PHARMACOKINETICS II

(An idea on drug distribution, metabolism and excretion with traditional views.)

Dr. K.J.Karthika, Final year P.G scholar. Department of R&B, GAVC, Tripunithura.

Drug distribution

Drug metabolism

Drug excretion

Contents…

Drug distribution

Diffusion Tissue perfusion

Plasma proteins

Factors controlling

drug distribution

Pshysico chemical

properties of drugs

Physiological factors

Cardiac output

Regional blood flow

Capillary permeability

Tissue volume

•Cardiac output•Regional blood flow•Capillary permeability•Tissue volume

Drug administration

Partition of drug b/w blood and body tissue based on.- Transmembrane pH

- Lipid solubility

Initial distribution to well perfused organs(heart, liver, kidney, brain,etc)

second phase distribution to large fraction of body mass like muscle, skin, fat etc.(greater time needed to reach

equillibrium state)

Diffusion

Drug absorption or systemic administration.

Diffusion to interstitial or intercellular fluid.

Plasma protein and drug distribution

- Albumin – Majorly binds with acidic drugs.

- α 1 – acid glycoprotein – binds with basic drugs.- Non specific binding forming irreversible covalent binding of reactive drugs like alkylating agents.- Specific binding – sex hormone binding globulin for oestrogen and

testosterone.

The bound unbound drug concentration is determined by

- Affinity of binding sites.- Number of binding sites.- Existinc Pathology eg; liver diseases,

nephrotic syndrome causes hypoalbuminemia.

cancer, arthritis, MI, Crohns disease elevate α 1 –acidglycoprotein enhancing

binding of basic drugs.Drug- drug interaction – competition or site, alteration of physiology, etc.

Effects of protein binding.

•Limits drug concentration in tissues and site of action.

•Only the unbound drug is in equilibrium across the membranes.

•limits the drugs glomerular filtration.

•Drug transport and metabolism are also limited.

Tissue concentration of drugs-Many drugs accumulate in the tissues at higher concentrations than those in extra cellular fluids and blood.

-Eg. antimalarial drug quinacrine- liver concentration may exceed several thousand times than blood concentration.

-The tissue concentration build up can be due to.

•Active transport•Tissue binding( mostly reversible) to

- Proteins- Phospholipids- Nuclear proteins, etc

Effects of tissue concentration of drugs

•local drug toxicity e.g; Gentamicin in kidney and vestibular system.

Cellular reservoirs- Fat- Bones- Trans cellular fluid- Sites with active transport of drugs and tissues with affinity to drugs. Vary with the type of drug. Eg, liver, kidney, etc

Fat as reservoir-Many lipid soluble drugs are stored in by physical solution in neutral fat.

-A stable reservoir due to relatively low blood flow.

Difficulty to predict lipophilic drug distribution in obese individuals.Eg, β blockers, barbiturate thiopental.

Bone: •Tetracycline antibiotics and heavy metals adsorb onto bone surface and eventually to crystal lattice.

•Reservoir for slow release toxic agents e.g. lead or radium .Their effects persist long after their exposure has stopped.

local destruction of bone medulla

reduced blood flow

prolongation of reservoir

effect.

Therapeutic advantages: Treatment of osteoporosis by phosphonates like sodium etidronate which is resistant to pyrophosphatases enzyme thus stabilizes bone matrix.

Transcellular fluid reservoir:

•Drugs cross the epithelial cells and accumulate in the transcellular fluids.

•The major trans cellular reservoir being the gastrointestinal tract and others are CSF, aqueous humor, endolymph, synovial fluid,etc.

•The levels accumulated are not significant.

Redistribution• The redistribution from site of action to other sites cause termination of drug effect before drug withdrawal.

•Primarily seen when a highly lipid soluble drug that acts on brain or cardiovascular system is administered rapidly by intravenous injection or inhalation.

•As the I V administration is ceased once attaining the peak concentration in the desired tissue, the drug diffuses to other tissues like muscles. Gradually the concentration in desired tissue falls to match the plasma concentration.

CNS and cerebro spinal fluid.-Factors preventing transport of drug to brain

1. BBB (brain capillary endothelium and pericapillary glial cells)

2. Blood CSF barrier (at choroid plexus where epithelial cells are joined by tight junctions.)

Drug penetration into the brain depends on trans-cellular transport.

Lipid soluble

Non ionized

Unbound state

Essential factors for uptake of drug by brain.

• Meningeal and encephalic inflammation increases local permeability.

• Recently BBB destruction has emerged as a strategy in treatment of certain brain tumors where the intention is to directly deliver the chemotherapy agent to the brain tumor while maintaining the cognitive function that is often damaged by conventional radiotherapy.

Volume of Distribution:

-Relates to the amount of drug in the body to the concentration of drug in blood /plasma depending on the fluid volume.

The blood plasma volume of a 70kg man is considered to be 3l blood volume is 5.5l.The extracellular fluid volume 12l total body water is 42l.

The volume of drug distribution depends on:•pKa of drug

•the degree of binding to plasma proteins

•partition coefficient of drug in fat.

•Degree of binding to other tissue.

Age, gender, disease, body composition.

Ayurvedic aspects

Drug metabolism

Phase 1- functionalization• introduce a functional

group to parent compound.

• Loss/ alteration of pharmacological activity.

• Enzyme system located mainly in endoplasmic reticulum.

Pase 2- biosynthetic reaction• Formation of covalent

linkage between the functional group of phase 1 metabolite and endogenously derived glucuronic acid, sulphate, glutathione, amino acids or acetates. >> Actively excreted.

• Enzymes mainly located in Cytosol.

Site for biotransformation (location):•Mainly liver•GIT•Kidneys•Lungs

Cell organelles involved•Mainly smooth endoplasmic reticulum•Cytosol•Mitochondria•Nuclear envelope•Plasma membrane.

Systems involved in drug metabolism• Cytochrome P450 mono oxygenase

system.• hydrolytic enzymes.• conjugation reactions.

Cytochrome P450 mono oxygenase system-Heme containing membrane protein found in smooth endoplasmic reticulum of numerous tissues.

-catalyzes wide range of oxidative and reductive reactions.

-the xenobiotic substrates reacts with the Fe3+ of the cytochrome P450 and form enzyme substrate complex and thereafter further reactions of biotransformation proceeds. Electons from NADPH is utilized by it.

- 12 gene families have been identified for cytochrome P450 enzyme and a number of distinct cytochrome P450 exist in a cell.

Hydrolytic enzymes:- Found in endoplasamic reticulum of human liver intestine and other tissues.

- The alcohol and amine group exposed following the hydrolysis of esters and amines are the substrates.

Conjugation Reactions- Hallmark of phase 2.

- Most significant is glucuronidation following which there is increased water solubility and promotes drug elimination through urine.

- conjugation of electrophilic metabolites of xenobiotics with tripeptides of glutathione is the major detoxification pathway for drugs and carcinogens.

Factors effecting drug metabolism•Genetic variation:

-For an increasing number of enzymes allelic variants with different catalytic activities have been identified.

-The differences involve a variety of molecular mechanisms leading to complete lack of activities, a reduction in catalytic ability or in case of gene duplication enhanced activity.

•Environmental determinants:

The activity of most of the drug metabolizing enzymes may be modulated by exposure to certain exogenous compounds. These may result in :-

•Inhibition of drug metabolism•Inuction of drug metabolism

•Disease factors: k

- Hepatitis , alcoholic liver disease, biliary cirrhosis, fatty liver and hepatocarcinoma can potentially lead to impaired drug metabolism.

- The oral availability of drugs that undergo first pass metabolism and reduced bioavailability is increased 2-3 fold.

- Severe cardiac failure and shock can result in both decreased perfusion of liver and impared metabolism.

•Age and sex: •Cytochrome P450 isoforms develop early in foetal development but levels at birth are lower than those found post natal.

•Both phase 1 and phase 2 enzymes begin to mature gradually following the first two to 4 wks. Thus newborn infants are able to metabolize drugs but slower than adults.

•Elderly generally requires moderate reduction in drug dose and awareness of possibility of exaggerated pharmacodynamic responsiveness.

•Responsiveness of men and women may be different for certain drugs. some sex related

Excretion of drugs

Polar compounds excreted more efficiently than the lipid soluble drugs.

Drug is excreted as

Unchanged form

metabolites

Routes for drug

excretion

tear

Renal(mutra)

Biliary and

fecal (sakrut

)

sweat

saliva

Breast

milk

Renal excretion Involve 3 distinct process

• Glomerular filteration• Tubular secretion• Tubular reabsorption

Age and renal functionNeonates – low renal function low in the beginning which matures rapidly.In adulthood the renal function gradually declines approx 1% per year.Elderly- substantial rate of renal impairment.

Factors determining drug entry to tubular lumen• GFR• Extend of plasma binding(unbound drug

filtered)• Carrier mediated tubular secretion in PCT• Reabsorption by membrane transport at

DCT• Passive reabsorption non ionized forms of

wk acids and bases in PCT and DCT• pH of urine( alterations can result in

significant change in drug elimination

Other routes• sweat• saliva- some drug concentration here parallels

plasma concentration thus can be collected when inconvenient to collect blood. Ethanol n urea readily enters B.M.

• tears• breast milk- slightly more acidic than plasma

basic compounds may be accumulated

Elimination by these routes depends mainly on diffusion of non-ionized lipid soluble form of drugs through the epithelial cells of the gland based on pH.

Biliary and fecal excretion

•transporters present in the canalicular membrane of hepatocytes actively secrete drugs and metabolites into the bile

Secretory transporters on the apical membrane of enterocytes causes direct secretion of drugs and metabolites to the intestinal lumen.

Absorption from intestine for hepatic clearence

Bio availability

It is the term used to indicate the fractional extend to which a dose of drug reaches its site of action.

The bioavailability depends on• Nature of drug• Route of administration.• Anatomical site from which absorption takes place• Other anatomical, physiological and pathological factors.

When the hepatic Clearence of the drug is more in relation to the hepatic circulation the bioavailability of drug when orally administerd will be low. so is the case of other routes that is subjected to first pass loss.

In AyurvedaMore biovailability is possibly be in the order1. Basthi prayoga. 2. Oral intake3. Abhyandadi bahya prayoga4. Nasya5. Nethra kriyakrama