Pharmacokinetics- Distribution Flashcards
Define Distribution
- process where the absorbed chemical moves away from the site of absorption to other areas of the body
- process by which a drug is transferred from the blood stream (plasma) to tissues (interstitial fluid and cells)
What do the rate and degree of drug distribution depend on?
Hint: CAMP B
C: capillary permeability
A: accumulation in and redistribution to other sites
M: miscellaneous factors (i.e. age, obesity, diet, etc.)
P: protein binding (i.e. to albumin)
B: blood flow
What is Re-distribution?
- when well-perfused organs initially receive most of the drug before being received by lesser perfused organs
- results in the termination of drug action
What are the well-perfused organs?
Hint: BLacK
B: brain
L: liver
K: kidney
What are the lesser-perfused organs?
Hint: MS VF
M: muscle
S: skin
V: (most) viscera
F: fat
Where would the drug likely be found if there are very large drug molecules?
drug confined to circulation
Where would the drug be if drug molecules are very polar?
drug excluded by cell membrane
Where would the drug be if drug is lipophilic?
in fat within the cells
Why is drug distribution not uniform throughout the body?
because different tissues receive the drug from the plasma at different rates and to different extents
Define Volume of Distribution (Vd)
- apparent volume of distribution
- theoretical volume that would be necessary to contain the total administered drug at the same concentration as seen in the plasma
- predicts whether drug will reside in blood or tissue
Where will water soluble drugs reside?
the blood
Where will lipid soluble drugs reside?
Hint: CAFe
C: cell membrane
A: adipose tissues
F: fat-rich areas
What is the Vd for drugs that are charged?
tend to bind to serum proteins -> increase in molecular size -> does not pass through cell membrane easily -> confined to circulation
- low Vd
What is the Vd of hydrophilic or charged drugs?
- low Vd
What is the Vd if there is an underlying disease of renal failure?
- increased Vd
- due to fluid retention
What is the Vd if there is an underlying disease of liver failure?
- increased Vd
- due to altered body fluid and plasma protein binding
What are factors that affect Vd?
Hint: MALT PWP
M: molecular weight of drug
A: acidity
L: lipid solubility
T: tissue perfusion
P: pathological condition
W: water solubility
P: plasma protein binding
Explain how the molecular weight of a drug affects Vd
- low molecular weight of drugs -> high Vd (can pass through pores)
- high molecular weight -> low Vd
Explain how the acidity of a drug affects Vd
- acidic drugs have low Vd (high affinity for albumin)
- basic drugs have high Vd (high affinity for alpha-1 acid glycoprotein / free drug)
Examples of acidic drugs
Hint: Basic drugs don’t Bind To Plasma Very Fast
Basic: bilirubin Bind: bile acids To: tetracycline Plasma: penicillin Very: Vitamin C Fast: fatty acids
What do acidic drugs have high affinity for (blood binding)?
plasma albumin
What do basic drugs have high affinity for (blood binding)?
alpha-1 acid glycoproteins
Explain how lipid solubility of a drug affects Vd
lipid soluble drugs have high Vd
- can move through the plasma membrane freely
Explain how tissue perfusion of a drug affects Vd
- low tissue perfusion means low Vd
- high tissue perfusion means high Vd
Explain how pathological conditions may affect Vd
e.g. in edematous conditions, water soluble drugs have high Vd
Explain how water solubility of a drug affects Vd
- water soluble drugs have low Vd
- due to the inability to cross the plasma membrane on its own
Explain how plasma protein binding (PPB) of a drug affects Vd
- high PPB of a drug means low Vd (increases the molecular size -> cannot pass through pores)
- low PPB of a drug means high Vd
What is the affect of lipid solubility of a drug on redistribution?
- the greater the lipid solubility of the drug, the faster its redistribution
Define Bioavailability
fraction of the administered drug that reaches the systemic circulation
Define Absolute Bioavailability
compares the bioavailability of the active drug in systemic circulation following non-IV administration vs the same drug with IV administration
When will the bioavailability of a drug be 100%?
when the drug is administered intravenously
What is the purpose of absolute bioavailability?
to determine the best route of administration
Define Relative Bioavailability
compares the bioavailability of formulation A of a certain drug compared with another formulation B (of the same drug)
What is the difference between Absolute Bioavailability and Relative Bioavailability?
- absolute bioavailability: compares bio-availabilities of (the same) active drug administered via non-IV vs IV
- relative bioavailability: compares bio-availabilities of formulations of the same drug
Define Bioequivalence
when two related drugs show comparable
- bioavailability
- similar times to achieve peak blood concentrations
Define Therapeutic Bioequivalence
when two similar drugs show comparable
- efficacy
- safety
What are factors that influence bioavailability?
Hint: FSCN (like fasten)
F: first-pass hepatic effect
S: solubility
C: chemical instability
N: nature of the drug formulation
How does the first-pass effect influence bioavailability?
- drug absorbed from the GI tract is first delivered to the liver before entering the systemic circulation
- liver is where metabolism occurs -> if the drug is rapidly metabolised, the amount of unchanged drug that enters the system circulation is decreased
- > greater the first-pass effect = less drug to reach systemic circulation
Under what circumstances does hepatic first-pass effect take place?
when drug is administered orally
When does the drug bypass first-pass effect?
when administered via:
- IV
- IM rectal
- sublingual
How does the solubility of the drug influence bioavailability?
- hydrophobic drugs (increase bioavailability)
- hydrophilic drugs (decrease bioavailability)
How does chemical instability influence bioavailability?
instability decreases bioavailability
i. e.
- penicillin G is unstable in pH of gastric contents
- insulin is destroyed in the GI tract by degradative enzymes
How does the nature of the drug formulation influence bioavailability?
Hint: PEE
nature of drug formulation includes-
P: particle size
E: enteric coatings
E: excipients
- can influence ease of dissolution -> therefore altering the rate of absorption
How are drugs transported in the blood?
- free form
- bound form
What is the free form of a drug?
Hint: DAA
- diffusible
- active
- available for metabolism and excretion
What is the bound form of a drug?
- bound to plasma albumin
- inactive
- neither metabolised nor excreted
What can protein binding be divided into?
- intracellular binding
- extracellular binding
What is the significance of plasma-protein binding?
- affects distribution (cannot pass through capillaries and cell membranes due to large molecular size)
- inactive
- non-diffusible
- not available for metabolism nor excretion
- reservoir (supplies free drug when required- stays within circulation longer)
True or False:
The plasma-protein binding of drugs can be irreversible.
True
- binding of drugs to proteins is generally reversible & irreversible
What constitutes for an irreversible plasma-protein binding of a drug?
- when there is a covalent binding (rare)
What constitutes for a reversible plasma-protein binding of a drug?
weak chemical bonds
- hydrogen bonds
- hydrophobic bonds
- ionic bonds
- Van der waal’s forces
What happens when a irreversible plasma-protein binding occurs with a drug?
- carcinogenicity or tissue toxicity
What drug can bind to both primary and secondary site of albumin?
flucoxacillin
What drug has three different binding sites on albumin?
indomethacin
Example of basic drugs
Hint: LIP
L: lidocaine
I: imipramine
P: propranolol
How do drugs bind to lipoproteins?
via hydrophobic bonds
What does alpha-1 globulin bind to?
steroidal drugs
What does alpha-2 globulin bind to?
Vitamins K, A, D, E
What does Beta-1 globulin bind to?
ferrous ions
What does Beta-2 globulin bind to?
carotinoids
What does gamma-globulin bind to?
antigens
How are some drugs displaced by other drugs?
drugs with high affinity for plasma proteins can displace other drugs/endogenous compounds that have lower affinity
