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PHARMACOKINETICS
Pharmacokinetic is the study of the movement of drugs in the body.
Processes of Pharmacokinetics
(i) Absorption
(ii) Distribution
(iii) Metabolism (Bio-transformation)
(iv) Elimination
Cell Mb: Consists of a bilayer of Amphipathic lipids with the hydrocarbon chains oriented inward to the
center of the bilayer to form a continuous hydrophobic phase and their hydrophilic head is oriented
outward.
Drugs cross the membrane either by passive processes or by mechanism involving active participation of
components of the Mb.
A. Passive Transport
(i) Simple diffusion-most common-usually lipid soluble drug. e.g Propranolol, Diazepam,
Thiopentone Na…..
(ii) Paracellular transport.
B. Active Transport
(i) Facilitated diffusion e.g BI2, folic acid
(ii) Drug transporters
Facilitated transport: Describes a carrier-mediated transport process in which there is no input of
energy.
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Absorption
It is the movement of a drug from its site of administration into the central compartment and the extent
to which this occurs.
2. Water/Lipid solubility
Drug given in aqueous solution mix more readily with the aqueous phase of the
absorbing the surface than when given in solution.
Aqueous solution more easily absorbed.
3. Particle size
Solid dosage forms containing smaller particles-microfine crystals are better absorbed
from the gut. e.g Aspirin , Warfarin ,Griseofulvin.
Solid dosage containing larger particles are little absorbed e.g Neomycin.
6. Dissolution-Time of a drug
Time taken for a solid dosage form e.g tablet to go into the solution form in the gut after
it has disintegrated. Shorter dissolution time, higher will be the rate of absorption.
7. Enteric-coated tablet
They are made-enteric coated by means of cellulose/Phthalate.
They resist disintegration & dissolution by gastric juice, but permits disintegration
& dissolution in alkaline medium of the gut.
They have prolonged action- e.g S.R Tablet-Prolonged action.
The higher the blood flow, the more and faster is the absorption.
4. Route of absorption
1. Epithelial lining of GIT is lipoidal; lipid soluble drug are better absorbed.
2. Gastric juice is acidic; therefore acidic drugs are readily absorbed from the stomach as they are non-
ionised. e.g Aspirin /ethanol.
In general food in stomach retards absorption e.g Rifampicin, Ampicicillin, Iron, Isonicinil.
Rifampicin is best given on empty stomach.
Fatty food increases the absorption of:
Ribavirin
Albendazole /Mebendazole
Effavirenz
Atovaquone
Vitamin C increases absorption of Iron.
Phytates /oxalates decreases absorption of iron
Iron & Tetracycline (tetracycline chelates iron)
Phenytoin &sucralfate (sucralfate decreases the absorption of phenytoin).
6. Rate of absorption increases with increasing rate of gastric emptying. Pregnancy delays gastric
emptying: decreases absorption by oral route.
Migraine also cause gastro-paresis
PCM + Metoclopramide
Rabeprazole + Domperidone in Gastroparesis
7. Pathological state
CCF→Mucosal oedema delays absorption
GIT→Malabsorption
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C. Topical
Inflamed, Denuded areas has increased vascularity such that absorption of the given drug
increases drastically to such an extent that toxicity can easily occurs.
Contact time of the site of absorption: If a drug moves through the GIT very quickly as in severe
diarrhea, it will not be absorbed.
N.B: Anything that delays the transport of drug from stomach →Intestine → delays rate of
absorption. e,gDicyclomine
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Bio-availability
It is defined as the fraction of the drug dose that reaches the systemic circulation in unchanged
form after pre-systemic elimination and is available for action.
Bio-availability
IV route : 100%
Oral: 0- 100%
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Entero-hepatic Recycling
It is the process of re-circulation of drugs whereby the drug enters the liver from intestine by portal vein
and back to the intestine via Bile-duct.
β-Glucoronidase is needed for entero-hepatic recycling to occur. Hydrolysis is needed such that
reabsorption can occur.
Significance
1. Help in prolongation of action of the drug but however decreases its potency.
2. Certain drugs inhibit EHC and are useful in the treatment of toxicities of drugs that are capable
of undergoing entero-hepatic recycling.
e.g Activated charcoal
Anion exchange resin for Digoxin
Drug Distribution
It refers to the reversible transfer of a drug between the blood and the extravascular fluids and Tissues
of the body (e.g fat, muscle & brain tissue).
Distribution of a drug is not uniform throughout the body because different tissues receive the drug
from plasma at different rates and to different extents.
Following absorption or systemic administration into the blood stream, a drug distributes into interstitial
and intracellular fluids.
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Redistribution
Highly lipid soluble drugs when given by IV or inhalational route initially gets distributed to
organs of high blood flow such as brain /heart /Kidney.
If site of action of the drug was in one of those highly perfused organ; the onset of action will be
very rapid (e.g thiopental –IV GA)
Later less vascular but more bulky tissues (muscles /fat) take up the drug & plasma
concentration falls and the drug is withdrawn from these sites.
In the above case, redistribution leads to terminate of action of the drug.
N.B: Greater the lipid solubility of the drug, faster is its rate of redistribution. However, when the same
drug is given repeatedly /continuously over longer periods , the low perfusion, high capacity sites gets
progressively filled up & the drug becomes longer acting.
Example
Nitrazepam sedative action lasting 6-8 hrs initially but after prolonged use the t1/2 becomes 30 hours.
The real volume of distribution has physiological meaning and is related to body water (total 42L).
N.B: Drugs that are extensively bound to PPB are largely restricted to the vascular compartment
Therefore they have a low volume of distribution.
e.g Warfarin 99% PPB
Vd: 9.8 L/70kg
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3. Sequestration in tissues
Vd of such drugs are much more than the total body water or even body mass.
Morphine: 230L/70kg
Digoxin: 500L/70kg
Chloroquine: 13000L/70kg
5. Pathological states
CCF / Cirrhosis /anaemia / Obesity
Alternate of distribution of water
Permeability of Mb altered
6. Drug-interaction /Pregnancy
Clinical Significance
1. Drugs with very high volume of distribution have much higher concentration in extravascular
tissue than in vascular compartment. Therefore, they are not homogenously distributed.
Drugs with small volume of distribution are homogeneously distribution.
2. In case of Poisoning with drugs low Vd, in general Haemodialysis can be of use e.g these
drugs are confined to the vascular compartment.
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Non specific binding to other plasma Proteins occurs to a much smaller extent. e.g certain drugs bind to
proteins that function as specific hormone carrier protein. E.g Thyroid hormone-Thyroxine binding
globulin.
Implication of PPB
1. Highly Plasma protein bound drugs are largely restricted to the vascular compartment, therefore
they have a low Vd.
2. Bound fraction is not available for action
Acts as drug reservoir
They are in equilibrium with free drug in Plasma and dissociate when conc of the water
is reduced.
3. Makes the drug longer acting.
Not available for metabolism /excrete unless they are actively extracted by liver /kidney tubules.
Limits the drug Glomeruler filtration
N.B: PPB generally does not limit renal tubular secretion / biotransformation as when the
free drug concentration decreases, dissociation will occur.
4. One drug can bind to many sites of albumin molecule and also more than one drug can bind to
the same drug.
5. Drug-Drug interaction.
Drugs having higher affinity will displace the one with lower affinity. If the drug is having high
affinity for different sites-no interaction occurs.
Acidic drug will not displace basic drug
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Tissue Binding
Many drugs accumulates in tissues at high concentration rather than ECF
e.g Quinacrine-Liver
Chloroquine-Relina
Iodine-thyroid
Thiopentone-Adipose tissue
Tetracycline –Bone / teeth
N.B: Only lipid-soluble drugs are able to penetrate and have action on CNS.
Significance:
Important for designing drugs e.g 2nd generate Anti-histaminics
Less sedating as less lipid solution.
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Fetal plasma is slightly more acidic than that of the mother ( PH 7.0-7.2 v/s 7.4)
Therefore iron trapping of basic drugs occurs.
Here also, P-Gp + other export transporters are present which limit the exposure of the fetus to
potentially dangerous agents.
N.B: Placental barrier is not an absolute barrier. The fetus is to some extent exposed to all drugs
taken by the mother.
Drug metabolism
Drugs are most often eliminated by bio-transformation/ and or excreted into urine or bile. Liver is the
major site of drug metabolism; Other tissues involves the kidney, intestine, lung.
Half –life
Plasma half life
It is the time taken for the plasma concentration of a drug to fall to one half of its value during
elimination (during a constant infusion).
T1/2 = ln 2 x Vd
CL
Note:
Most drugs have an alpha T1/2 and remain in plasma; due to distribution.
Some drugs have beta- T1/2: they have 2 T1/2; one in plasma and one in tissues; due to elimination.
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Biological T1/2
It is the time in which the pharmacological effect of a drug or its active metabolite is reduced to half.
It is applicable to drugs whose effects persists long after the drug has been eliminated.
Eg anti-cancer drugs.
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Accumulation factor
Whenever drug doses are repeated, the drug will accumulate in the body until dosing is stopped. This is
because in theory, it will take an infinitely long time to eliminate all of a given drug from the body.
Example
For a drug given once every T1/2,
Cpss is said to be achieved when the rate of absorption of a drug and its elimination are equal such that
subsequent administration of the same dose have no effect on the plasma conc.
Cpss is achieved after 5 T1/2.
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In such cases, it is best to a chieve a certain plasma conc within the therapeutic range.
Loading dose
It is a single or quickly repeated dose given in the beginning of treatment to achieve the target conc
rapidly. It is governed by the bio-availability and volume of distribution.
Maintenance dose
These are doses that are administered at regular interval of time to keep the steady state plasma
concentration. It balances elimination.
Clearance
It is the fraction of the theoretical volume of fluid( plasma) that is completely cleared of the drug/unit
time.
CL = rate of elimination
Plasma conc of the drug
Significance
For knowing proper dosing regimen and to maintain steady state concentration.
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Kinetic of elimination
95% of drugs in use at therapeutic concentration are eliminated by first order kinetics.
It is the kinetic characteristic of a drug whereby the rate of elimination of the drug remains constant
irrespective of the drug concentration; clearance decreases with increase in concentration.
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Significance
The clinical use of such drugs needs proper monitoring and maintenance of their plasma concentration
because small increase in their concentration may result in drug toxicity.
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Elimination of Drugs
Drugs are eliminated from the body either in unchanged by the process of excretion or converted to
metabolism.
N.B: Lipid soluble drugs are not readily eliminated. They have to be metabolized to more polar.
Renal excretion
Glomerular filtration
Active tubular secretion
Passive tubular reabsorption
Tubular secretion
Active Process
The process requires a carrier and supply of energy
They are also subjected to competitive inhibition e.g( Penicillin + Probenecid)
e.g substance secreted para-amino hippuric acid.
The Process is saturable.
Tubular Reabsorption
Passive reabsorption of lipid-soluble drugs take place in distal tubule.
Very few drugs undergo reabsorption actively, e.g electrocytes /Glucose /Vitamin.
N.B: Drugs which are present in Glomerular filtrate can be reabsorbed in the tubules.
In proximal and distal tubules, the non-ionised form of weak acids and bases undergo net
passive reabsorption.
When tubular urine is made more alkaline, weak acids are largely ionized such that they are
excreted more rapidly and to a greater extent.
Eg: Aspirin + NaHCO3
N.B: Whether alteration PH results in significance change in drug elimination depends on the extent &
(i) Persistance of pH change and
(ii) Contribution of pH dependent passive reabsorption to total drug elimination.
This effect is greater for weak acids and bases with pKa values in range of urinary pH 5-8
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Exhaled Air
Lung is the major organ of excretion for gaseous & volatile substance e.g Anaesthetic gases.
Salivary excretion
Not really a method of drug excretion as the drug is swallowed again and reabsorbed. The concentration
of some drugs in plasma parallels that in plasma. Therefore, saliva is a useful biological fluid to
determine drug concentration when it is inconvenienced to obtain blood e.g Lithium , Rifampicin.
Other ways
In sweat / tear / hair/ Skin
Sensitive method of detection of drugs in these tissues; have forensic significance.
Breast milk
Milk is more acidic than plasma.
Basic lipids may be slightly more concentrated in milk e.g β-Blockers
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Note:
Drugs needed for brief therapeutics effect need not be made long-acting e.g hypnotics /
headache remedy.
Epinephrine decreases the rate of entry of LA from Local site to systemic circulation and
prolongs duration of action and decrease systemic toxicity of bloodless field.
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e.g
(iv) Combination of the drug with protein from which it is slowly released.
e.g Protamine-zinc-insulin (really used now)-24-36 hrs.
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References
BERTRAM,G.K., SUSAN,B. & ANTHONY, J.T.,2010. Basic and clinical pharmacology. 12th ed. US: Mc Graw Hill.
GOODMAN & GILMAN’S.,2011. The pharmacological basis of therapeutics. 12th ed. US: Mc Graw Hill.
ROYAL PHARMACEUTICAL SOCIETY., 2012. BNF. London: BNF publication.
Lippincott’s illustrated 4th edition
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