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Pharmacokinetics

Chapters 8 and 11

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Pharmacokinetics and pharmacodynamics

• Pharmacodynamics is the study of how drugs interact with a molecular target, i.e; effect of the drug on the body.

• Pharmacokinetics is the study of how a drug reaches its target in the body and how it is affected on that journey, i.e; effect of the body on the drug.

• Pharmacokinetics is the study of how is the drug absorbed, distributed, metabolized and excreted in the body

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Pharmacokinetics & related topics

The four main issues in Pharmacokinetics are:

absorption, distribution, metabolism and excretion

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Pharmacokinetics & related topics

Drug absorption • Refers to the route or method by which

the drug reaches the blood supply, this depends on how the drug is administered.

• The most common and preferred method of administration is the oral route.

• It depends on hydrophilic/hydrophobic properties, polarity and ionization of the drug.

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I-Stability: ”Oral drugs have to be chemically stable to

survive the stomach HCl and metabolically

stable to survive the digestive enzymes in GIT

and metabolic enzymes in liver (mainly

cytochrome P450 ).

-Insulin, local anaesthetics and first penicillins

are acid labile , so they can't be taken orally but

are given parentrally.

Drug absorption

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Pharmacokinetics & related topicsDrug absorption

• II-Solubility• The drug should have the correct balance of

water versus fat solubility

• Oral drugs should be sufficiently polar to dissolve in the GIT and blood supply, but sufficiently fatty to pass through the cell membranes (optimum hydrophophobic/hydrophilic balance).

• Most oral drugs obey Lipinski’s rule of five, i.e.

1-A molecular weight less than 500

2-No more than 5 hydrogen bond donor groups

3-No more than 10 hydrogen bond acceptor groups

4-A calculated log P value less than + 5

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Pharmacokinetics & related topicsDrug absorption

• II-Solubility

A- Polarity:

• Some polar drugs break these rules are usually

poorly absorbed and have to be administered

by injection.

• Highly polar drugs will dissolve in GIT but they will fail to

be absorbed through the lipid cell membrane of the gut

wall while nonpolar drugs will be poorly soluble in the

GIT instead they will dissolve in the fat globules leading

to poor surface contact with cell membranes resulting in

poor absorption , too.

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Pharmacokinetics & related topics

Drug absorption B-Ionization:The presence of the weak ionizable -NH- group in many drug structure would have three advantages:A- good solubility due to =NH2+ cation in stomach acidB- good absorption due to conversion to non ionized form in intestine in slightly alkaline pHC-good target interactions due to participation of ammonium ion in them

N H N

H

H

+ H+

- H+

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Drug absorption

-Henderson-Hasselbalch equation

pH= pKa + log [A-]/[HA]

C-Size :

Large molecular weight drugs generally have

poor absorption because they mostly have a

large number of polar groups which will lead to

poor absorption of these drugs.

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Pharmacokinetics & related topics Drug absorption

mechanisms:• Most drugs with proper solubility in

both water and lipid will be absorbed through the lipid cell membrane of the gut wall cells .

• Carrier proteins are essential to a cell’s survival as they transport highly polar building blocks required for various biosynthetic pathways.

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Pharmacokinetics & related topics Drug absorption mechanisms:

• Some polar drugs, are absorbed by special carrier proteins such as levodopa fluorouracil, lisinopril, methotrexate and erythromycin, which are similar in structure to (or bear a structural resemblance to) one of the building blocks (such as amino acid) then it too may be smuggled into the cell

• Other polar drugs with high molecular weight are absorbed by pinocytosis (without passing through the membrane).

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Pharmacokinetics & related topics Drug absorption mechanisms:

• Some polar drugs with low molecular weight (<200) are absorbed by passing through the pores between cells lining the gut wall.

• Thus polar drugs are orally active if they are

small enough to pass between the cells of the gut wall or are recognized by carrier proteins or are taken across the gut wall by pinocytosis.

• N.B: sometimes drugs are designed to be highly polar to be retained in the gut and not absorbed to treat gut infections as some antibacterial agents for gut infections.

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Pharmacokinetics & related topics

• Dosage:• Drug dosing or dose regimen (regime) means drug

amount in each dose and frequency of

administration.

• Due to the number of pharmacokinetic variables

involved, it can be difficult to estimate the correct

dosing regime for a drug.

• The drug should be administered at the correct dose

levels and at frequency to ensure that blood

concentration remain within the therapeutic window.

• Therapeutic window means drug levels in blood lie

between therapeutic and toxic levels).

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Pharmacokinetics & related topics• Dosage:

• In general, the concentration of free drug in

blood (non bound to plasma proteins) is a good

indication of the availability of that drug at its

target site.

• Other dosing complications include differences

in age, sex, race, diet, environment, obesity,

time of dosing (due to change in metabolic

rates throughout the day), drug-drug

interactions.

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Dosage

• The half-life of a drug is the time taken for the blood concentration of the drug to fall by half. A knowledge of half-life is required to calculate how frequently doses should be given to ensure a steady state concentration.

• Drug tolerance is where the effect of a drug diminishes after repeated doses.

• In physical dependence a patient becomes dependent on a drug and suffers withdrawal symptoms on stopping the treatment.

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Formulation of drug Formulation refers to the method by which the

drugs are prepared for administration, where by solution, pill, capsule, liposome (small vesicles consisting of a phospholipid bilayer mambrane), or microsphere (small spheres made up of a biologically degradable polymer

The way a drug is formulated can avoid some of the problems associated with oral administration.

Drugs are normally taken orally as tablets or capsules.

A tablet is a compressed preparation that contains 5-10% of the drug (active ingredient), in addition to many additives which help to ensure easy disintegration, and dissolution of the tablet in the stomach or intestine.

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Formulation of drug

Tablet formulation can be modified to give rapid effect (sublingual tablets) or sustained release. Special coatings can make the tablet resistant to stomach acid but disintegrates only in intestine (enteric coated tablets).

Drug administration

• The main routes are oral, sublingual, rectal,

topical, epithelial, inhalation and injections. The

method chosen depends upon the target organ

and the pharmacokinetics of the drug.

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Methods (routes )of drug administration

• Oral administration is the preferred method of administering drugs, but it is also the most demanding on the drug.

• Drugs administered by methods other than oral route avoid the first pass effect

– Oral

– Sublingual

– Rectal

– Epithelial

• Topical

• Nasal spray

• Eyedrops

– Inhalation

– Injection• Intravenous

• Subcutaneous

• Intramuscular

• Intrathecal

– Implants

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Drug administration o Drugs can be administered such that they are

absorbed through the mucous membranes of the mouth, nose, or eyes.

o Some drugs are administered rectally as suppositories.

o Topically administered drugs are applied to the skin. Some drugs are absorbed through the skin into the blood supply.

o Inhaled drugs are administered as gases or aerosols to act directly on the respiratory system. Some inhaled drugs are absorbed into the blood supply to act systemically.

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Drug administration

o Polar drugs which are unable to cross cell

membranes are given by injection.

o Injection is the most efficient method of

administering a drug but it also the most

hazardous. Injection can be intravenous,

intramuscular, subcutaneous, or intrathecal.

o Implants have been useful in providing

controlled drug release such that blood

concentrations of the drug remain as level as

possible. (e.g. insulin, gliadel)

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Drug distribution• Once the drug is absorbed, it is rapidly

distributed around the blood supply, then slowly

distributed to the various tissues and organs.

• Distribution to the interstitial fluid surrounding

tissues and organs is rapid if the drug is not

bound to plasma proteins .

• Some drugs have to enter cells in order to reach

their target.

• A certain percentage of a drug may be absorbed

into fatty tissue (e.g. Barbiturates) and/or bound

to macromolecules

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Drug distribution• Drugs entering the CNS have to cross the blood-

brain barrier. Polar drugs (e.g. Penicillin) are

unable to cross this barrier unless they make

use of carrier proteins or are taken across by

pinocytosis (e.g. insulin).

• Some drugs cross the placental barrier into the

fetus and may harm development or prove toxic

in newborn babies (e.g. alcohol, nicotine,

cocaine, barbiturates)

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Drug-drug interactions

These are defined as the effects that one drug has on

the activity of another drug if both drugs are taken

together.

Examples are Warfarin or methotrexate bound to

albumin and plasma protein in the blood and they will

be unavailable to interact with their targets.

When another drug is taken which can compete for

plasma protein binding (e.g. sulphonamide), then a

certain percentage of previously bound drug(warfarin

or methotrexate) is released, increasing the

concentration of the drug

and its

effect.

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Drug Metabolism• Drugs are exposed to enzyme-catalyzed

reactions which modify their structure. This is called drug metabolism and can take place in various tissues. But, most reactions occur in liver.

• Orally taken drugs are subjected to the first pass effect.

• Drugs administered by methods other than the oral route avoid the first pass effect.

• Phase I metabolic reactions typically involve the addition or exposure of a polar functional group.

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Drug Metabolism• Cytochrome P450 enzymes present in the liver

carry out important phase I oxidation reactions. The type of cytochrome P450 enzymes present vary between individuals, leading to varying rates of metabolism.

• The activity of cytochrome P450 enzymes can be affected by food, chemicals, and drugs, resulting in drug-drug interactions and possible side effects.

• Phase II metabolic reactions involve the addition of highly polar molecules to a functional group. The resulting conjugate are more easily excreted.

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Drug Excretion

• Drugs excretion can take place through sweat, exhaled air, or bile, but most excretion takes place through the kidneys.

• The kidneys filter blood such that drugs and their metabolites enter nephrons.

• Non-polar substances are reabsorbed into the blood supply, but polar substances are retained in the nephrons and excreted in urine.

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To control chemical and physical properties…

• Drug design

• Alter functional groups

• Quantitative SARs

• Computational methods

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Solubility

• Hydrophobic/hydrophilic balance:• The hydrophobic/hydrophilic character of the drug is the

crucial factor affecting absorption through the gut wall.

• Decrease polarityBy masking a polar functional

group with an alkyl or acyl group.

• Increase polarityBy adding a polar orMore polarfunctional group to a drug to increase its

polarity.

• Ionization

R OH O CR OR' R'

O

or

R C OR'

O

R C OH

O

R

F

N

N

N

HO

N

NN

F

Cl

NN

H

O

Cl

SCl

(I)Ticonazole -----------------------(II)Fuconazole

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Stability• Option A: Make drugs more resistant

to metabolism and hydrolysis1. Steric shield• Some functional groups are susceptible to

chemical and enzymatic degradation than others.

• To protect such groups, a steric shield designed to hinder the approach of a nucleophile or enzyme to those groups is added.

• These usually involve the addition of a bulky alkyl group close to the functional group. E.g., t-butyl group.

R

O

R'

O

R

O

R'

O

C CH3

CH3

CH3

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Stability

2- Bioisosteres To protect a labile functional group by

stabilizing it electronically using a bioisostere.

Using bioisostere is to replace a chemical

group within the drug with another chemical

group (of the same size and valency but

with different electronic property) without

affecting the important biological activity. This

may also improve drug’s stability.

O

C

OCH3

R

O

C

OH2N

R

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Stability3- Stereo electronic modification This means steric hinderance together with

electronic stabilization are used stabilize labile groups.

Example: lidocaine from procaine Proocaine is short lasting due to quick

hydrolysis of its ester group. Changing this ester group into less reactive amide reduces chemical hydrolysis.

Moreover, the presence of two o-methyl groups on aromatic ring provides a steric shield for the carbonyl group.

NH2

O

N

O

NH

N

O

CH3CH3

Lidocaine

Proocaine ornovocaine

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Stability4. Metabolic blockers Example: Some drugs are

metabolized by the introduction of polar groups at particular positions in their skeleton.

Megestrol acetate is oxidized at position 6 to give a hydroxyl group, leading to quick elimination of the water soluble conjugate.

By introducing a methyl group in its analogue at this position, metabolism is blocked and its action is prolonged.

R R' R R'

OH

R R'

CH3

Ox

Ox

O

O O

H

H H

O

Megestrol acetate analogue

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Stability5. Remove metabolic

groups• Certain chemical groups

are susceptible to metabolic enzymes.

• Example: CH3-group on aromatic ring are often oxidized into –COOH, which can be quickly eliminated from the body.

• These groups are either removed or replaced by groups that are stable to oxidation to prolong the lifetime of the drug.

CH3 CO2H

OH

Cl

Ox

Ox

Ox

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Stability5. Remove metabolic groups Chlorpropamide from tolbutamide

CH3 group was replaced by Cl atom and

action is more prolonged.

H3C S

O

O

NH

O

NH

Cl S

O

O

NH

O

NH

ChlorpropamideTolbutamide

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Stability

6. Group Shifts

When a vulnerable chemical group can’t be replaced or removed because it is involved in important binding interactions with the binding site, we have two possible solutions.

One is to mask this group temporarily by using a prodrug. The second is to try shifting this group within the molecular skeleton.

OH OCH3metabolize

metabolizeOH

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Stability6. Group Shifts

Example: Salbutamol from noradrenaline, where in noradrenaline, both phenolic groups are involved in hydrogen bonding to the receptor, thus

metabolic methylation of one of these groups makes the compound inactive and has a short duration.

A solution is to move one phenolic group out from the ring by one carbon unit only (if more, activity is lost, due to improper binding)HO

OH

OH

NH

C(CH3)3

HO

HO

OH

NH2

Salbutamol

Noradrenaline

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Stability

• Option B: Make drugs less resistant to metabolism:

• A drug that is extremely stable to metabolism and is very slowly excreted can pose just as many problems as one that is susceptible to metabolism.

• If the effects of the drug could last too long then it would cause both:

→ Toxicity→ Lingering side effects Therefore, designing drugs with decreased

chemical and metabolic stability can sometimes be useful. This is called shortening the lifetime of the drug.

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Other factors in drug design

• Reducing Toxicity:

• A drug fails clinical trials because of its toxic

side effects. This may be due to toxic

metabolites.

• Thus, the drug should be made more resistant

to metabolism by knowing functional groups

prone to producing toxic metabolites and

removing them or changing them into harmless

substituents or varying their position.

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Other factors in drug design

• Prodrugs:• Prodrugs are inactive

compounds but which are converted in the body into

the active drug

• I-Valium (more sustained action) → nordazepam:

• Valium sedative is believed to be a prodrug and is metabolized by N-demethylation into Nordazepam. The latter has been used as a sedative, but loses activity by metabolism and excretion.

O

N

Cl

N

Valium

O

N

Cl

NH

Nordiazepam

N-demethylation

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Other factors in drug design• Prodrugs:

II-L-dopa → dopamine (approach for carrier protein):

prodrug---→ active drug– Levodopa is a prodrug for the

neurotransmitter dopamine which is used in Parkinson’s disease. levodopa is much more polar than dopamine but yet it can cross the BBB because it is an amino acid and is recognized by the carrier proteins for amino acids. NH2HO

HO

dopamine

NH2

O OH

phenylalanine

NH2

O OH

levodopa

HO

HO

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Other factors in drug design• Prodrugs:

III-Aspirin → salicylic acid:To mask drug toxicity and side effectsSalicylic acid is a good painkiller but causes

gastric bleeding due to phenolic OH which is converted into an ester in aspirin. The ester is later hydrolysed to free the active drug.

Also, aspirin is an antiinflammatory action.

OH

OH

O

salicylic acid

O

OH

O

O

aspirin

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Sentry drugsA second drug is administered alongside the principal

drug where the role of the second drug is to guard or assist the principal drug.

1- Carbidopa:Levodopa is a prodrug for dopamine but large doses are required to be effective due to its Decarboxylation before it reaches the CNS .Carbidopa is an inhibitor of dopa decarboxylaseAnd thus it allows smaller doses of levodopa to be used

with lower side effects. Furthermore, carbidopa is highly polar so it can’t pass BBB where the decarboxylation of levodopa is required.

INHIBITIONINHIBITION

CNHNH2

HO

Me

HO

CO2H

L-DOPA DOPAMINEENZYME

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• Sentry drugs

2- Clavulanic acid and amoxicillin

Clavulanic acid inhibits the enzyme β-lactamase in microorganisms and is therefore able to protect penicillins (amoxicillin) from that particular microbial enzyme.

O

SH

HN

R

O

N

O

OH

O

OH

N

O

OH

H

OH