Pharmacokinetics

Pharmacokinetics The dynamics of drug absorption, Distribution,  Metabolism, elimination

Drugs at site of administration Absorption Drugs in plasma

Distribution Drugs in tissues Metabolism Metabolite(s) in tissues Elimination

Drugs &/or matabolites in urine, feces, bile

Metabolism  General considerations ­ drug metabolism 

(biotransformation) usually results in more water­ soluble, more polar metabolites, thus facilitating  their excretion by reducing renal tubular  reabsorption  drug metabolism does not always result in  detoxification and inactivation of drugs, although  these usually occur.

Biotransformation 1. Inactivation: most drugs and their active metabolites are rendered inactive or less active e.g. pentobarbitone , morphine , chloramphenicol.

Biotransformation 2. Active metabolite from an active drug: many drugs have been found to be partially converted to one or more active metabolite , the effects observed are the sum total of that due to the parent drug and its active metabolites .

Biotransformation 3. Activation of a inactive drug – few drugs are inactive as such and need conversion in the body to one or more active metabolites . Such a drug is called a prodrug . The prodrug may offer advantage over the active form in being more stable, having better bioavailability or other desirable pharmacokinetics properties or less side effect and toxicity .

Kinetics of Metabolism 1. First order Kinetics: Rate of drug metabolism is directly proportional to the conc. of free drug. 2. Zero order Kinetics: Rate of drug metabolism is not dependent on the conc. of free drug. And rate of metabolism remain constant over time.

Biotransformation Biotransformation reaction can be classified into : a. Nonsynthetic /.phase 1 reactions – metabolites may be active or inactive . b. Synthetic / conjugation / phase 2 reaction – metabolite is mostly inactive .

Directly

Some drugs directly Enter Phase II metabolism

Oxidation , Drug

Phase I

reduction

Phase II

Conjugation products

and/or hydrolysis Following Phase I, the drug may be activated, unchanged, inactivated.

Conjugated drug Is usually inactive.

The biotransformation of drugs

Nonsynthetic reaction 1. oxidation – this reaction involves addition of oxygen / negatively charged radical or removal of hydrogen / positively charge radical . Oxidations are the most important drug metabolizing reaction . Various oxidation reaction are :

Nonsynthetic reaction Hydroxylation , oxygenation at C, N,or S atoms ; N or O –dealkylation , oxidative deamination , etc , it may cases the initial insertion of oxygen atom into the drug molecule produces short lived highly reactive quinone / epoxide / superoxide intermediates which then convert to more stable compounds .

Nonsynthetic reaction Oxidative reaction are mostly carried by a group of monooxygenases in the liver , which is the final step involve a cytochrome P-450 heamoproteins , NADPH , cytochrome P- 450 reductase and O2 . There are 30 – 100 cytochrome P 450 isoenzymes differing in their affinity for various substrates .

Microsomal enzyme oxidation system

Oxidation

Oxidation is the addition of oxygen and/or the removal of hydrogen. Most oxidation steps occur in the endoplasmic reticulum. Common reactions include :Alkyl group ----> alcohol

for example phenobarbitone Aromatic ring ----> phenol

Reduction Addition of a hydrogen or removal of oxygen. azo (-N=N-) or nitro groups (-NO2) ---> (-NH2) amines

Nonsynthetic reaction 2. Reduction – This reaction is the converse of oxidation and involves cytochrome P 450 enzymes working in the opposite direction . Drugs primarily reduced are chloralhydrate , chloramphenicol , halothane .

Nonsynthetic reaction 3. Hydrolysis – This is cleavage of drug molecule by taking up a molecule of water . Ester + H2O esterase Acid + alcohol Similarly amides and polypeptides are hydrolysed by amidases and peptidases .

Hydrolysis Addition of water with breakdown of molecule. In blood plasma (esterases) and liver Esters ---> alcohol and acid

for example aspirin to salicylic acid

Nonsynthetic reaction Hydrolysis occurs in liver , intestines , plasma and other tissues . Ex- choline esters , procaine , lidocaine . 4. Cyclization – this is formation of ring structure from a straight chain compound , e.g. proguanil.

Nonsynthetic reaction 5. Decyclization --- This is opening up of ring structure of the cyclic drug molecule , e.g. barbiturate , phenytoin . This is generally minor pathway.

Enzyme Induction An interesting feature of some of these chemically dissimilar drug substrates is their ability , on repeated administration ,to induce cytochrome P450 by enhancing the rate of its synthesis or reducing its rate of degradation .

Enzyme Induction A large number of drugs can cause an increase over time in liver enzyme activity. This in turn can increase the metabolic rate of the same or other drugs. Phenobarbitone will induce the metabolism of itself, phenytoin, warfarin, etc. Cigarette smoking can cause increased elimination of theophylline and other compounds. Dosing rates may need to be increased to maintain effective plasma concentrations.

Enzyme Induction induction results in an acceleration of metabolism and usually in a decrease in the pharmacologic action of the inducer and also of coadministered Drugs. however in the case of drugs metabolically transformed to reactive metabolites ,enzyme induction may exacerbate metabolite –mediated tissue toxicity.

Enzyme inhibition Certain drugs substrate may inhibit cytochrome P450 enzyme activity . Imidazole-containing drugs such as cimetidine and ketoconazole bind tightly to the heme iron of cytochrome P450 and effectively reduce the metabolism of endogeneous substrate .

Enzyme inhibition  Alternately

some drugs can inhibit the metabolism of other drugs. Drug metabolism being an enzymatic process can be subjected to competitive inhibition. For example, warfarin inhibits tolbutamide elimination which can lead to the accumulation of drug and may require a downward adjustment of dose.

Synthetic reaction 1.Glucuronide conjugation – this is the most important synthetic reaction . Compounds with a hydroxyl or carboxylic acid group are easily conjugated with glucuronic acid which is derived from glucose . Ex- chloramphenicol , aspirin , morphine . Not only drug but endogenous substrate like bilirubin , steroidal hormones and thyroxin utilized this pathway.

Diagram of entero-hepatic circulation conjugated drug

biliary tract

liver

bacteria absorptio

portal vein

to circulation

unconjugated drug

gut

Synthetic reaction 2. Acetylation – Compounds having amino or hydrazine residues are conjugated with the help of acetyl coenzyme – A , e.g. sulfonamides , isoniazid , hydralazine . Multiple genes control the acetyl transferases and rate of acetylation shows genetic polymorphisn .

Synthetic reaction Methylation – The amine and phenols can be methylated , methionine and cysteine acting as methyl doners , e.g. adrenaline , histamine , nicotinic acid . 4. Sulfate Conjugation :The phenolic and steroid compounds are sulfated by sulfokinase.

Synthetic reaction 5. Glycine conjugation – salicylates and other drugs having carboxylic acid group are conjugated with glycine , but this is not a major pathway of metabolism. 6. Glutathione conjugation: 7. Ribonucleoside / nucleotide synthesis :

Elimination/ Excretion Excretion is the passage out of systemically absorbed drug. Drugs and their metabolites are excreted in –

1. Urine 2. Faeces 3. Exhaled air 4. Saliva and sweat 5. Milk

Elimination via the kidney Depends on - blood flow to kidney (normal 1500ml/min) - glomerular filtration rate (normal 100mls/min) - active secretion of drugs into the kidney tubule - passive reabsorption back into the tubule Therefore those with a poor renal function will not eliminate so well

- renal failure or dysfunction elderly or neonates

Elimination by the kidney drug filtered

some drugs reabsorbed

some drugs actively secreted

Drug elimination via the liver Depends on  blood

flow to the liver  activity of the enzyme in the liver

Liver enzymes will chemically alter the drug to form ‘metabolites’ which are:  inactivate

or  equally or more active than the parent drug

Drug elimination and the liver Metabolites are eventually eliminated via the kidney as they become more water soluble Factors which may reduce elimination via the liver  elderly

have poorer blood flow  neonates have a low liver enzyme activity  some drugs reduce liver enzyme activity  any extensive liver damage

Diagram of first pass effect (excretion) metabolised drug

biliary tract

liver portal vein to circulation

unmetabolised drug

gut

Diagram of entero-hepatic circulation and elimination of drug conjugated drug

biliary tract

liver

bacteria absorptio

portal vein

to circulation

unconjugated drug

gut

Clearance Drug clearance principles are similar to the creatinine clearance which is defined as the rate of elimination of creatinine in the urine relative to its serum concentration. At the simplest level, clearance of a drug is the factor that predicts the rate of elimination is relation to the drug concentration: CL= Rate of elimination / C

The systemic clearance, CL, is a measure of the efficiency with which a drug is irreversibly removed from the body Elimination of drug from the body may involve process occurring in the Kidney, the lung, liver and other organs. Dividing the rate of elimination at each organ by the concentration of drug presented to its yields the respective clearance at that organs. Added together, these separate clearance equal total systemic clearance:

CL renal = Rate of elimination kidney / C ----(i) CL liver = Rate of elimination liver / C -----(ii) CL other = Rate of elimination other / C ---(iii)

CL systemic =CL renal + CL liver + CL other ---(iv)

Half Life Half life (t1/2) is the time required to change the amount of drug in the body by one half during elimination or during a constant infusion. In the simplest case --- and the most useful in designing drug dosage regimens--- the body may be considered as a single compartment of a size equal to the volume of distribution (Vd). While the organ of elimination can only clear drug from the blood or plasma in direct contact with the organ, this blood or plasma is in equilibrium with the total volume of distribution.

Thus , the time course of drug in the body will depend on both the volume of distribution and the clearance.

t

1/2 =

0.7 * Vd

/ CL

LOADING DOSE When the time to reach steady state is appreciable, as it is for drugs with long half-lives, it may be desirable to administer a loading dose that promptly raises the concentration of drug in plasma to the target concentration. This is a single or few quickly repeated doses given in the beginning to attain target concentration rapidly.

LOADING DOSE In theory, only the amount of the loading dose need be computed--- not the rate of its administration--- and, to a first approximation, this is so.

The volume of distribution is the proportionality factor that relates the total amount of drug in the body to the concentration in the plasma (Cp) ; if a loading dose is to achieve the target concentration, Loading dose= Amount of the body immediately following the loading dose =Vd

* TC /F

For the theophylline example, the loading dose will be 350 mg (35 L *10 mg/L) for a 70 kg person. For most drugs, the loading dose can be given as a single dose by the chosen route of administration.

Maintenance Dose  In

most clinical situations, drugs are administered in such a way as to maintain a steady state of drug in the body, ie, just enough drug is given in each dose to replace the drug eliminated since the preceding dose. Thus calculation of the appropriate maintenance dose is a primary goal.  This dose is one that is to be repeated at specified intervals after the attainment of target Cpss so as to maintain the same by balancing the elimination

Maintenance Dose  Clearance

is the most important pharmacokinetic term to be considered in defining a rational steady state drug dosage regimen.

At steady state (SS), the dosing rate (rate in) must equal the rate of elimination (rate out). Substitution of the target concentration (TC) for concentration (C) predicts the maintenance dosing rate: Dosing rate ss = Rate of elimination ss = CL*TC

Thus, if the desired target concentration is known, the clearance in that patient will determine the dosing rate. If the drug is given by a route that has a bioavailability less then 100%, then the dosing rate predicted by above equation must be modified. For oral dosing

Dosing rate oral = Dosing rate / F oral

If intermittent doses are given, The maintenance dose is calculated from maintenance dose=Dosing rate* Dosing interval

Tissue storage Brain--- Chlorpromazine, acetazolamide, isoniazid. Retina --- Chloroquine . Iris--- Ephedrine, atropine .

Tissue storage Bone and teeth– Tetracyclines, heavy metals . Adipose tissue--- Thiopentone, ether, minocycline , phenoxybenzamine, DDTdissolve in neutral fat due to high lipid solubility , remain stored due to pore blood supply of fat .

Biotransformation Biotransformation mean chemical alter action of the drug in the body . It is needed to render non polar components polar so that they are not reabsorbed in the renal tubules and are excreted . Most hydrophilic drugs , e.g. streptomycin, neostigmine , decamethonium , etc are not biotransformed and are excreted unchanged .

Biotransformation Mechanism which metabolize drugs have developed to protect the body from ingested toxins . The primary site for drug metabolism is liver , others are – kidney intestine , lungs and plasma . Biotransformation of drugs may lead to the following : 1.

Unique characteristics of the oral route

 Influences of gastric emptying, mucosal 

surface area, and drug inactivation important  for oral route  Small intestine usually most important because of large surface area (folds of Kerckring, villi, microvilli)

 Clinical

advantages

 Safest

route  Cheapest route  Best patient acceptance  Disadvantages  Delayed

effect  Patient cooperation required  Unique problems with GI toxicity

Absorption of drugs (2)  From oral, sublingual, or rectal mucosa: 

passive diffusion.

 May bypass first­pass inactivation 

 From the lungs: passive diffusion

 rapid absorption, dependent on particle size (6 µm 

cutoff)

 Absorption of drugs (3)  From injection sites: subcutaneous tissues, 

muscle or fat, absorbed by diffusion and  affected by blood flow  From miscellaneous sites: skin, spinal canal,  tooth pulp  Intravenous, intraarterial injection avoids  absorption

Bioavailability  Clinical

pharmacology of differential absorption  Related terms  biologic

equivalence  chemical equivalence  therapeutic equivalence

Distribution  Absorbed drugs leave capillary wall quickly 

and freely (via filtration and diffusion) to enter  interstitial fluid; blood flow being important in  the regional distribution of drugs

 Binding to plasma proteins (mostly to albumin and, 

for basic drugs, α1­acid glycoprotein)  major distribution site

 highest drug concentrations usually found in blood; serve 

as drug depots, thus prolonging half­life of drugs   pharmacologic effects and toxic manifestations affected  by hypoalbuminemia and copresence of other drugs also  bound effectively to albumin

 Central nervous system: permeable to lipid­

soluble drugs only; limited permeability to  water­soluble drugs when inflamed  Placental transfer: limited by blood flow, not  by a "barrier"

 Fat tissue: depot for thiopental and 

chlorinated hydrocarbon insecticides (e.g.,  DDT)  Sites for metabolism and excretion: liver,  kidney, intestine, lungs  Redistribution: especially important for IV  injection of lipophilic drugs

Redistribution of thiopental after intravenous injection

Drug clearance Drug clearance principles are similare to the clearance concepts of the renal physiology in which creatinine clearance is defined as the rate of elimination of creatinine of the urine relative to its serum concentration. At the simplest level clearance of a drug is the factor that predicts the rate of elimination in relation to the drug concentration. Rate of elimination CL= Concentration

Clerance  Elimination

pof drug from the body may involve processes occur the kidney, the lung, the liver, and other organs. Rate of elimination Kidney CL= Concentration

Half life:  Half

life t1/2 is the time required to change the amount of drug in the body by one half during elimination.

Distribution of drugs  Does

not generally target the site of action  Is diluted in the blood stream and carried to all parts of the body  Tissue concentration depends on  physico-chemical

properties e.g. lipid solubility, crossing blood/brain barrier  blood flow

Volume of distribution Definition Reflection of the amount left in the blood stream after all the drug has been absorbed  if

drug is ‘held’ in the blood stream it will have a small volume of distribution  if very little drug remains in blood steam has a large volume of distribution

Penetration into brain and CSF

The capillary endothelial cells in brain have tight junction and lack large intercellular pores . Further , an investment of neural tissues covers the capillaries . Together they constitute the so called blood – brain barrier . A similar blood – CSF barrier is located in the choroid plexus: capillaries are lined by choroidal epithelium having tight junction .

Penetration into brain and CSF Both these barriers are lipoidal and limits the entry of non – lipid soluble drugs , e.g. Streptomycin, neostigmine etc. only lipid soluble drugs , therefore , are able to penetrate and have action on the central nervous system .

Volume of distributionadvanced Formula for volume of distribution V=

D C

V= volume of distribution D= dose (assuming all a absorbed) C= concentration in blood stream

If you know the volume of distribution it is possible to calculate the concentration in the blood stream for a particular dose

Volume of distribution advanced Suppose there is a drug that gives a plasma concentration of 0.1mg/ml after giving a 1 gram bolus dose IV V=1000mg/0.1

= 10 litres

Usually expressed as litres/kg body wt. If this was a 50Kg person V=0.5L/Kg

Decline in renal function with Decline in renal function with age age Change in Glomerular Filtration Rate with age 160

Approxiamte GFR ml/min/1.73m2

140 120 100 80 60 40 20 0 0

1

10

20

30

Age (years)

40

50

60

S1 70

80

Diagram of entero-hepatic circulation (advanced) conjugated drug

biliary tract

liver

bacteria portal vein

to circulation

unconjugated drug

gut

Concentration (mg/L)

Log Concentration (mg/L)

Change in plasma concentration

Time (hours)

Time (hours) Rate of elimination proportional to amount in body

Half Life 110 100 Concentration (m g/L)

90 80 70 60 50 40 30 20 10 0 0

1

2

3

4

5

6

7

8

9

Tim e (hours)

Half-life is the time taken for the concentration of drug in blood to fall by a half

Accumulation and therapeutic window 4 3.5

Inject 1g stat drug gives 1mg/L

3.46

Log Concentration (mg/L)

3.29

Toxicity

3

3.055 2.74

2.5

2.46 2.32

2.29

2 1.75

1.5

2.055 1.9875

1.875 1.74

1.75

Half life = 1 hour Half life= 2 hours

1.996375

1.99275

1.5 1.32

1

1 0.75

0.5

0.996375

0.75

Therapeutic

0.5

0

0.99275

0.9875

0.875

0

0

1

2

3

4 Time (hrs)

5

6

7

8

Section 3: Therapeutics Translating the pharmacological actions of drugs into beneficial effects for patients

Therapeutic and adverse effects  Therapeutic  the

or adverse effects

result of a drug’s pharmacological actions

 Important  how

considerations

drug action may be modified  how both therapeutic and adverse effects may be mediated  speed of onset and duration of action  interactions between drugs and disease states

Quantitative aspects of drug action  Response  defined

alters as the dose changes

by the shape of the dose response

curve Response

Full agonist Partial agonist

Dose (log)

 Drugs

that activate receptors

 possess

both affinity and efficacy  full agonists have high efficacy  partial agonists have lower efficacy  Efficacy

or potency

 terms

that are often confused  efficacy is the capacity to produce an effect  Drugs  have

that are antagonists

affinity but not efficacy  may be competitive or non-competitive

Drug efficacy  The

ability of a drug to produce an effect

 refers

to the maximum therapeutic effect  adverse effects may make the maximum unobtainable  Classes

of analgesic differ in their efficacy

 morphine

is a high efficacy analgesic  nefopam is a moderate efficacy analgesic  morphine gives more pain relief than nefopam irrespective of the dose of nefopam given

Drug potency  Amount

of drug in relation to its effect

 drugs

may differ in potency, but have similar efficacy

 Opioid

analgesic have different potencies

 hydromorphone

1.3mg is equivalent to

morphine 10mg  hydromorphine is more potent than morphine  but both drugs can achieve the same max effect

Excretion  Renal excretion

 involves glomerular filtration and tubular 

reabsorption and secretion

 

 excretion increased by decreasing tubular 

reabsorption, thus basic drugs are excreted  better in acidic urine, acidic drugs better in  alkaline urine  clinical application—aspirin and barbiturate  poisonings are treated by alkalization of  patients’ urine by giving sodium bicarbonate

 Others  Others

 

 Bile

 Lung  Feces  Saliva (pp. 24­25, Table 2­1)  Sweat  Milk

Time Course of Drug Action  General

rules  Compartment models  Single­compartment

 Multiple­compartment

 Exceptions to general rules

General rules  Plasma

concentration related to degree of receptor binding, thus magnitude of drug effect  Disposition processes usually first order  Elimination usually slower process than absorption or distribution

 First-order  dC/dT

= k•C (constant fraction)

 Zero-order  dC/dT

process:

= k (constant amount)

 Capacity  low

process:

limited process:

C, first-order; high C, zero-order

Single-compartment model

ka Absorption

Vd Body

ke Elimination

C = D/Vd  or  Vd = D/C

Single compartment model: no absorption, first-order elimination

  cleared of the drug by elimination per unit 

 Clearance (CL): the measurement of blood 

time (as in units of mL/sec).  It and the  volume of distribution (Vd) create the  dependent variable T1/2.  They are related by  the following formula:

T1/2 = 0.693Vd/CL

With renal excretion C•Cl  = U•V Where C = plasma concentration, Cl  = clearance, U = urinary  concentration, and V = urinary  volume

Cl  = U•V/C

 Drug disappearance

 

 usually follows first­order kinetics (exponential decay), 

with a constant fraction (not amount) of drug being  eliminated per unit of time  the process is independent of the kind and amount of  drug  half­life (T1/2), not dose, is the primary factor in  prolonging drug effects

Overriding importance of halflife on duration of drug effect

Drug accumulation with repeated  dosing

Multicompartment models  combine 

kinetics  of  redistribution  and 

elimination  provide  best  description  of  drugs  with  high  lipid solubility and drugs given intravenously

Two-compartment model

Henderson-Hasselbach equation base pH ­ pKa = log acid For an acidic drug: acid = HA; base = A­ For a basic drug: acid = BH+; base = B

Theoretical absorption of aspirin and codeine for dental pain

Specialized transport Nonspecific active transport of drugs , their metabolities and some endogenous products occurs in renal tubules and hepatic sinusoids which have separate mechanisms for organic acid and organic bases . Certain drugs have been found to be actively transported in the brain and choroid plexus also .

Nonsynthetic reaction 3. Hydrolysis – This is cleavage of drug molecule by taking up a molecule of water . Ester + H2O esterase Acid + alcohol Similarly amides and polypeptides are hydrolysed by amidases and peptidases .