Dr.G.Vishnu Priya

DRUG DISTRIBUTION & DRUG ELIMINATION

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AbsorptionAbsorption is movement of a drug from site of

administration to the central compartment and the

extent to which this occurs.

Only lipid soluble drugs can cross the biological

Membranes

Lipid soluble drugs is unionised ,ionised form is water

soluble

DISTRIBUTION :Process by which drug reversibly leaves the blood

Stream and enters interstitium (ECF) & cells of the

tissues.

Delivery of drug from plasma to interstitium

depends on :

Regional blood flow Capillary permeability,Tissue volume,Degree of binding , Relative hydrophobicity of the drug.

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Permeability of barriers

Blood brain barrier : Endothelial cells of capillaries are continues

tight junction.

lipid soluble non ionised form of drugs penetrate more easily to brain.

More lipophilic a drug,more likely to cross the blood brain barrier.

BBB involves membrane transporters limits access of drugs to tissues

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BBB involves membrane transporters

limits access of drugs to tissues.

Inflammatory condition alter permeability charecterestics of BBB allowing entry of drugs that are restricted.

E.g- Penicillin, Chloramphenicol,Ampicillin

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• DRUGS - BBB• Volatile anesthetic- Ether,chloroform.• Ultra short acting barbiturates-Thiopental.• Narcotic analgesic-Morphine,heroin.• Dopamine precursor - L-dopa.• Sympathomimetics- Amphetimine & Ephedrine.• Propranolol & Diazepam

• DOES NOT CROSS-• Dopamine, serotonin& Streptomycin• quaternery substances- d-tubocurarine,• Hexamethonium, Neostigmine, Acetylcholine

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Blood CSF Barrier :Epithelial cells joined by tight junctionsallows non ionised lipid soluble drugs

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Placental barrierIt is lipid in nature

Lipid solubility,extent of plasma binding & degree of ionization of week acids & bases are determinants in drug transfer

Fetal plasma is slight acidic than the mother

7.0vs 7.4 – ion trapping of basic drugs occurs

As in brain ,P-gp & other export transporters present in placenta limits fetal exposure to toxic agents

e.x pentobarbital,alcohol ,certain antibiotics.

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Binding of drugs-

Plasma protein binding :

It’s a non linear & saturable process.

prolongs the drug availability & Duration of action.

Delays metabolic degradation & excretion of drugs

Fraction of total bound drug in plasma determined

by drug concentration,affinity of binding sites,number

of binding sites

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Diminishes its penetration into the CNS.

Hypoalbuminemia , secondary severe liver disease

or nephrotic syndrome ↓ binding.

Cancer, Arthritis, MI, Crohn’s disease -↑ level of α1 acid glycoprotein & enhanced binding of basic drugs.

As free drug is active & gets eliminated to replace the lost drug ,bound drug dissociates.

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Therapeutic range of plasma concentration is limited ,extent of binding & unbound fraction is constant

acidic drugs binds to plasma albumin

e.g- warfarin, Penicillins, Sulfonamides, Tolbutamide

& Salicylic acid.

basic drugs binds to αı acid glycoprotien

e.g- Propranolol, Lignocain, Quinidine.

Displacement interactions where drug bound with

higher affinity will displace the one having lower

affinity.

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e.g- Phenylbutazone, Salicylates & Sulfonamides displaces Tolbutamide → hypoglycemia

Salicylates,Indomethacin,Phenytoin & Tolbutamide

displaces Warfarin → haemorrhage.

Sulfonamides & vitamin K displace endogenous

ligands like bilirubin→ kernicterus in neonates.

Drug extensively protien binding has smaller

apparent volume of distribution.

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warfarin- 99% bound, Tolbutamide- 98% bound,

Phenytoin- 90% bound causes toxicity after getting

displaced from plasma protein binding sites.

Tissue binding:Drug accumlate in tissues at higher concentration

than in ECF & blood.

Some drugs have high apparent volume of

distribution,e.g- Digoxin, Emetine, Chloroquine

Chloroquine-1300 l/kg- high volume of distribution

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Reversible binding of drugs occurs with cellular

constituents - Protiens,phospholipids&nuclear

protiens.

Tissue binding & accumlation produces local toxicity

Griseofulvin in skin & finger nails

Fat-many lipid soluble drugs stored by physical

solution in neutral fat.

Serves as staable reservoir for lipid soluble drugs

Barbiturates,Thiopental present 3hrs after admin.

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Bone –Metal ions & chelating agents & heavy metals

accumlate in bone by adsorption onto crystal

surface incorporate into crystal latice.

Bone can be reservoir for slow release of toxic agents-

lead & radium.

Redistribution-termination of drug effect, after withdrawl of drug

Usually is by excretion but may also result from

redistibution

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when highly lipid soluble drugs given rapidly by i.v or

inhalation that act on brain & CVS redistribution takes

place.

i.V anesthetic Thiopental- reaches maximal conc in

brain within a minute of I.V. after injection is given

the plasma conc falls as it diffuses into other tissues-

Onset of anesthesia is rapid ,termination is also fast-

both related to conc of drug in brain.

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Volume of distribution:

Apparent volume of distribution : volume of fluid required to contain the total amount

of drug in the body at the same concentration as that

present in the plasma.

aVd = Total amt of drug

plasma conc

Fluid substancesVolume (liter) Test

Extracellular Fluid 19 Inulin, thiosulfate

Plasma 3 Evans blue, I125

albumin

Interstitial fluids 16

Intracellular fluids 23

Total body water 42 Antipyrine, D2O,

ethanol19

Plasma- High ionised,very large molecular weight & protein

bound drugs

e.x -Heparin

Extracellular fluid – Low molecular weight Large molecules

e.x-mannitol

Total body water - Small water soluble mol drug low molecular weight,

e.x-Alcohol

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ELIMINATION: Most common routes kidney via urine , others are

bile, intestine, sweat,saliva,lung ,& breast milk .

Renal elimination : Glomerular filteration. Proximal tubular secretion. Tubular reabsorption.

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Glomerular filteration: Allows drugs size below 20 000 to pass.

heparin is restricted

Only free drug is filtered, greater the glomerular

perfusion, faster drug removal from plasma.

Does not depend on lipid solubility

Tubular secretion: 80% drug passes to proximal tubule remaining 20%

drug is removed by glomerular filteration.

Its an Energy requiring carrier mediated active

transport

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Each carrier are non-selective they compete for same

Carrier System

e.g- Probenicid- Penicillins ↑ plasma half life &

effectiveness of penicillins

Acidic drugs- uric acid ↑ in levels

Two carrier system are involved

One for acidic drug – penicillin,salicylic acid

another is for basic drugs

e.x- Morphine, Quinidine, Procaine, Neostigmine,

Dopamine, Histamine.

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Tubular reabsorption: Reabsorption takes place by passive diffusion depends

-lipid solubility.

-pKa of drug.

-pH of urine

Acidic drugs → non ionisable

↓

reabsorption

↓ -alkalanization of urine

excretion

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This can be used in case of Salicylate & Barbiturate

poisoning by making urine alkaline.

weak basic drugs ionisable

↓ ascorbic acid

excreted

↓-alkalinization

reabsorbed

Strong acidic & basic drugs – ionised at all pH gets

eliminated

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Enterohepatic circulation: Drugs with low molecular weight reaches

hepatic extra cellular fluid.

Active& passive diffusion involved.

High protein bound & ionised drug do not

diffuse back into intestinal blood vessels get excreted

in faeces.

Most of drugs undergo passive reabsorption carried back to liver till drugs get metabolised & excreted by kidney.

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They act like reservoir for endogenous substances like

vitaminD3,B12,Folic acid

Condition where liver function impaired-accumlation of drugs will take place.

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Other routes:

Pulmunory -Volatile anesthetics- simple diffusion

Solubility of gas in blood is guiding factor-

e.x- nitrous oxide – rapid excretion

Agents with ↑ blood & tissue solubility

slowly excreted

e.x- Ethanol used to measure concentration in breath

of vehicle drivers.

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Sweat & saliva- Non ionised, lipid soluble drugs diffuse in epithelial

cells of glands.

pKa of drugs, Ph of secretion important regulate

excretion.

By sweat – Bromide, iodide.

saliva - phenytoin

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Clearance- Important concept to consider when designing a

rational regimen for long-term drug administration

important because metabolizing enzymes and

transporters are not saturated, and thus the absolute

rate of elimination of the drug is essentially a linear

function of its concentration in

plasma.

Amount of drug cleared from body/unit time.

Total clearance includes all mechanism of drug

elimination

CL =0.693×Vd

t1/2

Clearance is derived in units of volume/time.

Clearance of drug by several organs is additive.32

Added together, these separate clearances will equal

systemic clearance:

Cl (renal )+ CL (hepatic) + CL (other) = CL

clearance useful for understanding the effects of

pathological and physiological variables on drug

elimination, particularly with respect to an individual

organ

Cl organ = Q.E

E is the extraction ratio

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Kinetics of elimination –First order kinetics –A constant fraction of the drug is eliminated at

a constant interval of a time. 50% 50% 50% 50% 50%

100(µg/ml) → 50(µg/ml) → 25(µg/ml)→12.5(μg/ml)→6.25→3.125

2hr 2 hr 2 hr 2hr 2hr

50% 50% 50%

200µg/m →100(µg/ml) → 50(µg/ml) → 25(µg/ml)

2hr 2 hr 2 hr

The t1/2 of any drug following first order kinetics

would always remain constant irrespective of the

Drug, clearance also remains constant

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Rate of drug elimination is directly proportional to

plasma concentration

97% drugs gets eliminated after 5 t 1/2 .

steady state= (dosing rate =CL × Css)

upto 5th half life plasma Concentration keeps on

increasing thereafter reaches steady state level.

The rate of absorption equals the rate of

elimination and thus subsequent administration of

same doses thereafter no effect on plasma conc

Zero order kinetics ( saturation kinetics) :-

Constant or fixed quantity of the drug is

eliminated per unit time

Rate of elimination is independent of

plasma conc

Clearance is more at low conc less in high conc

Half life is less at low conc & more at high conc

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Very few drugs follow this kinetics like alcohol

Any drug at higher conc may show zero order kinetics

Eg:Alcohol,Phenytoin,Aspirin,warfarin,tolbutamine,

theophiline

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25μg 25μg 25μg

100 μg/ml→ 75 → 50 → 25

1hr 1hr 1hr

25μg 25μg 25μg

200 μg/ml→175→150→125→100 & so on

1hr 1hr 1hr 1hr

-high plasma conc would also decline at the rate of

25μg/hr

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On arithmetic scale –plasma fall out curve – Linear

Logarithm- plasma fall out curve – Curvilinear

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ά- and β-phase of Drug Clearance :

Β phase (elimination)

α phase (distribution)

Time

I.V. Drug

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HALF LIFE-

time duration in which plasma concentration of

Drug falls by 50% of the earlier value.

If metabolism is more half life is less vice

versa

Drugs having shorter half life are administered more frequently

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t1/2 = 0.693 × vd

cl

Therapeutic drug monitoring -dose of drug adjusted according to plasma conc

drugs having correlation between serum level &

toxicity

Done in drugs with wide variation in pharmacokinetics

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• Done for drugs having low therapeutic index Digitalis,aminoglycosides,theophylline,lithium& anti epileptics

• Done for drugs having known correlation between serum level & toxicity

• Done whose effects can be measured

• Not done for drugs which are activated in body

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H.L Sharma & K.K Sharma – The Principles of Pharmacology

second Edition.

Goodman & Gilman- pharmacological basis of therapeutics

R.S.Satoskar - Pharmacology

&Therapeutics -Twentieth Edition. Rang & Dale - Pharmacology –

sixthEdition

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