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PharmacokineticsBy;
Mrs. Kalaivani Sathish M. Pharm
Assistant Professor
PIMS - Panipat
What is Pharmacokineticshow the human body act on the drugs? Pharmacokinetics is the quantitative study of drug
movement in, through and out of the body. Intensity of effect is related to concentration of the drug at the site of action, which depends on its pharmacokinetic properties
Pharmacokinetic properties of particular drug is important to determine the route of administration, dose, onset of action, peak action time, duration of action and frequency of dosing
Relationship – Dynamics and Kinetics
AbsorptionDistributionMetabolismExcretion
Dosage Regimen
Concentration in Plasma
Concentration at the site of action
Pharmacokinetics
Pharmacodynamics
Effect
The Pharmacokinetic Process
BIOLOGICAL MEMBRANE
Drug Transportation
Drug molecules can cross cell membrane by:Passive DiffusionProtein – mediated transport (carrier mediated)
Facilitated TransportActive trnsport
Primary Secondary
Passive transport (down hill movement)
Most important Mechanism for most of the Drugs Majority of drugs diffuses across the membrane in the direction of
concentration gradient No active role of the membrane The rate of the transport being Proportional to lipid : water partition
coefficient Lipid soluble drugs diffuse by dissolving in the lipoidal matrix of the
membrane A more lipid solid drug attains higher concentration in the membrane
and diffuses quickly. Also greater the difference in the concentration of the drug on the two
sides of the membrane, faster its diffusion.
Passive transport
Affecting factors : the size of molecule lipid solubility polarity degree of ionization the PH of the environment such as: fluid of body fluid in cell blood, urine
REMEMBER
The drugs which are Unionized, low polarity and higher lipid solubility are easy to permeate membrane.
The drugs which are ionized, high polarity and lower lipid solubility are difficult to permeate membrane.
pH EffectMost of drugs are weak acids or weak
bases. The ionization of drugs may markedly
reduce their ability to permeate membranes.
The degree of ionization of drugs is determined by the surrounding pH and their pKa.
Henderson–Hasselbalch Equation
pKa = negative logarithm of acid dissociation constant
[A-] = ionized Drug
[HA] = unionized drug
Implications
Acidic drugs re absorbed are largely unionized in stomach and absorbed faster while basic drugs are absorbed faster in intestines
Ion trapping Acidic drugs are excreted faster in alkaline urine – urinary
alkalizers Basic drugs are excreted faster in acidic urine – urinary acidifiers
Filtration
Passage of Drugs through aqueous pores in membrane or through Para cellular space
Lipid insoluble drugs can cross – if the molecular size is small
Majority of intestinal mucosa and RBCs have small pores and drugs cannot cross
But, capillaries have large paracellular space and most drugs can filter through this
FILTRATION
Carrier Mediated Transport
Involve specific membrane transport proteins know as drug transporters or carriers – specific for the substrate
Drug molecules bind to the transporter, translocated across the membrane, and then released on the on other side of the membrane.
Specific, saturable and inhibitable
Depending on Energy requirement - Can be either Facilitated (passive) or Active Transport
Facilitative transporters
Move substrate of a single class (uniporters) down a concentration gradient
No energy dependent Similar to entry of
glucose into muscle (GLUT 4)
Active Transport – energy dependent
Active (concentrative) transporters can move solutes against a concentration gradient energy dependent
Primary active transporters - generate energy themselves (e.g. ATP hydrolysis)
Secondary transporters - utilize energy stored in voltage and ion gradients generated by a primary active transporter (e.g. Na+/K+-ATPase)
Symporters (Co-transporters) Antiporters (Exchangers)
Major Drug Transporters• ATP-Binding Cassette Transporters (ABC) Super family –
Primary active transport• P-glycoprotein (P-gp encoded by MDR1)
• Intestinal mucosa, renal tubules and blood brain barrier etc.• Mediate only efflux of solute from cytoplasm - detoxification
Solute Carrier (SLC) transporters – Secondary active transport Organic anion transporting polypeptides (OATPs) Organic cation transporters (OCTs)
Expressed in liver and renal tubules – metabolism and excretion of drugs
It involves the invagination of a part of the cell membrane and trapping within the cell of a small vesicle containing extra cellular constituents. The vesicle contents can than be released within the cell, or extruded from the other side of the cell. Pinocytosis is important for the transport of some macromolecules (e.g. insulin through BBB).
Pinocytosis
1. Absorption of Drugs Absorption is the transfer of
a drug from its site of administration to the blood stream
Most of drugs are absorbed by the way of passive transport
Intravenous administration has no absorption
Fraction of administered dose and rate of absorption are important
Factors affecting absorption
Drug properties:lipid solubility, molecular weight, and polarity etc
Blood flow to the absorption siteTotal surface area available for absorptionContact time at the absorption surfaceAffinity with special tissue
Routes of Administration (important):
Route of administration: Topical:
Depends on lipid solubility – only lipid soluble drugs are penetrate intact skin – only few drugs are used therapeutically
Examples – Hyoscine, Fentanyl, Nicotine, testosterone and estradiol
Organophosphorous compounds – systemic toxicity Abraded skin (burnt skin ): tannic acid – hepatic necrosis Cornea permeable to lipid soluble drugs (absorbed from
nasolacrimal duct) e.g. timolol may produce bradycardia and pricipitate asthma.
Mucus membranes of mouth, rectum, vagina etc, are permeable to lipophillic drugs
Route of administration:Subcutaneous and Intramuscular:
Drugs directly reach the vicinity of capillaries – passes capillary endothelium and reach circulation.
Capillaries having large paracellular spaces do not abstract absorption of large lipid insoluble molecules or ions.
Very large molecules are absorbed through lymphatics.Passes through the large paracellular poresFaster and more predictable than oral absorptionExercise and heat – increase absorptionAdrenaline – decrease absorption
Route of administration: Oral Route Physical properties – Physical state, lipid
or water solubility Dosage forms:
Particle size Disintegration time and Dissolution Rate Formulation – Biopharmaceutics
Physiological factors: Ionization, pH effect Presence of Food Presence of Other agents
Oral Administration – 1st pass metabolism
Before the drug reaches the systemic circulation, the drug can be metabolized in the liver or intestine. As a Result, the concentration of drug in the systemic circulation will be reduced.
Absorption – contd.Intravenous administration has no absorption phaseAccording to the rate of absorption:
Inhalation→Sublingual→Rectal→intramuscular→subcutaneous→oral→transdermal
Example – Nitroglycerine: IV effect – immediate, SL – 1 to 3 min and per rectal
– 40 to 60 minute
Bioavailability Bioavailability refers to the rate and extent of absorption of a drug
from dosage form as determined by its concentration-time curve in blood or by its excretion in urine. It is a measure of the fraction (F) of administered dose of a drug that reaches the systemic circulation in the unchanged form
Bioavailability of drug injected i.v. is 100%, but is frequently lower after oral ingestion, because:
The drug may be incompletely absorbed The absorbed drug may undergo first pass metabolism in intestinal wall
and/or liver or be excreted in bile. Practical Significance – low safety margin drugs
Biovailability – contd.
MTC
MEC
BIOEQUVALENCE
Oral formulation of a drug from different manufactures or different batches from the same mfr may have the same amount of the drug (chemically equvalent) but may not yield the same blood levels- biologically inequivalent .
Before a drug administered orally in solid dosage form can be absorbed,it must break into individual particle of the active drug (disintegration) .Tablets and capsules contains-diluents,stabilizing agents ,binders ,lubricants etc.
Manufacture process – force used in compressing the tablet may affect disintegration.
The rate of dissolution – solubility, particle size, crystal form,and other physical properties of the drug.
Differences in bioavilability- may arise due to variation in Disintegration and dissolution rates.
Reduction in particle sizees the rate of absorption of asprin(micrifine tablet)
2. Distribution of Drugs
It is the passage of drug from the circulation to the tissue and site of its action.
The extent of distribution of drug depends on its lipid solubility, ionization at physiological pH (dependent on pKa), extent of binding to plasma and tissue proteins and differences in regional blood flow,
Movement of drug - until equilibration between unbound drug in plasma and tissue fluids
Volume of Distribution (V)
Definition: Apparent Volume of distribution is defined as the volume that would accommodate all the drugs in the body, if the concentration was the same as in plasma
Expressed as: in Liters
V =
Dose administered IV
Plasma concentration
Volume of Distribution (V)
Total Body Fluid = 42 L (approx.)
Volume of Distribution (V)
Chloroquin – 13000 liters, Digoxin – 420 L, Morphine – 250 L and Propranolol – 280 L
Streptomycin and Gentamicin – 18 L
Factors influencing Vd
Lipid solubility (lipid : water partition coefficient)
pKa of the drugAffinity for different tissuesBlood flow – Brain Vs FatDisease statesPlasma protein Binding
RedistributionHighly lipid soluble drugs – distribute
to brain, heart and kidney etc. immediately followed by muscle and Fats
later ,less vascular but more bulky tissues take up the drug –plasma concentration falls and the drug is withdrawn from the sites.
Redistribution results in termination of the drug action. Greater lipid solubility of a drug ,faster is its
redistribution. Aneathetic action of thiopentone terminated in few min
due to redistribution.
Blood brain barrier (BBB): includes the capillary endothelial cells (which have tight junctions and lack large intracellular pores) and an investment of glial tissue, over the capillaries.
Brain and CSF Penetration
Brain and CSF Penetration – contd BBB is lipoidal and limits the entry of non-lipid soluble drugs
(amikacin, gentamicin, neostigmine etc.).(Only lipid soluble unionized drugs penetrate and have action
on the CNS) Efflux carriers like P-gp (glycoprotein) present in brain
capillary endothelial cell (also in intestinal mucosal, renal tubular, hepatic canicular, placental and testicular cells) extrude drugs that enter brain by other processes
brain increases permeability of BBB) Dopamine (DA) does not enter brain, but its precursor
levodopa does. This is used latter in parkinsonism.
Placental Transfer
Only lipid soluble Drugs can penetrate – limitation of hydrophillic drugs
Placental P-gp serves as limiting factorBut, REMEMBER, its an incomplete
barrier – some influx transporters operate
Thalidomide
Plasma Protein Binding Plasma protein binding (PPB): Most drugs possess
physicochemical affinity for plasma proteins. Acidic drugs bind to plasma albumin and basic drugs to α1-glycoprotein
Extent of binding depends on the individual compound. Increasing concentration of drug can progressively saturate the binding sites
The clinical significant implications of PPB are:a) Highly PPB drugs are largely restricted to the vascular
compartment and tend to have lower Vd.b) The PPB fraction is not available for action.c) There is an equilibration between PPB fraction of drug and
free molecules of drug.
Plasma Protein Binding – contd.d) The drugs with high physicochemical affinity for plasma
proteins (e.g. aspirin, sulfonamides, chloramphenicol) can replace the other drugs(e.g. acenocoumarol, warfarin) or endogenous compounds (bilirubin) with lower affinity.
e) High degree of protein binding makes the drug long acting, because bound fraction is not available for metabolism, unless it is actively excreted by liver or kidney tubules.
f) Generally expressed plasma concentrations of the drug refer to bound as well as free drug.
g) In hypoalbuminemia, binding may be reduced and high concentration of free drug may be attained (e.g. phenytoin).
3. BiotransformationMetabolism of Drugs
What is Biotransformation? Chemical alteration of the drug in the bodyAim: to convert non-polar lipid soluble
compounds to polar lipid insoluble compounds to avoid reabsorption in renal tubules
Most hydrophilic drugs are less biotransformed and excreted unchanged – streptomycin, neostigmine and pancuronium etc.
Biotransformation is required for protection of body from toxic metabolites
Results of Biotransformation1. Active drug and its metabolite to inactive metabolites –
most drugs (ibuprofen, paracetamol, chlormphenicol etc.)2. Active drug to active product (phenacetin –
acetminophen or paracetamol, morphine to Morphine-6-glucoronide, digitoxin to digoxin etc.)
3. Inactive drug to active/enhanced activity (prodrug) – levodopa - carbidopa, prednisone – prednisolone and enlpril – enlprilat)
4. No toxic or less toxic drug to toxic metabolites (Isonizide to Acetyl isoniazide)
(teratogenicity, carcinogenicity, hepatotoxicity)
Biotransformation - Classification 2 (two) Phases of
Biotransformation:• Phase I or Non-synthetic
– metabolite may be active or inactive
• Phase II or Synthetic – metabolites are inactive (Morphine – M-6 glucoronide is exception)
Phase I - OxidationMost important drug metabolizing reaction –
addition of oxygen or (–ve) charged radical or removal of hydrogen or (+ve) charged radical
Various oxidation reactions are – oxygenation or hydroxylation of C-, N- or S-atoms; N or 0-dealkylation
Examples – Barbiturates, phenothiazines, paracetamol and steroids
Phase I - Oxidation Involve – cytochrome P-450 monooxygenases (CYP),
NADPH and Oxygen More than 100 cytochrome P-450 isoenzymes are
identified and grouped into more than 20 families – 1, 2 and 3 …
Sub-families are identified as A, B, and C etc. In human - only 3 isoenzyme families important – CYP1,
CYP2 and CYP3 CYP 3A4/5 carry out biotransformation of largest
number (30–50%) of drugs. In addition to liver, this isoforms are expressed in intestine (responsible for first pass metabolism at this site) and kidney too
Inhibition of CYP 3A4 by erythromycin, clarithromycin, ketoconzole, itraconazole, verapamil, diltiazem and a constituent of grape fruit juice is responsible for unwanted interaction with terfenadine and astemizole
Rifampicin, phenytoin, carbmazepine, phenobarbital are inducers of the CYP 3A4
Nonmicrosomal Enzyme Oxidation
Some Drugs are oxidized by non-microsomal enzymes (mitochondrial and cytoplsmic) – Alcohol, Adrenaline, Mercaptopurine
Alcohol – DehydrogenaseAdrenaline – MAO and COMT(catechol –o-methyl
transferase)Mercaptopurine – Xanthine oxidase
Phase I - Reduction
This reaction is conversed of oxidation and involves CYP 450 enzymes working in the opposite direction.
Examples - Chloramphenicol, levodopa, halothane and warfarin
Levodopa (DOPA) Dopamine
DOPA-decarboxylase
Phase I - Hydrolysis This is cleavage of drug molecule by taking up of a molecule of water. Similarly
amides and polypeptides are hydrolyzed by amidase and peptidases. Hydrolysis occurs in liver, intestines, plasma and other tissues.
Examples - Choline esters, procaine, lidocaine, pethidine, oxytocin
Ester + H20 Acid + AlcoholEsterase
Phase I – contd.
Cyclization: is formation of ring structure from a straight chain compound, e.g. proguanil.
Decyclization: is opening up of ring structure of the cyclic molecule, e.g. phenytoin, barbiturates
Phase II metabolism Conjugation of the drug or its phase I metabolite with an endogenous
substrate - polar highly ionized organic acid to be excreted in urine or bile - high energy requirements
Glucoronide conjugation - most important synthetic reaction
Compounds with hydroxyl or carboxylic acid group are easily conjugated with glucoronic acid - derived from glucose
Examples: Chloramphenicol, aspirin, morphine, metroniazole, bilirubin, thyroxine
Drug glucuronides, excreted in bile, can be hydrolyzed in the gut by bacteria, producing beta-glucoronidase - liberated drug is reabsorbed and undergoes the same fate - enterohepatic recirculation (e.g. chloramphenicol, phenolphthalein, oral contraceptives) and prolongs their action
Phase II metabolism – contd.
Acetylation: Compounds having amino or hydrazine residues are conjugated with the help of acetyl CoA, e.g.sulfonamides, isoniazid
Genetic polymorphism (slow and fast acetylators) Sulfate conjugation: The phenolic compounds and
steroids are sulfated by sulfokinases, e.g. chloramphenicol, adrenal and sex steroids
Factors affecting Biotransformation
Factors affecting biotransformation Concurrent use of drugs: Induction and inhibition Genetic polymorphism Pollutant exposure from environment or industry Pathological status Age
Enzyme Inhibition
One drug can inhibit metabolism of other – if utilizes same enzyme
However not common because different drugs are substrate of different CYPs
A drug may inhibit one isoenzyme while being substrate of other isoenzyme – quinidine
Some enzyme inhibitors – Omeprazole, metronidazole, isoniazide, ciprofloxacin and sulfonamides
Microsomal Enzyme Induction
CYP3A – antiepileptic agents - Phenobarbitone, Rifampicin and glucocorticoide
CYP2E1 - isoniazid, acetone, chronic use of alcohol Other inducers – cigarette smoking, charcoal broiled meat, industrial
pollutants – CYP1A Consequences of Induction:
Decreased intensity or duration of action of drugs – Failure of OCPs Increased intensity – Paracetamol poisoning Tolerance – Carbmazepine (if the drug induce its own metabolism) Some endogenous substrates are metabolized faster – steroids, bilirubin
4. Excretion
Organs of Excretion
Excretion is a transport procedure which the prototype drug (or parent drug) or other metabolic products are excreted through excretion organ or secretion organ
Hydrophilic compounds can be easily excreted. Routes of drug excretion
Kidney Biliary excretion Sweat and saliva Milk Pulmonary
Hepatic Excretion Drugs can be excreted in bile, especially when the are conjugated with – glucuronicAcid
• Drug is absorbed glucuronidated or sulfatated in the liver and secreted through the bile glucuronic acid/sulfate is cleaved off by bacteria in GI tract drug is reabsorbed (steroid hormones, rifampicin, amoxycillin, contraceptives)
• Anthraquinone, heavy metals – directly excreted in colon
Portal vein
Bile duct
Intestines
Renal Excretion
Glomerular FiltrationTubular ReabsorptionTubular Secretion
Glomerular Filtration Normal GFR – 120 ml/min Glomerular capillaries have pores larger than usual The kidney is responsible for excreting of all water soluble
substances All nonprotein bound drugs (lipid soluble or insoluble)
presented to the glomerulus are filtered Glomerular filtration of drugs depends on their plasma
protein binding and renal blood flow - Protein bound drugs are not filtered !
Renal failure and aged persons
Tubular Re-absorption Back diffusion of Drugs (99%) – lipid soluble drugs Depends on pH of urine, ionization etc. Lipid insoluble ionized drugs excreted as it is – aminoglycoside (amikacin,
gentamicin, tobramycin) Changes in urinary pH can change the excretion pattern of drugs
Weak bases ionize more and are less reabsorbed in acidic urine. Weak acids ionized more and are less reabsorbed in alkaline urine
Utilized clinically in salicylate and barbiturate poisoning – alkanized urine (Drugs with pKa: 5 – 8)
Acidified urine – atropine and morphine etc.
Tubular Secretion
Energy dependent active transport – reduces the free concentration of drugs – further, more drug dissociation from plasma binding – again more secretion (protein binding is facilitatory for excretion for some drugs) OATP – organic acid transport OCT – organic base transport P-gp
Bidirectional transport – Blood Vs tubular fluid Utilized clinically – penicillin Vs probenecid, probenecid Vs uric acid
(salicylate)• Quinidine decreases renal and biliary clearance of digoxin by inhibiting
efflux carrier P-gp
Renal Excretion
Acidic urine alkaline drugs eliminated
acid drugs reabsorbed
Alkaline urine - acid drugs eliminated
- alkaline drugs absorbed
Kinetics of Elimination Pharmacokinetics - F, V and CL Clearance: The clearance (CL) of a drug is the
theoretical volume of plasma from which drug is completely removed in unit time
CL = Rate of elimination (RoE)/CExample = If a drug has 20 mcg/ml and RoE is 100
mcg/minCL = 100/20 = 5 ml /min
Kinetics of Elimination
First Order Kinetics (exponential): Rate of elimination is directly proportional to drug concentration, CL remaining constant Constant fraction of drug is eliminated per unit time
Zero Order kinetics (linear): The rate of elimination remains constant irrespective of drug concentration CL decreases with increase in concentration Alcohol, theophyline, tolbutmide etc.
Plasma half-life
Defined as time taken for its plasma concentration to be reduced to half of its original value – 2 phases rapid declining and slow declining
t1/2 = In2/kIn2 = natural logarithm of 2 (0.693)k = elimination rate constant = CL / V
t1/2 = 0.693 x V / CL
CL = RoE/C
V = dose IV/C
Plasma half-life
1 half-life …………. 50% 2 half-lives………… 25% 3 half-lives …….…..12.5% 4 half-lives ………… 6.25%
50 + 25 + 12.5 + 6.25 = 93.75
93.75 + 3.125 + 1.56 = 98% after 5 HL
Excretion - The Platue Principle
Repeated dosing:• When constant dose of a drug is repeated before the expiry of 4 half-life – peak concentration is achieved after certain interval• Balances between dose administered and dose interval
Repeated Dosing
At steady state, elimination = inputCpss = dose rate/CLDose Rate = target Cpss x CLIn oral administration Dose rate = target Cpss x CL/FIn zero order kinetics: follow Michaelis Menten
kineticsRoE = (Vmax) (C) / Km + CVmax = max. rate of drug elimination, Km = Plasma
conc. In which elimination rate is half maximal
CL = Roe/C
Target Level Strategy Low safety margin drugs (anticonvulsants, antidepressants,
Lithium, Theophylline etc. – maintained at certain concentration within therapeutic range
Drugs with short half-life (2-3 Hrs) – drugs are administered at conventional intervals (6-12 Hrs) – fluctuations are therapeutically acceptable
Long acting drugs: Loading dose: Single dose or repeated dose in quick succession – to
attain target conc. Quickly Loading dose = target Cp X V/F
Maintenance dose: dose to be repeated at specific intervals
Monitoring of Plasma concentration
Useful in Narrow safety margin drugs – digoxin, anticonvulsants,
antiarrhythmics and aminoglycosides etc Large individual variation – lithium and antidepressants Renal failure cases Poisoning cases
Not useful in Response mesurable drugs – antihypertensives, diuretics etc Drugs activated in body – levodopa Hit and run drugs – Reseprpine, MAO inhibitors Irreversible action drugs – Orgnophosphorous compounds
Summary – Must Know Definition of Pharmacokinetics Transport of Drugs across Biological Membrane – different
processes with example Factors affecting absorption of drugs Concept of Bioavailability Distribution of Drugs – Vd and its concept Biotransformation Mechanisms with examples Enzyme induction and inhibition concept and important
examples Routes of excretion of drugs Orders of Kinetics Definition and concept of drug clearance Definition of half life and platue principle
Prolongation of Drug action
By prolonging absorption from the site of action – Oral and parenteral
By increasing plasma protein bindingBy retarding rate of metabolismBy retarding renal excretion