| How do drugs get eliminated from the body? | Either unchanged or converted to metabolites through oxidation-reduction or conjugation/hydrolysis reactions (enhancing hydrophilicity of the drugs
Most of them are excreted by renal/ lymphatic excretion |
| What are the routes of excretion of drugs? | Renal excretion (most common, relies on hydrophilicity)
Biliary excretion (small number of drugs)
Fecal excretion (if incompletely absorbed by the body)
Dermal excretion (sweat)
Breathing (through lungs for anethetic gases (and ethanol - alcohol intoxication) |
| What mechanisms does renal excretion involve? | Involves (glomerular filtration, active tubular secretion, passive tubular reabsorption, excretion of urine) |
| Talk about glomerular filtration of drugs. | Free drugs will go through slits to the bowman's space as a part of glomerular filtrate.
Normal GFR= 120ml/min and it is not affected by lipid solubility and pH. |
| Talk about proximal tubular secretion of drugs. | There are two energy-requiring active transport systems, one for anions and one for cations, each one with specificity of some compounds
There may be competition among compounds being secreted.
Infants and neonates have an incompletely developed tubular secretory mechanism. |
| Talk about distal tubular reabsorption of drugs. | Drug concentration gradient in distal tubules exceeds that in the perivascular space, thus the drug if uncharged may diffuse into systemic circulation.
To control this we may manipulate urine pH to get drugs to become charged to be eliminated, so weak acids are eliminated by alkalinization of urine, and weak bases are eliminated by acidification of urine (this is ion trapping)
ex: phenobarbital overdose (weak acid) we alkalinize the urine to eliminate it |
| What is the role of drug metabolism in excretion of drugs? | as most drugs are lipid soluble, and uncharged, most drugs will be reabsorbed from tubular lumen to circulation, so modifications of these drugs into more polar substances in the liver will decrease this decreased elimination. |
| What are the transporters used in renal excretion of drugs? | two types:
Ones responsible for secretion of anions and cations (P-gp and MRP2...) at apical brush border.
Ones responsible for active reabsorption of drugs in distal convoluted tubule back into circulation |
| Give an example of renal excretion of organic anion. | Penicillin is a drug transported by active transport or active secretion in proximal tubule.
We may see competition between it and probenecide. |
| What are the factors affecting renal excretion of drugs? | Factors affecting their entry into glomerulus are renal blood flow, GFR and drug binding to plasma protein.
It is excreted more rapidly when blood flow is enhanced, increased GFR and decreased plasma protein binding |
| How is biliary excretion of drugs? | Transporters similar to those in kidney are present in liver hepatocytes and excrete drugs into bile.
P-gp transporters (amphipathic molecules) and MRP2 (conjugated metabolites).
The drugs are present in bile and go to GI during digestive process
Then these drugs may be reabsorbed back (this is the enterohepatic circulation) after hydrolysis by intestinal microflora. |
| Give examples of drugs excreted through bile? | steroids, digoxin, chemotherapeutic drugs.
Some drugs may be given orally to bind substances and present them to bile like resin given in case of mercury poisoning) |
| What are other routes of drug clearance? | Maybe directly from circulation to intestinal lumen by transporters into feces
lungs in elimination of anesthetic gases (isoflurane)
breast milk (may be given from mother to child)
Sweat saliva tears hair in a small extent |
| What is drug clearance? | It is the rate at which a drug is removed from plasma/ concentration of drug in plasma
Elimination rate (mg/min)= clearance (ml/min) * plasma concentration
It is the volume of drug removed from plasma per unit of time
CL (total body clearance) by all organs (hepatic, renal, pulmo...) |
| Talk about creatinine clearance. | Creatinine is secreted due to muscle breakdown, it is excreted as a whole in the kidney (no reabsorption at all)
Creatinine Clearance is how much is cleared per time, in normal kidney functioning it is 125ml/min so it can be used as an estimate to renal function |
| What is the half-life of a drug? | It is the time needed for concentration of a drug to become at its half (in plasma)
It decreases with the decrease in concentration given
formula is t1/2= ln2*Vd/clearance |
| What are factors affecting half-life of a drug? | Decrease of drug clearance or increase in volume of distribution increases it
Effect on Vd: aging (decreases muscle mass so decreases it)
Obesity (increases fat tissue so it increases)
Effects on clearance: CYP induction (decrease) or inhibition (increase)
Cardiac failure (decrease clearance), hepatic failure or kidney failure (decrease clearance) so increase half-life
So doses of drugs are given according to drug responsiveness on half-life |
| What are the most important pharmacokinetic parameters? | AUC, Vd, Cl, half-life |
