1. LECTURE 5
PHARMACOLOGY
DRUG ELIMINATION

2. Drug Elimination Excretion Sites of Action Absorption PLASMA
Unbound Drug
PLASMA
Metabolism
Tissue Depots
Bound Drug
Excretion

3. elimination through kidneys
Drug Elimination
Direct filtration &
elimination through kidneys
Drug
Elimination
Metabolism by liver
to inactive product
Drug
Metabolism by liver
to active product
Active secretion
by kidneys

4. elimination through kidneys
Drug Elimination
Direct filtration &
elimination through kidneys
Drug
Elimination
Drug
Active secretion
by kidneys

5. Drug Elimination MAJOR ROUTES Minor routes of elimination Liver
Kidneys
Minor routes of elimination
Lungs (Volatile general anesthetics)
Sweat
Saliva
Mother’s milk

6. NEED FOR METABOLISM

7. KIDNEY Is Major Site of Drug Elimination
Water Soluble
Filtration
in Glomerulus
Lipid Soluble
LIVER
KIDNEY
Lipid soluble drugs are reabsorbed!!!
Back diffusion is dependent on pH of tubular fluid & lipid solubility of drug
Secretion of organic acids and bases
Excretion in Urine

8. The Kidney Arterial supply Glomerulus Collecting tubule Proximal
(1.3 L/min)
Glomerulus
Collecting
tubule
Proximal
tubule
Distal
tubule
Venous
return
Active secretion
Reabsorption
Urine
(1.5 L/day)
e.g., gentamicin, cephalexin
Loop of Henle

9. Blood Flow in the Kidney Is Important
Renal blood flow is ~25% of cardiac output
1.3 L/min
Renal plasma flow is 50% of renal blood flow
650 ml/min
Glomerular filtration rate (GFR) is 20% of plasma flow
130 ml/min
In 24 hr, Liters are filtered by the glomerulus
24 hr urine output is Liters
More than 99% of glomerular filtrate volume must be reabsorbed
BUT water reabsorption does NOT equal solute reabsorption

10. Drug Excretion in the Kidney
Two Components
Glomerular filtration
Passive (no energy)
Clears free drug only
130 ml/min
Tubular secretion
Active (requires energy)
Can clear % of drug flowing through kidney
650 ml/min (5X glomerular filtration)

11. Glomerular Filtration
The Glomerulus
Filters 100% of blood supply
Filters everything <40 kDa
Plasma & small proteins
Glomerular Filtration Rate
~130 ml/min
Measured by inulin or creatinine
Creatinine clearance is a measure of kidney health
Used to adjust drug dosage if needed
Arterial
supply
(130 ml/min)

12. Tubular Secretion Energy-dependent transport (secretion)
Occurs from blood into
Proximal tubule
Distal tubule
Loop of Henle
Can clear blood of 100 of drug passing through kidney
Separate transport systems for
Weak organic bases (WOBs)
Weak organic acids (WOAs)
Most drugs and metabolites are WOAs
Probenecid is a substrate for WOA transporters
Its administration inhibits secretion of many drugs

13. Tubular Secretion Drugs are NOT normal substrates
Drugs compete with other drugs
BUT Drugs compete with endogenous metabolites
In particular metabolic acids
Sulfate
Phosphate
Glucuronate (sugar acids)
Can cause electrolyte disturbances

14. Tubular Reabsorption Mostly by passive non-ionic diffusion
Non-ionized forms of drug reabsorbed
60% in proximal tubule
Uric acid (urate) is the exception (active)
Acid & base forms of drugs are secreted
Lipophilic (non-ionic) forms of drugs are reabsorbed
Blood and urine pH affect drug elimination
THEREFORE
CONSEQUENTLY

15. CLEARANCE A very important concept for drug use
Clearance (Cl) is the VOLUME of fluid (plasma) “cleared” (freed) of drug per unit time
Clearance of most drugs is a first order process
A constant fraction of drug is cleared per unit time
A fraction is NOT a concentration
Therefore, first order clearance is independent of drug concentration

16. CLEARANCE
Clearance is independent of the method and route of clearance
Hepatic clearance
Renal clearance
Lung (inhalational) clearance
Saliva
Mother’s milk

17. Therapeutic Implications of Clearance
Highly ionized drugs tend to be rapidly cleared
Minimal tubular reabsorption since only non-ionized drug is reabsorbed
Alkalinizing urinary pH with Na bicarbonate can accelerate clearance of WOAs
Salicylate and barbiturates
Acidifying urinary pH with arginine hydrochloride can accelerate clearance of WOBs
Amphetamines

18. Therapeutic Implications of Clearance
Drug forms that are quite lipid soluble at the pH of the urine (5.5) are readily reabsorbed
Maximal tubular reabsorption since non-ionized drug is reabsorbed
Increasing osmolarity of urine (mannitol) may increase elimination of a lipophilic drug

19. Therapeutic Implications of Clearance
Tubular secretion of a drug may be inhibited by another drug by competition for the transporter
Probenecid competes with penicillins
Thus prolongs action of antibiotic
Probenecid competes with some diuretics (furosemide) and thus may prevent diuretic access to the tubule which is where they act
Decreases effect of diuretic

20. Therapeutic Implications of Clearance
Drug clearance is decreased by renal disease
Measured by creatinine clearance
Caused by
Decreased renal blood flow
Glomerular tubular damage
Tubular nephropathy
Drug clearance is greater in an adult than in
Children (immaturity of kidney function)
Elderly (decreased renal function
Alcoholics

21. Drug Metabolism
Most metabolic products are less pharmacologically active
Important exceptions:
Where the metabolite is more active
(Prodrugs, e.g. Erythromycin-succinate (less irritation of GI) --> Erythromycin)
Where the metabolite is toxic (acetaminophen)
Where the metabolite is carcinogenic
Close relationship between the biotransformation of drugs and normal biochemical processes occurring in the body:
Metabolism of drugs involves many pathways associated with the synthesis of endogenous substrates such as steroid hormones, cholesterol and bile acids
Many of the enzymes involved in drug metabolism are principally designed for the metabolism of endogenous compounds
These enzymes metabolize drugs only because the drugs resemble the natural compound

22. Phases of Drug Metabolism
Phase I Reactions
Convert parent compound into a more polar (=hydrophilic) metabolite by adding or unmasking functional groups (-OH, -SH, -NH2, -COOH, etc.)
Often these metabolites are inactive
May be sufficiently polar to be excreted readily
Phase II Reactions
Conjugation with endogenous substrate to further increase aqueous solubility
Conjugation with glucoronide, sulfate, acetate, amino acid
Phase I usually precede phase II reactions
Liver is principal site of drug metabolism:
Other sites include the gut, lungs, skin and kidneys
For orally administered compounds, there is the
“First Pass Effect”
Intestinal metabolism
Liver metabolism
Enterohepatic recycling
Gut microorganisms - glucuronidases

23. Drug Metabolism - Phase I
Phase I Reactions
Oxidation
Reduction
Hydrolytic cleavage
Alkylation (Methylation)
Dealkylation
Ring cyclization
N-carboxylation
Dimerization
Transamidation
Isomerization
Decarboxylation

24. Drug Metabolism - Oxidation
Two types of oxidation reactions:
Oxygen is incorporated into the drug molecule (e.g. hydroxylation)
Oxidation causes the loss of part of the drug molecule
(e.g. oxidative deimination, dealkylation)
Microsomal Mixed Function Oxidases (MFOs)
“Microsomes”
form in vitro after cell homogenization and fractionation of ER
Rough microsomes are primarily associated with protein synthesis
Smooth microsomes contain a class of oxidative enzymes called
“Mixed Function Oxidases” or “Monooxygenases”
These enzymes require a reducing agent (NADPH) and molecular oxygen
(one oxygen atom appearing in the product and the other in the form of water)

25. Drug Metabolism - Oxidation
MFO consists of two enzymes:
Flavoprotein, NADPH-cytochrome c reductase
One mole of this enzyme contains one mole each of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD)
Enzyme is also called NADPH-cytochrome P450 reductase
Cytochrome P450
named based on its light absorption at 450 nm when complexed with carbon monoxide
is a hemoprotein containing an iron atom which can alternate between the ferrous (Fe++) and ferric (Fe+++) states
Electron acceptor
Serves as terminal oxidase
its relative abundance compared to NADPH-cytochrome P450 reductase makes it the rate-limiting step in the oxidation reactions

26. Cytochrome P450
At least 57 different isozymes in humans, over 7700 forms in Nature
isozyme-catalytically and structurally similar but genetically
distinct enzymes-different genes and amino acid sequences
Different isozymes have different substrate specificities
Individuals have several alleles for P450’s and differ in which isozymes they have
Since individuals have different combinations of P450’s, they differ in their response to specific drugs
A subset of cytochrome P450’s can be induced, so that more is expressed upon exposure to a compound.
Because of the number of different isozymes and their different substrates and inhibitors, the metabolism of a drug can be altered if an individual takes a second drug.

27. Some substrates of cytochrome P450 isozymes

28. Drug Metabolism - Phase II
Conjugation reactions
Glucuronidation by UDP-Glucuronosyltransferase:
(on -OH, -COOH, -NH2, -SH groups)
Sulfation by Sulfotransferase:
(on -NH2, -SO2NH2, -OH groups)
Acetylation by acetyltransferase:
Amino acid conjugation
(on -COOH groups)
Glutathione conjugation by Glutathione-S-transferase:
(to epoxides or organic halides)
Fatty acid conjugation
(on -OH groups)
Condensation reactions

29. Drug Metabolism - Glucuronidation
Glucuronidation ( = conjugation to a-d-glucuronic acid)
Quantitatively the most important phase II pathway for drugs and endogenous compounds
Products are often excreted in the bile.
Enterohepatic recycling may occur due to gut glucuronidases
Requires enzyme UDP-glucuronosyltransferase (UGT):
Genetic family of enzymes
Metabolizes a broad range of structurally diverse endogenous and exogenous compounds
Structurally related family with approximately 16 isoforms in man

30. Drug Metabolism - Glucuronidation
Glucuronidation – requires creation of high energy intermediate:
UDP-Glucuronic Acid:

32. NEXT LECTURE AUTONOMIC NERVOUS SYSTEM APPLIED PHARMACOLOGY

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