BIO PHARMACEUTICS

1. Excretion of Drugs
Praveen Gujjula M.pharm.,(Ph.D)
Department of Pharmaceutics

2. EXCRETION OF DRUGS
➢ “ Excretion is defined as the process where by drugs or
metabolites are irreversibly transferred from internal to
external environment through renal or non renal route.”
➢ Excretion of unchanged or intact drug is needed in
termination of its pharmacological action.
➢ The principal organ of excretion are kidneys.
✓ Agent that excreted in urine are :
1.water soluble 2.non volatile
3. small in molecular size(< 500 daltons.)
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3. TYPES OF EXCRETION
1. RENAL EXCRETION
2. NON RENAL EXCRETION
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Biliary excretion.
Pulmonary excretion.
Salivary excretion.
Mammary excretion.
Skin / Dermal excretion.
Gastrointestinal excretion.
Genital excretion.
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4. ANATOMY OF NEPHRON
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6. Major ExcretoryProcessesin the Nephron
• Glomerular filtration
✓Increase drug concentration in urine
• Tubular secretion
✓Increases drug concentration inurine
• Tubular re-absorption
✓Decreases drug concentration in
urine

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1) GLOMERULAR FILTRATION
• ItIs non selective,unidirectional process
• Ionizedor unionizeddrugs arefiltered,exceptthose thatarebound to plasma
proteins.
• Driving force for GF is hydrostatic pressure of blood flowing in
capillaries.Moleculesoflowmolecularweightarefiltered outoftheblood
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• Mostdrugsarereadilyfiltered fromthebloodunlesstheyaretightlyboundto plasma
proteinorhavebeenincorporatedintoredblood cells.
NormalGFR inhealthyindividuals is110to 130ml/min.
About10%ofthebloodwhichenterstheglomerulusis filtered
GLOMERULAR FILTRATION RATE:
Out of 25% of cardiac output or 1.2 liters of blood/min that goes to the
kidney via renal artery only 10% or 120 to 130ml/min is filtered through
glomeruli. The rate being called as glomerular filtration rate
GFR can be determined by an agent which are excreted by filtration and is
neither reabsorbed nor secreted in tubules. Thisfiltrationrateis often
measuredbydeterminingtherenalclearanceofinulin.,creatinine
Inulinisreadilyfilteredintheglomerulus,andisnotsubjecttotubularsecretion orre-
absorption.ThusinulinclearanceisequaltotheGFR.
• The normal GFR rate is 120-130 ml/min.

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2) ACTIVE TUBULAR SECRETION
• It is carrier mediated active process(requires a carrier and a
supply of energy)
• This mainly occurs in proximal tubule.
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• The process; also subject to competitive inhibition (e.g. Penicillin
& Probenecid), and is saturable.
Not affected by pH and protein binding.
Drugs or compounds which are extensively secreted, such as p-
aminohippuric acid (PAH), may have clearance values
approaching the renal plasma flow rate of 425 to 650 ml/min,
Two secretion mechanisms are identified.
System for secretion of organic acids/anions
E.g. Penicillin, salicylates etc uric acid secreted
System for organic base / cations
E.g. morphine

9. • It occurs after the glomerular filtration of
drugs.
It takes place all along the renal tubules.
• Reabsorption of drugs indicated when the
excretion rate value are less than the GFR
130ml/min.e.g. Glucose
• TR can be active or passive processes.
• Active Tubular Reabsorption:
Its commonly seen with endogenous substances
or nutrients that the body needs to conserve e.g.
electrolytes, glucose, vitamins, amino acids.
3) TUBULAR REABSORPTION

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Passive Tubular Reabsorption:
➢ It is common for many exogenous substances
including drugs. The driving force is Conc.
Gradient which is due to re-absorption of water,
sodium and inorganic ions.
➢ If a drug is neither secreted nor re-absorbed its conc.
In urine will be 100 times that of free drug in plasma.
➢ Reabsorption is mainly depend on several factor that
are pH, pKa, lipophilicity of drug, urine flow rate.

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FACTORS AFFECTING RENAL EXCRETION
1) Urine pH and pKa.
2) Urine flow rate.
3) Physicochemical properties of drug.
4) Distribution and Binding characteristic of drug.
5) Blood flow to the kidneys.
6) Biological factors.
7) Drug interactions.
8) Disease states.

12. i) pH and pKa of the urine :
• It varies between 4.5 to 7.5 depending on the diet (e.g. meat can cause
a more acidic urine) or food rich in carbohydrate ↑ pH
• Many drugs are either weak bases or acids and therefore the pH
of the filtrate can greatly influence the extent of tubular re-
absorption for many drugs.
• When urine is acidic, weak acid drugs tend to be reabsorbed.
Alternatively when urine is more alkaline, weak bases are more
extensively reabsorbed
• Excretion of some drugs can be increased by suitable adjustment of
urine pH e.g. pentobarbital (a weak acid) overdose may be treated by
making the urine more alkaline with sodium bicarbonate injection.
• Acetazolamide(carbonic anhydrase inhibitor) and antacids produce
alkaline urine, while ascorbic acid makes it acidic
• Relative amount of ionized ,unionized drug in the urine at particular
pH & % drug ionized at this pH can be given by “ HENDERSON-
HESSELBACH” equation.

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HENDERSON-HESSELBACH EQUATION
➢ For weak base:
pH=pKa +log [unionized]
[ionized]
➢For weak acids :
pH= pKa +log [ ionized ]
[unionized]
% of drug ionized = 10
(pH – pKa)
X 100
1+10 (pH – pKa)
(pKa - pH)
% of drug ionized = 10 X 100
1+10 (pKa -pH)

14. ✓ A polar & ionized drug will be poorly reabsorbed passively
& excreted rapidly.
✓ Reabsorption is also affected by the lipid solubility of drug ;
an ionized but lipophilic drug will be reabsorbed while an
unionized but polar one will be excreted.
✓ The toxicity due to overdose of the drug whose excretion is
sensitive to pH change can be treated by acidification or
alkalinisation of the urine.

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ii)PHYSICOCHEMICAL PROPERTIES OF DRUG :
Like molecular size, pKa , lipid solubility
Molecular size
Drugs with Mol.wt <300 are excreted in kidney.
Mol.wt 300 to 500 Dalton are excreted both through urine
and bile.
iii)BINDING CHARACTERISTICS OF THE DRUGS :
• Drugs that are bound to plasma proteins behave as
macromolecules and cannot be filtered through
glomerulus.
• Only unbound or free drug appear in glomerular filtrate.
• Protein bound drug has long half lives.

16. iv) BIOLOGICAL FACTORS :
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• Age, sex, species, strain difference etc alter the excretion of
the drug.
Sex – Renal excretion is 10% lower in female than in males.
Age – The renal excretion in newborn is 30-40 % less in
comparison to adults.
Old age – The GFR is reduced and tubular function is altered
which results in slow excretion of drugs and prolonged half
lives.
v) BLOOD FLOW TO THE KIDNEY :
• Important in case of drug excreted by glomerular filteration
and those are actively secreted only.
• Increase the perfusion enhance the elimination.

17. vi) URINE FLOW RATE :
➢ Polar drug are not affected by urine pH hence not get
reabsorbed so unaffected by urine flow rate.
➢ Only those drugs whose reabsorption is pH sensitive Ex.
Weak acids and bases depend on urine flow rate.
➢ Urine flow rate can be incresed by forced diuresis by large
fluid intake or other diuretics.
vii)DRUG INTERACTIONS :
✓Any drug interaction that result in alteration of binding
characteristics, renal blood flow, active secretion, urine pH,
and forced diuresis would alter renal clearance of drug.
✓Alkalinization of urine with citrates and bicarbonates
promote excretion of acidic drugs.

18. viii) DISEASE STATE :
RENAL DYSFUNCTION
• Greatly cause the elimination of drugs those are
primarily excreted by kidney.
• Some of the causes of renal failure are hypertention,
Diabetes, hypovolemiya(low blood supply to kidney),
heavy metals.
UREMIA(azotemia)
• Characterized by Impaired GF , accumulation of fluids
& protein metabolites(NH3),resulting in drug
accumulation and increased toxicity.

19. Drug Clearance :
‘Clearance is defined as the hypothetical volume of body
fluids containing drug from which the drug is removed or
cleared completely in a specific period of time.’
Clearance [CL]=Elimination rate/plasma drug conc.
The sum of individual clearance by all eliminating organ
(kidney, liver, lungs, bilary systems) called as ‘Total body
clearance’.
Renal Clearance ;
• ‘The volume ofplasma which is completely cleared of the unchanged drug by
the kidney per unit time’

20. • If the renal clearance islessthan 120 ml/min then we
canassumethat at least two processesare in operation,
glomerular filtration and tubular re-absorption.
• If the renal clearance isgreater than 120 ml/min
then tubular secretion must be contributing to the
elimination process.
• It isalsopossiblethat all three processesare occurring
simultaneously..

21. ✓Renal clearance values can range from 0 ml/min ( glucose) to a value equal to
the renal plasma flow of about 650 ml/min (for compounds like p-
aminohippuric acid).
✓We can calculate renal clearance using the pharmacokinetic parameters ke and
Vd.
✓CLrenal = ke * Vd.

22. RENAL CLEARANCE
RC = UV/P • RC = rf +rs –rr /P
RC = renal clearance
U = drug concentration in urine
V = flow rate of urine (ml/min)
P = plasma drug concentration
rf = rate of filtration
rs = rate of secretion
rr = rate of re absorption

23. • Biliary Excretion
• Pulmonary Excretion
• Salivary Excretion
• Mammary Excretion
• Skin/dermal Excretion
• Gastrointestinal
Excretion
• Genital Excretion
NON RENAL
EXCRETION
NON-RENAL ROUTE OF DRUG EXCRETION

24. 1 ) BILIARY EXCRETION :
due to increased polarity.
• Ex. of drugs excreted in the bile are chloromphenicol,
morphine and indomethacin.
• The reabsorbed drugs are again carried to the liver
for resecretion via bile into the intestine.
• Bile juice is secreted by hepatic cells of the liver.
• Its Important in the digestion and absorption of fats.
• 90% of bile acid is reabsorbed from intestine(illium) and
transported back to the liver for resecretion.
The metabolites are more excreted in bile than parent drugs
Factors affecting :
1)Molecularweight.2)Polarity.3)Other factor like
sex,spices, disease state, drug interation.

25. Enterohapatic circulation

26. This phenomenon of drug cycling between the intestine & the
liver is called Enterohepatic circulation
Enterohepatic Circulation is important in conservation of
vitamins, folic acid and hormones.
This process results in prolongation of half lives of drugs
like DDT, oral contraceptives.
2 ) PULMONARY EXCRETION :
Gaseous and volatile substances such as general anesthetics
(Halothane) are absorbed through lungs by simple diffusion.
Pulmonary blood flow, rate of respiration and solubility of
substance effect pulmonary excretion.
Intact gaseous drugs are excreted but not metabolites.
Alcohol which has high solubility in blood and tissues are
excreted slowly by lungs.

27. 3 ) SALIVARY EXCRETION :
The pH of saliva varies from 5.8 to 8.4. Unionized lipid
soluble drugs are excreted passively.
The bitter taste in the mouth of a patient is indication
of drug excreted. Some basic drugs inhibit saliva
secretion and are responsible for mouth dryness.
Compounds excreted in saliva are Caffeine, Phenytoin,
Theophylline.mettalic taste in mouth after taking
flagyl(metronidazole) is other example
4 ) MAMMARY EXCRETION :
Milk consists of lactic secretions which is rich in fats and
proteins. 0.5 to one litre of milk is secreted per day in lactating
mothers.
Excretion of drug in milk is important as it gains entry
in breast feeding infants.

28. Highly plasma bound drug like Diazepam is less secreted in milk.
Since milk contains proteins. Drugs excreted can bind to it.
Amount of drug excreted in milk is less than 1% and fraction
consumed by infant is too less to produce toxic effects. Some
potent drugs like barbiturates and morphine may induce toxicity.
ADVERSE EFFECTS :
Discoloration of teeth with tetracycline and jaundice due to
interaction of bilirubin with sulfonamides.
Nicotine is secreted in the milk of mothers who smoke.

29. 5 ) SKIN EXCRETION :
Drugs excreted through skin via sweat follows pH partition
hypothesis.
Excretion of drugs through skin may lead to urticaria and dermatitis.
Compounds like benzoic acid, salicylic acid, alcohol and heavy
metals are excreted in sweat.
6 ) GASTROINTESTINAL EXCRETION :
Excretion of drugs through GIT usually occurs after parenteral
administration.
Water soluble and ionized form of weakly acidic and basic drugs are
excreted in GIT.
Example are nicotine and quinine are excreted in stomach.
Drugs excreted in GIT are reabsorbed into systemic circulation
& undergo recycling.

30. EXCRETIONPATHWAYS,TRANSPORT
MECHANISMS
Excretory
route
Urine
Mechanism Drug Excreted
GF/ ATS/ ATR, PTR Free, hydrophilic, unchanged drugs/
metabolites of MW< 300
Hydrophilic, unchanged drugs/
metabolites/ conjugates of MW >500
Gaseous &volatile, blood & tissue
insoluble drugs
Free, unionized, lipophilic drugs. Some
polar drugs
Free, unionized, lipophilic drugs (basic)
Free, unionized lipophilic drugs
Water soluble. Ionized drugs
Bile Active secretion
Lung Passive diffusion
saliva Passive diffusion
Active transport
Passive diffusion
Passive diffusion
Passive diffusion
Milk
Sweat
Intestine

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