Pharmacokinetics Flashcards
Pharmacokinetics (PK)
The study of the disposition of a drug
The disposition of a drug includes the processes of ADME
▪ Absorption
▪ Distribution
▪ Metabolism/Biotransformation
▪ Excretion
To be effective, the drug must
To be effective, the drug must leave the vascular space and enter the intercellular or intracellular spaces or both.
Drugs are transported across the membrane by
- Passive diffusion
- Filtration
- Specialized transport
- Others mechanisms (e.g bulk transport, exocytosis).
ABSORPTION
Absorption is the movement of drug from its site of administration into the systemic circulation and the extent to which this occurs.
Factors affecting drug absorption are
- pH
- Aqueous solubility: Drugs given in solid form must dissolve in the aqueous biophase before they are absorbed. For poorly water soluble drugs (e.g. aspirin), the rate of dissolution governs the rate of absorption. If a drug is given as water solution, it is absorbed faster than the same given in solid form.
- Concentration: Passive transport depends on the concentration gradient. A drug given as concentrated solution is absorbed faster than dilute solution.
- Area of absorbing surface: If the area is larger, the absorption is faster.
- Vascularity of absorbing surface: Blood circulation removes the drug from the site of absorption and maintains concentration gradient across the membrane. Increased blood flow hastens drug absorption.
- Route of drug administration: This affects drug absorption because each route has its own peculiarities.
What is BIOAVAILABILITY?
When is bioavailability 100%
How is is determined? And calculated?
Bioavailability is the fraction of administered drug that reaches the systemic circulation in a chemically unchanged form
▪ If 100mg are of a drug is administered orally and 70mg of the drug is absorbed unchanged, then bioavailability is 70%.
▪ Bioavailability of a drug administered IV =100%.
- Bioavailability is determined by comparing plasma levels of a drug after a particular route of administration (after oral) with plasma levels achieved (e.g. after IV)
- When given orally only part of the administered drug appears in the plasma
- By plotting plasma concentrations of the drug versus time, one can measure the surface area under the curve (AUC)
Types of bioavailability
• Absolute bioavailability: Measures the availability of the active drug in systemic circulation after non-intravenous administration (i.e., after oral, rectal, transdermal, subcutaneous administration).
• Relative bioavailability: Measures the bioavailability of a certain drug when compared with another formulation of the same drug, usually an established standard, or through administration via a different route.
▪ When the standard consists of intravenously administered drug, this is known as absolute bioavailability
BIOEQUIVALENCE
• Two related drugs are bioequivalent if they show comparable bioavailability and similar times to achieve peak plasma concentration.
• Two related drugs with a significant difference in bioavailability are said to be bio-inequivalent
DRUG DISTRIBUTION
• Drug distribution refers to the movement of drug to and from the blood and various tissues of the body (for example, fat, muscle, and brain tissue) and the relative proportions of drug in the tissues.
• After a drug is absorbed into the bloodstream, it rapidly circulates through the body. And as the blood re-circulates, the drug moves from the bloodstream into the body’s tissues.
•Once absorbed, most drugs do not spread evenly throughout the body.
•Other drugs concentrate mainly in only one small part of the body (for example, iodine concentrates mainly in the thyroid gland), because the tissues there have a special attraction for and ability to retain (affinity) the drug.
Describe water-soluble drugs
• Drugs that dissolve in water (water-soluble drugs), such as the antihypertensive drug, atenolol, tend to stay within the blood and the fluid that surrounds cells (interstitial space).
Describe fat-soluble drugs
• Drugs that dissolve in fat (fat-soluble drugs), such as the anaesthetic drugs halothane and thiopental, tend to concentrate in fatty tissues.
The total volume of the fluid compartments of the body into which drugs may be distributed is approximately
40L in a 70-kg adult.
The total body water, in which a drug can be dissolved, can be roughly divided into three compartments
Intravascular (blood plasma found within blood vessels), 3 litres (4% BW)
Interstitial/ extracellular tissue (fluid surrounding cells), 9 litres (13% BW).
Intracellular (fluid within cells, i.e. cytosol), 28 litres (41% BW).
How are drugs distributed?
After a drug is absorbed into the bloodstream, it rapidly circulates through the body. And as the blood re-circulates, the drug moves from the bloodstream into the body’s tissues.
Once absorbed, most drugs do not spread evenly throughout the body.
Why do some drugs concentrate in one part of the body?
Other drugs concentrate mainly in only one small part of the body (for example, iodine concentrates mainly in the thyroid gland), because the tissues there have a special attraction for and ability to retain (affinity) the drug.
Total extracellular water is the sum of…
the plasma and the interstitial water.
Why is distribution typically uneven?
Distribution is generally uneven because of differences in binding in tissues, regional variations in pH, differences in the permeability of cellular membranes and physical and chemical properties of the drug
APPARENT VOLUME OF DISTRIBUTION
The volume into which the drug distributes is called the Apparent Volume of distribution (Vd).
It relates the amount of drug in the body to the concentration of drug (C) in the blood or plasma depending on the fluid measured
Vd may vary widely depending on:
▪ Blood flow rate and accumulation in poorly perfused tissues (such as fat and
muscles).
▪ Capillary permeability
▪ Plasma protein and tissue protein binding
▪ Partition coefficient of the drug in fat
FACTORS AFFECTING DRUG DISTRIBUTION
- Capillary permeability
- Blood flow
- Physicochemical properties of the drug
- Plasma and tissue protein binding
Capillary permeability
Determined by capillary structure and chemical nature of the drug
Endothelial cells have slit junction (except in brain) where large part of basement membrane is exposed due to large discontinuous capillaries through which large proteins can pass e.g. liver and kidneys
Blood brain barrier: drugs have to pass through endothelial cells of the capillaries of the CNS or be actively transported. E.g. the large neutral amino acid carrier transports levadopa into the brain.
Lipid soluble drugs readily penetrate into the CNS
Blood flow
▪ Rate of blood flow to tissues and capillaries varies widely as a result of unequal distribution of cardiac out put to the various organs
▪ Blood flow to the brain, liver and kidney is greater than that to the skeletal muscles and adipose tissue.
▪ Redistribution. Highly lipid soluble drugs given i.v. or by inhalation get distributed to organs with high blood flow. Later they get distributed to less vascularized tissues and the drug-plasma concentrations falls.
▪ The greater the lipid solubility of the drug, the faster its redistribution. Anesthetic action of thiopental is terminated in few minutes due to redistribution. However, when the same drug is given repeatedly or continuously over long periods the low perfusion high capacity sites get progressively filled up and the drug becomes longer acting.
Physicochemical properties of the drug
- Partition Coefficient: The Partition coefficient (Po/w) and can be used to determine where a drug will likely be distributed in the body.
Any drug with a Po/w greater than 1 (diffuse through cell membranes easily) is likely be to found throughout all three fluid compartments.
Drugs with low Po/w values are often unable to cross and require more time to distribute throughout the rest of the body.
2 Size of the drug:.
Tiny drugs (150-200 Da) with low Po/w values like caffeine can passively diffuse through cell membranes.
Antibodies and other drugs range into the thousands of daltons . Drugs >200 Da with low Po/w values cannot passively cross membranes . They require specialized protein-based transmembrane transport systems resulting in slower distribution
Drugs < thousand daltons with high Po/w values simply diffuse between the lipid molecules that make up membranes, while anything larger requires specialized transport.
- Hydrophobic drugs with a uniform distribution of positive and negative charges readily cross plasma membranes.
- Hydrophilic drugs have to go through slit junctions
3.
Plasma and tissue protein binding
The extent of the distribution of drugs into tissues depends on binding to plasma proteins and tissue components.
Most drugs found in the vascular compartment are bound reversibly with one or more of the macromolecules in plasma (e.g plasma proteins and blood cells).
Drugs bind to plasma proteins mainly Albumin, α1-acid glycoprotein, and lipoproteins. Other proteins are globulins, transferrin, and ceruloplasmin.
Acidic drugs (e.g. warfarin, digoxin and salicylic acid) bind more extensively to albumin. Basic drugs (e.g . amphetamine, Propanolol, TCAs) bind to either alpha 1-acid glycoprotein
(1-AGP), or lipoproteins, or both.
The ratio of bound to free drug in the plasma is determined by the reversible interaction between a drug molecule and a molecule of the protein in which it binds.
