ELimination Flashcards
What is Elimination? Where does elimination take place for IV administration?
The removal of a drug molecule from the body without chemical modification
Following i.v administration;
No metabolism takes place
Elimination is 100% via renal excretion
What are the three elimination processes that occur via the kidney?
The kidney uses three mechanisms of drug excretion: glomerular filtration, active secretion through the proximal tubules, or distal tubule reabsorption.
What is Glomerular Filtration? Which molecules are filtered and what type of transport is used?
The glomerular filtration rate (GFR) shows how well the kidneys are filtering
Passive process (Pressure driven)
20% of plasma volume is filtered
Small molecules - Yes
Large molecules - No
Most proteins not filtered. Drugs which are extensively protein bound will also not be filtered.
What is Active Secretion?
The majority of drugs do not enter the kidney tubule by glomerular filtration but do so by tubule secretion. This is an active process since drugs are carried against a favourable chemical gradient from the capillary network into the tubule.
Energy requiring
Can generate positive concentration
gradients
Two separate mechanisms for acids & bases
Saturable
Possible interactions
Give example of active secretion acidic drugs?
Furosemide (diuretic) , Penicillins, Probenecid (for gout)
Penicillin and Probenecid share same mechanism
Probenecid competes with penicillins
Penicillin clearance reduced
Give examples of active secretion bases?
Quinine, Quaternary ammonium salts
What molecules are reabsorbed and what molecules can be efficiently excreted by the kidneys?
99% of water is reabsorbed
Lipid soluble drugs reabsorbed along with the water.
Only very water soluble molecules can
be efficiently excreted by the kidneys.
What is ion trapping?
ion trapping is the build-up of a higher concentration of a chemical across a cell membrane due to the pKa value of the chemical and difference of pH across the cell membrane. This results in basic chemicals accumulating in acidic bodily fluids such as the cytosol, and acidic chemicals accumulating in basic fluids.
What is given when a barbiturate overdose?
Urine pH varies (4.5 - 8.0). Consider a barbiturate overdose. Sodium bicarbonate may be given to make the urine alkaline
Barbiturate moves into urine - eliminated from body
What is High Renal Clearance?
If renal clearance is greater than G.F.R. then there must be active secretion
Max possible renal clearance is approx.
650 ml/min (All plasma cleared)
e.g. Aminohippuric acid
What is Low renal clearance?
If clearance is much less than G.F.R. then either:
Not filtered or
Extensively reabsorbed
e.g. antipyrine, thiopental
What is creatine and creatine clearance?
Creatinine is a waste product formed continuously by muscle.
Filtered by kidneys
Almost no active secretion
Almost no reabsorption
Creatine clearance approx equals filtration rate (G.F.R.)
Creatinine clearance used as an estimate of G.F.R.
Why are creatinine clearance and GFR important in ADME?
The clearances of many renally excreted drugs are closely linked to GFR
e.g. The clearance of gentamicin approximately equals GFR and therefore also approximates to creatinine clearance.
When calculating a dosage regime we can assume that gentamicin clearance will equal creatinine clearance
What are Factors influencing serum creatinine concentration
1) Creatinine production rate
depends upon muscle mass, which in turn depends upon:
Body weight
Age (% muscle declines with age)
Gender (Men have higher % muscle than women)
2) Creatinine clearance rate
What are routes of excretion?
Biliary
Pulmonary
Mammary
Salivary
First Pass Metabolism
What is Biliary Excretion?
Similar to kidneys
Lipid soluble drugs filter initially, but get re-absorbed along with the bulk of the water. Not excreted efficiently.
Acids and bases have active secretion mechanisms.
BUT
only works effectively if Mol Wt high enough. Limit varies for different species. (>300-500 for humans)
What is the problem with Biliary excretion and how is it solved?
Most drugs’ Mol Wt too low for efficient biliary excretion.
Conjugation to glucuronide often increases Mol Wt sufficiently for biliary excretion.
Acetate or glycine generally too small.
What drugs is bile used for excretion?
Bile is significant route of excretion for:
Glucuronide conjugates (e.g. morphine)
Limited number of ionised drugs with very high
Mol Wt (e.g. cromoglycate)
What is enterohepatic circulation?
Enterohepatic circulation refers to the process whereby a drug or a metastable metabolite thereof in the liver is secreted into the bile, stored in the gall bladder, and subsequently released into the small intestine, where the drug can be reabsorbed back into circulation and subsequently returned to the liver.
Mainly bacteria in colon that hydrolyse the conjugates
What is Pulmonary excretion
Excretion via the lungs and breath.
Significant route of excretion for some volatile molecules - especially anaesthetics.
What is mammary?
MILK
No active secretion, just passive diffusion.
Concentration in milk reflects free concentration in blood (apart from ion trapping).
Milk is slightly acid (pH 7.0) compared to blood(pH 7.4).
What drug is in high concentration in milk?
Erythromycin concentrations approx 8 times higher in milk than blood. Blood pH 7.4 and Milk (pH 7.0)
What drugs cause a problem in milk?
Mainly the effect of the drug on the baby. e.g.
Chloramphenicol: Possible bone marrow suppression.
Diazepam: Accumulation and sedation.
Heroin: Prolonged neonatal dependence.
Methadone: Possible withdrawal syndrome if breast feeding stopped suddenly.
Tetracycline: Permanent staining of infant teeth
What is filtration dependant on?
Glomelurous- using glomelular filtration(pressure) filtrate across bowmans capsule into the proximal tubule.
Reduced GFR (chronic kidney disease) means less plasma that is excreted from the plasma into bowmans capsules therefore less drug in the blood plasma is moved therefore remains in body for longer and not urinated out. therefore less filtered drug and higher blood conc. More toxic side effects
Proteins (albumin) binds to drugs. Move out of bowmans capsule the drug cant be heavily protein bound. When lots of protein bounding will dec filtration from glomelurous into bowmans capsule and inc conc of blood. Less elimination and secretion of drug when protein bounded.
cirrhosis have less albumin therefore more drug is filtered from glomeluorus into bowmans capsule dec which means sometimes more drug is needed to get the required therapeutic effect
what is filtration and what is it dependant on?
The hydrostatic pressure pushes things out of the afferent atrial - plasma into the bowmans capsule dependant on GFR and proteins (albunin)
What is secretion
Drugs filtrate from glomelurous into the bowmans capsule however some drug do not filtrate and move to the efferent arterial and remain in peritubular capsule blood where it can diffuse into lumen to be easily secreted.
The diffusion depends on solubility and conc gradient of drug. (needs to have ATP and -low to high conc for large, charged molecule, water soluble molecule, more filtered across into bowmans high conc in lumen low conc in blood)
Whereas small, non polar, hydrophobic, lipid soluble, conc is higher in blood, lower in kidney tubules) therefore moves from high to low so it easily moves through phospholipid bilayer passive diffusion.
What does cimetidine, trimethropin do in excretion
Directly interact with the transporters moving from the efferent atrial to the lumen.
What type of drug does not need ATP or transporters to be reabsorbed?
non polar, hydophobic, small,
What happens if a patient takes an overdose on phenorbital or aspirin?
These drugs are weak acids HA > H+ and A-
HA is non polar so would be easily absorbed
A- would not be reabsorbed because its polar/charged
SHIFT REACTION TO RIGHT, if you make more A- it will be excreted and trapped in the urine
The proton conc is decreased H+ by making urine alkaline shift reaction to right and its polar so will trap the A- to excrete in urine.
ADD sodium bicarbonate
Patient who takes amphetamine overdose?
These are a weak base BH+ -> B + H+
B is non polar so will be reabsorbed
BH+ will not be reabsorbed because its polar
BH it will be excreted and trapped in urine.
INC right side by inc conc of protons to shift the reaction to left. ACIDIFY urine inc protons
ADD AMMONIUM CHLORIDE -
Amphetamine is a CNS stimulant that causes hypertension and tachycardia with feelings of increased confidence, sociability and energy
