| How does lipophilicity affect drug distribution? | Lipophilic drugs cross membranes easily whereas hydrophilic ones cannot.
Ex: antiHTN hydrophilic (Atenolol) lipophilic (Propanolol) |
| How does binding of drugs to plasma proteins affect drug distribution? | When drugs bind proteins they arenot able to cross membranes, so more binding means less transfer
Albumin binds drugs and serves as a reservoir maintaining constant fraction of free drug in plasma
Ex: >99% of ketorolac (NSAIDs) is protein bound |
| How does binding to tissue proteins affect drug distribution? | As drugs can accumulate in tissues, they may be bound to lipids, proteins or nucleic acids or may be actively transported to the tissue.
So tissue binding can prolong drug action or cause local toxicity
Ex: Digoxin accumulates at muscles acts as a reserve to make a balance into blood when drug is reduced prolonging the effect.
Ex: Acrolein (cyclophophamide) can cause hemorrhagic cystitis as it accumulates in bladder |
| What is volume of distribution? | It is a way if estimating the volume in which the administered drug is present in inside the body
Since we can get drug concentration in blood and the mass administered we can get the volume where this drug is present in (the volume of distribution Vd) = Dose/Concentration in blood |
| What are indications given by volume of distribution? | Vd greater than body fluids means drug is gone to tissues highly.
So drugs with higher lipophilicity, less charge and less weight will have a higher volume of distribution than drugs with high ionization and weight... |
| What are the compartments of distribution of drugs? | Water compartments (4 L plasma, 10 L interstitial fluids, 28 L intracellular)
So total water in body is 42 L .
Drugs could also get into tissues (not water) acc to type of drug and tissue |
| Talk about plasma drug distriubution compartment. | Heparin has this type of distribution, high molecular weight and extremely protein bound, trapped in plasma so low Vd almost equal plasma concentration (4L) |
| Talk about interstitial fluid drug distriubution compartment. | Aminoglycosides, low molecular weight but hydrophilic so stays extracellular but out of capillary
Vd=14 L (of interstitial and plasma fluid) |
| Talk about drugs of total body water distribution? | low molecular weight and lipophilic, Vd=42L
Like ethanol |
| How are drugs bound to plasma proteins? | Drugs bind reversibly to plasma proteins.
Mostly albumin, acts as a reservoir, amount of free drugs increase if it is displaced by another drug on albumin, or albumin levels are decreased
Thus if free drug is increased we have a higher rate of going into tissues and elimination |
| Give examples on plasma proteins binding drugs. | Albumin for acidic drugs, a1 acid glycoproteins for basic drugs.
Sex-hormone binding globulin for estrogen or testosterone.
Thyroxine-binding globulin (TBG)
Non-specific binding (lesser extent)
usually 2 bond types electrostatic and hydrophobic. |
| What factors affect drug binding to plasma proteins? | Drug concentration, affinity to binding sites and number of binding sites.
Also some disease affect it (hypoalbuminemia (2ary to liver disease), Acute phase response conditions (MI, Crohns, cancer...) elevate a1 acidic glycoprotein enhancing the binding
Competition may occur between drugs (unconjugated bilirubin replaced by sulfonamide on albumin binding sites causing bilirubin encephalopathy for newborns |
| What affects tissue binding of the drug? | Some drugs accumulate at tissues more than blood, like antimalarial drug quinacrine (at liver) resulting in more active transport into cells. It occurs on proteins, lipids or nucleic proteins
Reversible binding and may be used as reservoir causing prolonged action or maybe toxicity (aminoglycoside gentamycin in kidney and vestibular system ) |
