBUTION
- RATE:
a. Membrane permeability e.g. Drugs perfuse faster through the highly permeable renal capillaries
b. Blood perfusion e.g. Drug reaches highly vascularised tissues more rapidly e.g. lung/liver - EXTENT OF DISTRIBUTION
a. Lipid solubility
e. g. Ionised lipid insoluble drugs cannot easily enter cells
b. pH-pKa
- -> plasma protein binding
- -> tissue binding
Distribution – plasma protein binding drugs
Drugs can bind reversibly to plasma proteins in the blood (ppb)
__________ is the most important plasma protein (for many acidic and some basic drugs)
Acid-glycoprotein and beta-globulin plasma proteins bind basic drugs
Albumin.
Only _________ is pharmacologically active
FREE DRUG.
Free drug + Plasma protein
<=> Drug-Plasma protein complex
Extensive ppb SLOWS drug action and elimination - slower acting BUT prolonged therapeutic effects
-
Distribution – tissue binding of drugs
Drugs diffuse, or are transported, from the plasma into tissues.
Tissue can bind drugs:
- either due to their composition – lipid soluble drugs will accumulate in fat
- via binding to cellular components (proteins, pigments, minerals)
e. g. Tetracyclines (antibiotics) accumulate slowly in bones and teeth, because they have a high affinity for calcium, and should not be used in children for this reason.
e. g. Chloroquine (an antimalarial drug) has a high affinity for melanin and is taken up by the retina, which is rich in melanin granules, accounting for its ocular toxicity.
Distribution – volume of distribution
Vd = pharmacological term used to quantify the distribution of a drug between plasma and the rest of the body.
If drugs are confined to the plasma compartment the Vd will be small/low
If drugs accumulate outside the plasma e.g. by being stored in fat, the Vd will be large/high
Vd =
Vd= amount drug in body/[drug]plasma
Vd = drug in body / drug in plasma
Distribution – important compartments
Total body water = ICV+ECV = 42L
Extracellular fluid = plasma + ISV
Plasma
Fat
Drug distribution
1. Total body water
Drugs distributed throughout body water: - are lipid soluble drugs which readily cross cell membranes e.g. ethanol - Vd of ~41.5L
Drug distribution
2. Extracellular fluid
Drugs distributed in the extracellular compartment:
- cannot easily enter cells because of their low lipid solubility e.g. gentamicin- Vd of ~16L
- Plasma
Drugs confined to the plasma compartment:
- are too large to cross the capillary wall easily e.g. heparin - Vd of ~3.5L
- Fat
Drugs that accumulate outside the plasma compartment e.g. in fat or bound to tissues e.g. Chloroquine - Vd of ~15,000L
TRUE OR FALSE?
A low plasma binding protein level which may occur in old age or malnutrition will result in a higher proportion of unbound drug
TRUE
SUMMARY
An acidic drug will be mainly un-ionised in an acidic fluid compartment, and mainly ionised in a basic fluid compartment
When the pKa of a drug = pH of the solution, 50% of the drug will be ionised
Drugs can be bound to plasma binding proteins such as albumin. Only the unbound drug is pharmacologically active
Binding of drugs to plasma binding proteins is reversible and competitive
