1. Electives block 2.3 (2018-19) Introduction to pharmacology - kinetics
Elimination of drugs
Electives block 2.3 ( )
Introduction to pharmacology - kinetics
Prof Asghar Mehdi
Ph.D
Sulaiman Alrajhi College
Pharmacology

2. Objectives Clearance of drugs. Elimination of drugs - sites
Review of renal physiology.
Nature of drugs & factors affecting elimination.
Drug half life
Steady state concentration & Maintenance dose.
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3. Excretion of Drugs
Excretion is the removal of waste substances from body fluids and predominantly occurs via kidneys.
The process by which drugs or metabolites are irreversibly transferred from internal to external environment through renal or non renal route.
Most drugs are excreted in urine either as unchanged drugs or drug metabolites
There are other organs that contribute in the elimination of waste products and the drugs.
Some drugs are lipophilic ->through the process of metabolism converted into hydrophilic -> excreted out.
Drugs could be excreted out by non-renal excretion (pulmonary, salivary, biliary, dermal, and mammary) excretion.
- What is the significance of knowing extra-renal routes of excretion? Why it is so important?
For example, we should be cautious if a lactating mother takes drugs that are excreted primarily by mammary route.
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4. Routes of Excretion Non Renal Excretion Pulmonary Excretion
Salivary Excretion
Dermal excretion
Biliary Excretion
Mammary Excretion
Renal excretion
As kidneys are the predominant excretion route, sometimes we use them only to estimate total clearance of the plasma from a drug.
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5. About 20% of this is converted to glomerular ultra filtrate.
Physiology
The two kidneys constitute less than 1% of the total body weight, but receive about 25% of the cardiac output.
Afferent arterioles from the renal artery supply blood to the glomerulus at arterial pressure.
About 20% of this is converted to glomerular ultra filtrate.
Further reabsorption & secretion takes place at various points along the nephron.
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6. Physiology
The final product (urine) is only about 1% of the volume of the original glomerular filtrate.
Most drugs are metabolized first prior to being excreted. However, some drugs, such as aminoglycoside antibiotics are polar compounds and are excreted by the kidneys without being metabolized first.
Aminoglycoside: polar compounds, means they are charged, therefore, they will remain in the central vascular compartment. They are excreted as such without being metabolized.
If a person is having cirrhosis the metabolism by the liver will be effected, then Aminoglycoside (Gentamicin) group will be a good choice as they don’t need to be metabolized by the liver and they are confined in the central compartment
Gentamicin has got a propensity to deal with gram negative infections.
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7. Renal Excretion of drugs
The most important organ for drug excretion is the kidney.
The principle processes that determine urinary excretion of drugs are:
Glomerular filtration.
Active tubular secretion.
Passive or active tubular re-absorption.
Each site of the nephron is specific for its own purpose and is affected by the ion exchange.
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8. ↑ Excretion of dugs ↑ renal blood flow ↑Glomerular filtration
↓ Plasma protein binding
Because of ↑ glomerular filtration
Plasma protein binding will decrease the excretion of drugs.
Sometimes we combine Probenecid with Penicillin, to prolong Penicillin’s duration of action, as Probenecid competes Penicillin and gets excreted out.
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9. GLOMERULAR FILTRATION
Glomerular filtration occurs to:
Low molecular weight drugs
Free form of the drugs (not bound to plasma proteins).
Water soluble drugs , Aminoglycosides.
Drugs with low volume of distribution (Vd)
The amount of blood filtered by the glomeruli in a given time (GFR = ml/min)
Glomerular capillaries allow drug molecules of molecular weight below about to pass into the glomerular filtrate
Plasma albumin molecular weight approx is almost completely impermeant
Most drugs molecules cross the barrier freely.
If a drug binds to plasma albumin, only free drug is filtered
Anything is bound with plasma albumin will not be excreted.
Warfarin, a drug is 98% bound to albumin, concentration in filtrate is only 2% of that in plasma, and clearance by filtration is correspondingly reduced.
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10. Tubular secretion
Up to 20% of renal plasma flow is filtered through glomerulus, leaving at least 80% of delivered drug to pass on to the peritubular capillaries of the proximal tubule.
Because at least 80% of the drug delivered to the kidney is presented to the carrier, tubular secretion is potentially the most effective mechanism of renal drug elimination.
Unlike glomerular filtration, carrier-mediated transport can achieve maximal drug clearance even when most of the drug is bound to plasma protein.
Carrier mediators take care of drugs which are plasma protein bound.
Penicillin, although about 80% protein bound and therefore cleared only slowly by filtration, is almost completely removed by proximal tubular secretion, and is therefore rapidly eliminated
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11. OAT OCT Tubular secretion
Drug molecules are transferred to the tubular lumen by two independent and relatively non-selective carrier systems
acidic drugs
endogenous acids, such as uric acid
OAT
organic bases
OCT
The OAT carrier can transport drug molecules against an electrochemical gradient, and can therefore reduce the plasma concentration nearly to zero.
OCT facilitates transport down electrochemical gradient
The competition for each carrier depends on the affinity of certain drug to these carriers.
Low-affinity drugs will be available more in the vascular compartment and could lead to toxicity.
Many drugs compete for the same transport system, leading to drug interactions. Like, probenecid was developed originally to prolong action of penicillin by retarding its tubular secretion.
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12. DIFFUSION ACROSS THE RENAL TUBULE
The degree of ionization of many drugs—weak acids or weak bases—is pH dependent.
Ion-trapping effect means that a basic drug is more rapidly excreted in an acid urine which favors the charged form and thus inhibits reabsorption. Conversely, acidic drugs are most rapidly excreted if the urine is alkaline
if the tubule is freely permeable to drug molecules, some 99% of the filtered drug will be reabsorbed passively down the resulting concentration gradient
Lipid-soluble drugs are therefore excreted poorly, whereas polar drugs of low tubular permeability remain in the lumen and become progressively concentrated as water is reabsorbed
volume of urine being only about 1% of glomerular filtrate
Water is reabsorbed as fluid traverses the tubule
If the water is reabsorbed, then the drug remains concentrated in the urine.
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13. Group of drugs that are not affected by metabolism.
Only renal elimination determines their duration of action
Furosemide: loop diuretic.
Methotrexate: used to treat cancer.
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14. Polar drug= water soluble
Non polar drug = lipid soluble
Red drugs pass unchanged.
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15. Elimination - clearance
Clearance: Volume of plasma that is cleared of drug per unit time.
Elimination rate: is mass/amount of drug that is cleared from the body.
Clearance is related with elimination by a constant proportion factor.
If the clearance is low then less drug lost in urine and more in body.
If the clearance is high then more drug in urine and less in body.
Inverse relationship – decreased GFR – increased plasma concentration.
Units are in L/hr or L/hr/kg
If the drug is not eliminated as fast as it is given = more will be available.
This is an inverse relationship between clearance and the availability of drug in the body.
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16. Clearance Volume of plasma that is cleared of drug per unit time Volume per unit time = ml/min
Clearance = Elimination rate VOLUME Plasma drug conc
Rate of drug elimination = Cl X Conc amount of drug MASS
Cl = 40 mg/hr in urine = 2 ml/hr mg/ ml (remaining)
Clearance is related with elimination by a constant proportionate factor
Cl = 120 mg/hr in urine = 6 ml/hr mg/ ml (remaining)
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17. To calculate Dose & Frequency of drugs Two vital things of drugs which determine their behavior
Clearance
Volume of distribution
Inverse relationship
Low Vd – high conc in plasma, distributed in blood large charged molecules, Hydrophilic & high clearance.
High Vd – Low conc in plasma, Hydrophobic, lipophilic, bound to proteins & fat tissues
Inverse relationship
Low = Less drug is lost in urine, more in the body.
High = More drug is lost in urine, less in the body.
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19. Exponential decay refers to fixed percentage (not the volume) of a drug that is removed from the system (plasma is cleared by fixed percentage).
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24. Drug Half-Life
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25. Natural log 2 which is equal to 0. 7
Natural log 2 which is equal to 0.7. This is the extraction ratio of an organ.
0.2
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32. If we take oral route as an example, absorption will be more than the elimination in the first half, and the concentration of drug will rise.
In the second half (for oral route), absorption will be less, elimination will be more, and the concentration of the drug will fall (decrease).
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34. Kinetics of Metabolism:
First Order Kinetics
Zero Order Kinetics
The rate of drug metabolism is constant and independent of the drug dose.
A constant amount of drug is metabolized per unit of time.
The rate of drug metabolism is directly proportional to the concentration of the drug.
A constant fraction of drug is metabolized per unit of time.
Difference between two:
First order kinetics depends on the concentration and it follows exponential decay while Zero order kinetics depends on fixed amount of a drug.
In first order kinetics, the line never touches the zero level of baseline as there are some drugs are left, but in zero order kinetics it can touch the baseline.
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36. Factors affecting renal excretion of drug
Physiochemical properties of drugs
Molecular weight
Lipid solubility
Volume of distribution
Binding character
Degree of ionization
Blood flow to the kidney - CCF
Urine pH
Biological factor - Age
Disease states
In cardiac failure, we expect the drug will remain in the system more than a normal person because the kidneys doesn’t get adequate blood flow, therefore, the elimination is decreased, but there could be renal problems. In such problems, although there is an adequate blood flow kidneys are not working properly.
After age of 40, renal function starts to decline.
Diabetes and Hypertension affect renal functions invariably, even with a good control.
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37. Factors affecting renal excretion
Drug MW: larger MW drugs are difficult to be excreted than smaller MW especially by glomerular filtration. Drug lipid solubility: urinary excretion is inversely related to lipophilicity, increased lipid solubility increase volume of distribution of drug and decrease renal excretion. Volume of distribution: clearance is inversely related to volume of distribution of drugs (Vd). A drug with large Vd is poorly excreted in urine. Drugs restricted to blood (low Vd) have higher excretion rates.
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38. Factors affecting renal excretion
Renal blood flow: increased perfusion leads to increased excretion; important for drugs excreted by glomerular filtration. 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. Biological factor: age can affect renal clearance. Renal clearance is reduced in neonates and elderly. Disease states impairs the elimination of drugs e.G. Hypertension, diabetes, pyelonephritis
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39. URINE pH
Urine pH is a great influence on whether a drug is excreted quickly or slowly and in some clinical situations is manipulated to control the excretion of certain drugs from the body.
Urine is normally slightly acidic and favors excretion of basic drugs.
Most drugs are either weak acids or weak bases. In alkaline urine, acidic drugs are more readily ionized. In acidic urine, alkaline drugs are more readily ionized. Ionized substances (also referred to as polar) are more soluble in water so dissolve in the body fluids more readily for excretion.
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40. Urinary pH trapping
It is used to enhance renal clearance of drugs during toxicity.
Urine acidification: by ammonium chloride (NH4Cl) increases excretion of basic drugs (amphetamine).
Urine alkalization: by sodium bicarbonate NaHCO3 increases excretion of acidic drugs (aspirin).
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41. Ion trapping Consider a barbiturate (weak acidic drug) overdose.
Urine Blood
pH pH 7.4
Non-ionised weak acid drug +
Ionized
Urine
Most of acidic drug will be reabsorbed back into body.
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42. Ion trapping
In presence of sodium bicarbonate, urine is alkaline and more excretion of acidic drug into urine
Urine Blood
pH pH 7.4
Less Non-ionised weak acid drug +
More Ionized
Urine
Most of acidic drug will be eliminated into urine.
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43. Effect of Lipid solubility and pH
ionised drug is less lipid soluble
Glomerular blood flow; filtrate
99% of GF is re-absorbed;
concentration of drug rises in tubule
If lipid soluble drug moves
down concentration gradient back into blood
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Re-absorption

44. Drug renal clearance:
If renal clearance is impaired, this may increase
T ½ of drugs and toxic levels of drugs may remain in the body.
Renal clearance is especially important for some drugs which are:
Mainly excreted by the kidney
Have narrow therapeutic index (eg. Lithium, digoxin, warfarin). 
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45. So what should we do in renal impairment?
Diseases that can decrease renal clearance
Reduced renal blood flow
Congestive heart failure.
Hemorrhage
Cardiogenic shock
Decreased renal excretion :
renal disease (eg. Glomerulonephritis).
This may increase half-life (t ½ ) of drugs
So what should we do in renal impairment?
Dose reduction of drugs is required (when creatinine clearance is below 60 ml/min).
Keep the usual dose but prolong the dosing intervals (eg. Gentamicin)
Decrease the dose without changing dosing intervals (eg Digoxin)
Monitor blood levels of drugs (therapeutic drug monitoring).
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46. Dose reduction in renal impairment
Antibiotics:
Penicillins, cephalosporins
Aminoglycosides (gentamycin)
Sulfonamides
Non steroidal anti-inflammatory drugs (NSAID’s)
Lithium
Digoxin
Immunosuppressants (cyclosporine)
Anticancer drugs (cisplatin - cyclophosphamide)
When dose reduction is not required in renal impairment ?
Drugs like Ceftriaxone, minocycline that are excreted into feces (biliary excretion) doesn’t need dose adjustment in renal impairment.
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50. Thank you References
Basic & clinical Pharmacology Katzung 12th edition
Lippincott’s Pharmacology 6th edition.
Rang & Dale 8th edition
Clinical pharmacology 11th edition peter Bennett
Principles of pharmacology: the pathophysiologic basis of drug therapy, By Golan 2nd edition
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