L5-Pharmacokinetics (Part 1) Flashcards
What is pharmacokinetics?
Pharmacokinetics is the study of what the body does with a drug or toxin, including how it is absorbed, distributed, metabolized, and excreted.
How do drugs move across cell membranes?
- Diffusion through the lipid bilayer.
- Diffusion through aqueous pores formed by aquaporins.
- Via transmembrane carrier proteins.
- By pinocytosis.
Which passage routes are important for drug movement?
Lipid-mediated and carrier-mediated transport are the most important in relation to pharmacokinetics, while diffusion through aquaporins is not considered significant for most drugs.
Where is Pinocytosis used?
For the transport of some macromolecules like insulin but not for small molecules like drugs.
What is Pinocytosis?
Process by which the cell takes in the fluids along with dissolved small molecules.
What is the role of lipid solubility in drug transport?
Lipid solubility is a key determinant of a drug’s pharmacokinetics.
Lipid solubility influences…
- Rate of absorption from the gut.
- Penetration into tissues (such as the brain).
- Extent of renal elimination.
How does the ionization state of a drug affect its ability to cross lipid membranes?
Only the uncharged form of a drug can cross lipid membranes. For weak acids and bases, the ionization state depends on the pH of the environment.
A weak acid (AH ↔ A- + H+)
can cross when in the protonated (uncharged) form
A weak base (BH+ ↔ B + H+)
can cross when in the unprotonated (uncharged) form
PKa equilibrium constant
The pH where 50% of the drug is ionized (charged)
pH partition
- pH partitioning occurs when drugs accumulate in parts of the body where the pH favors their ionized or unionized state.
- Weak acids tend to accumulate in compartments of relatively high pH (alkaline), whereas weak bases do the reverse.
How does acidifying urinary affect drug excretion?
- Acidifying the urine increases the excretion of weak bases and decreases the excretion of weak acids.
How does alkalinizing urinary affect drug excretion?
- Alkalinizing the urine has the opposite effect, increasing the excretion of weak acids and decreasing that of weak bases.
How does the increase in plasma pH affect drug distribution?
Increasing plasma pH can cause weakly acidic drugs to move from the central nervous system (CNS) to the plasma, reducing neurotoxicity.
. How does the decrease plasma pH affect drug distribution?
Lowering plasma pH can cause weakly acidic drugs to become concentrated in the CNS, increasing neurotoxicity.
How do carrier-mediated transport systems work?
- Carrier-mediated transport involves a transmembrane protein that binds one or more molecules or ions, changes conformation, and releases them on the other side of the membrane.
- It shows saturation kinetics because of the limited number of transport proteins.
In which parts of the body is carrier-mediated transport important?
- Renal tubules
- Biliary tract
- Blood-brain barrier
- Gastrointestinal tract
Where can P-glycoprotein be found in the body?
- Renal tubules
- Micro vessels in brain
- Gastrointestinal tract
What’s the role of P-glycoprotein?
- Absorption of drugs
- Distribution of drugs
- Elimination of drugs
What’s the drug transporter responsible for multidrug resistance in cancer cells?
P-glycoprotein
What’s the physiological role of P-glycoprotein?
Elimination of environmental toxins.
. How do plasma proteins affect drug activity?
- Drugs bound to plasma proteins are pharmacologically inactive. Only the free (unbound) fraction of a drug is active.
- The extent of protein binding depends on the concentration of the free drug, its affinity for the binding sites, and the concentration of the plasma proteins.
Most important protein in plasma that binds many acidic drugs…
Albumin
Binding depends on…
- concentration of free drug
- affinity for the binding sites
- concentration of protein
How does plasma protein binding affect drug elimination?
Extensive plasma protein binding slows down the elimination of a drug, as it reduces the amount of free drug available for metabolism and excretion.
How do lipid-soluble drugs accumulate in the body?
Lipid-soluble drugs can accumulate in body fat when given chronically. Environmental contaminants like insecticides, which are poorly metabolized, also accumulate in body fat.
Example for a lipid-soluble drug:
Benzodiazepines
How does environmental contaminants work when ingested regularly?
Xenobiotics (insecticides) will accumulate slowly but progressively in body fat.
What is Chloroquine used for?
- Antimalarial drug
- Additional in treating rheumatoid arthritis
Chloroquine has high affinity for…
Melanin
Chloroquine can cause…
Retinopathy due to the retina that are rich in melanin granules uptake the drug.
What is the blood-brain barrier?
The blood-brain barrier is formed by tightly packed endothelial cells in the brain’s capillaries.
How does blood-brain barrier affect drug distribution?
This structure prevents drugs with low lipid solubility from passing into the brain, limiting the effectiveness of certain antibiotics and cancer drugs.
What is drug absorption?
Drug absorption is the passage of a drug from its site of administration into the plasma. It is important for all routes of administration except intravenous injection.
How does drug ionization affect oral absorption?
Strong acids and bases are poorly absorbed from the intestine because they are fully ionized and cannot easily cross lipid membranes.
What is an example of a drug that is poorly absorbed due to ionization?
Curare, a strong base used as an arrow poison, is poorly absorbed through the intestine because it is fully ionized.
In which case does drug not enter plasma before its site of action?
Inhalation of bronchodilator aerosol to treat asthma.
What factors influence gastrointestinal drug absorption?
- Gastrointestinal motility.
- Splanchnic blood flow (higher blood flow leads to greater absorption).
- Particle size and formulation (e.g., slow-release capsules).
- Physicochemical factors, such as ion binding impairing absorption.
What are examples of non-oral drug administration routes?
- Cutaneous administration
- Nasal sprays.
- Eye drops
- Inhalation
Cutaneous administration
- Nicotine
- Estrogen patches
Eye drops
Glaucoma medications
Inhalation
Bronchodilators
How is drug distribution measured?
Drug distribution is measured by the volume of distribution (Vd), which is the volume of fluid required to dissolve a dose of drug at the same concentration as detected in the blood plasma.
How is the volume of distribution (Vd) calculated?
Vd = Dose / [Drug]plasma
If 400 mg of a drug is administered and the plasma concentration is 0.01 mg/L, the Vd is calculated as:
Vd = Dose / [Drug]plasma
Vd = 400 mg / 0.01 mg/L = 40,000 L
What are examples of drugs with different volumes of distribution?
- Insulin
- Morphine
Insulin has low Vd…
because it is retained highly in plasma.
Morphine has high Vd…
because accumulates in fat tissue.
