Lecture 4, Drug metabolism (Script)

8/4/2019 Lecture 4, Drug metabolism (Script)

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At the end of the last lecture I was discussing with you thesubject of drug metabolism and we discussed why drugare metabolize , the site of drug action and metabolism,and we discussed the pathway of the drug metabolism ,

let us now discuss the factors that affect the drugmetabolism.Drug metabolism is affected by the followingfactors:1. genetic factors people are classified into bad or slow

metabolism due to genetic factor, for exampleisoniazid(drug is used for TB) in some people will beslowly metabolized in other people will be rapidly

metabolized, the consequences of this fast and slowmetabolism will be discussed later, isoianzid,hydralazine, cobinamide could be metabolizedrapidly in some people and slowly in other groups.

2. The age : for example neonate or newly born infant,usually neonate and very old age they metabolizethe drug slowly why ?? because in neonate the drugmetabolizing enzymes are immature , and in very oldaged drug metabolizing enzymes will be not so

effective or what is called aged enzyme therefore inneonate and in very old ages we should give smalldoses, why?? Because drug elimination will be slow.3. Pathological factor: can determine the rate ofdrug metabolism, because drug metabolism is slowand elimination is also slow, for example a patientwith liver disease should be given low doses becausethe rate of drug metabolism is low.4. enzyme induction and inhibition : most drugsare usually metabolized within by the liver by a set ofenzymes called micromsomal enzymes you know theMicrosome we have intracellular organellescalledmicrosomes and ribosomes , we have theendoplasmic reticulum smooth one and rough:

Rough ribosomeprotein synthesis

Smooth Microsomedrug & chemical metabolism


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Microsome: are enzymes responsible for metabolism of

drugs, they could be induced after prolong use of the drugs or

chemicals the amount or the activity could be increase

(induction: is the process of increment in the micromsomal

enzymes after prolong use of certain drugs or chemicals),

these enzymes not only could be induced, it could be

inhibited , inhibition of these enzymes called

micromsomal inhibitors enzymes .

We have two groups of drugs called:

1- Inducing agent (increase the amount and the activity

of enzymes after prolong use)

2- Inhibiting agent (decrease the amount and the activity

of enzymes after prolong use)

Don't worry about this list:

Inducing agent Inhibiting agent

Phenobarbitone (antibiotic) Isoinazid

Rifamicin Ciprofloxacin

Carbamazepine Erythromycin

Phenytoin Cimetidine

This is the concentration-time curve,

and we can see the curve of the

concentration of drug called A , if we

add drug B to drug A and this drug B is

an inducerso it will increase the rate of

metabolism and the rate of elimination

also will be increased , therefore the

concentration of drug in the serum

should be decreased so the therapeutic

effect should be decreased . so to

increase the effect or the activity of drug

A we should increase the dose.


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Therapeutic effect is direct

proportional to the

concentrationIn this case we use drug Bas

inhibitor, therefore the rate of drug

metabolism will slow down so the

serum concentration will increase

so the therapeutic activity will

increase .

Toxicity might be

produced if we

add microsomal

inhibitor enzymes

to certain drug.

Therapeutic activity

will decrease or

therapeutic failure

might be produced if

we use microsomal

inducer enzymes.


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Drug excretion (Elimination)The next step after metabolism ( the aim of metabolism is to decrease

toxicity and to increase water solubility ( decrease lipid solubility ) in

order to make the drug easy to eliminate by kidneys .

Some drugs can be eliminated by other organs such as skin (sweet),milk, through lung (exhalation, like drugs for general anesthesia is

taken by inhalaition and excreted by exhalation).

Excretions include:1- glomuleral filtration .2- tubular reabsorbtion (is a ph and Pka dependent as we have

already explained according Hassel-balch Henderson equation)

3- Tubular secretion.

Main order of execretion is the

kidney.

Main order of metabolism is the

liver


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Drugs which are filtered through the glomerulus after being metabolized,

converting to more water soluble drug , so the majority of drug will not

absorbed and eliminated with urine and the only fraction that could beabsorbed is the lipid soluble fraction ( the minor after metabolizing ) ,

some drugs will be actively secreted through .. for example penicillin

when it taken by injection or orally it will be filtered through the

glomeruli and some of it will be reabsorbed and the other will be actively

secreted ( push into the renal tubule )

Drugs that are actively secreted into the renal tubule usually have a

very short duration of action .

To prolong the duration of action of penicillin for example we have to

inhibit it active secretion , when we inhibit the active secretion to the

tubular , we will leave it for longer time inside the body so that we

prolong it's duration of action.

Penicillin + probenicid =increase the duration of action

of penicillin

From previous year


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The other routes of drug secretion :

Sweat

milk

lung bile : drugs might be secreted by the .

Pharmacodynamics

Drug half-life

Drug half-time: the time taken for the concentration to fall to half it'soriginal concentration.

Some drugs they are absorbed from the intestine through the portal circulation to the liver ,

metabolized by the liver , excreted by the bile , then to the intestine for example : a conjugated

drug( drug + glucuronic acid ) = ( DG ) { conjugation is the process of metabolism which can

convert the drug to more water solubility } this conjugated drug ( DG) in the liver will be

eliminated by the bile to the intestine , and in the intestine there is a bacteria , and these bacteria

can deconjucated some drugs , so in the intestine DG will be again Drug +Glucuronic acid andthe deconjucated drug ( which highly lipid soluble) will be reabsorbed again into liver forming

a cycle between the intestine and the liver , the intestine in Latin called the intro and the liver

called hepatic so this cycle is called the intro-hepatic cycle ( intestine to the liver cycle ).

The drugs which are eliminated by the intro-hepaticcycle usually have a very long duration of

action, because the drug will remain in the body for a long period of time. While drugs which

have actively secreted by the renal tubule have a short duration of action.


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CLINICAL IMPORTANCE OF KNOWING HALF-LIFE :

1- To determine the drug frequency: drug with long half-life

should be given less frequently, while the drug with short half-lifeshould be given more frequently or repeated. Most of you are heard

that antibiotics usually they have a short half-life that's why they

are given every 4 hours or 6 hours (the patient should take 1-2

capsule every 4 or more hours) while other drugs for example

Digoxin which has a very long half-life it should be given once

daily.

Drugs with long half-life they are called accumulative drugs.

2- To determine the time needed for nearly complete

elimination of the drug. For example a drug in a dose of (100mg)

give us a concentration of (100g/liter) so after 1 half-life the

concentration will be 50, the second half-life will be 25, the third

half-life will be 12.5, after the fourth half-life will 6.25, after fifth

half-life 3.125 so we can expect that 97% of the drug will be

eliminated after 5 half-life's, The time needed for nearly ( not

complete) eliminated is 4-5 half-life's, we said nearly because we

will never reach the 0.3- To determine the time needed for reaching steady state

serum concentration ( concentration of the drug with minimum

fluxuation and best therapeutic effect) , if we take a drug at time 1

it's concentration will be gradually elevated until it reaches peak

then the process of elimination and excretion will start and the

concentration of the drug will be reduced , when the time comes

for next dose the process will be repeated again , so there will be

always fluxuation in the concentration of the drug.


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This is the steady state serum concentration and again the time needed for

reaching the steady state serum concentration is 4-5 half-life's.

How to plot this curve ??

We give the drug IV , and we take repeated blood samples after different

periods , the will be sent to the lab and the concentration of drug will be

measured after that we take the log of the concentration and then we plot

it against the time, by this way we will have a straight line , this line we

call it log C-time curve , the half life of the drug will be measured by this

equation :

Ke : is the slop of the line

Constant of the eliminationindicate constant rate of elimination.

Drug clearance (Cl)

Clearance is defined as the volume of the fluid which is cleared from the

drug in unit of time.

The unit of clearance Unit of volume.The unit of volume of distribution Unit of volume.

How to measure the half life ??

By plotting a log concentration time curve

t 1\2 =0.693\ke

Ke = tan


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The unit of drug half life Unit of time.

The clearance will be calculated according to this equation:

Cl= ke X Vd

Ke is calculated from the log concentration-time carve.If the drug is taken IV then:

Volume of distribution (Vd) = Dose

Conc. of protein

If the drug is taken in another route:

Volume of distribution (Vd) = F * Dose /Conc. of protein

** F denotes the bioavailability**

Pharmacokinetics terms :

We haveFirst order and Zero order kinetics:

First order: fixed fraction of the drug is

eliminated per unit of time.

Zero order: fixed amountof the drug is

eliminated per unit of time.

Example:

A drug is given in 100mg dose, its half life (t1/2) is

one hour and it will be eliminated by fixed

fraction of 10% every one hour, so one tenth of

the drug will be eliminated each hour, which

means that the 100mg will be 90mg after one

period of time (1 hr), then the second hour, it will

be 10% NOT of the 100mg BUT of the remaining

(90mg) so it will be 81mg, then 72,63,54 and so


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on. Thats why when we plot the concentration

versus time, well have a curly (curved )linear line.

While in Zero order kinetic, there is a fixed

amount here which is always 10mg eliminated per

unit of time , 100, 90, 80, . Therefore, when we

plot concentration versus time, well have a

straight line but when we plot log concentration

versus time, well have a curly (curved) line.

Look here:

I said that we can determine the half life by measurement of the slope of

the line which equals tan of that is fixed whether at high concentration

or low concentration. Therefore, the half life for drugs which are

metabolized by First order kinetic are usually stable or have fixed half

life. On the other hand, in Zero order kinetic, the half life will be

The slope of this line is less than the slope of this line which means that

the half life here is very long because is low, we divide 0.693/:

If is low t1/2 will be very long.

If is high t1/2 will be very short.


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This means that the drugs which are metabolized by zero order kinetic

have long half life at high concentration and very short half life at low

concentration, why? Because the drug will saturate the enzyme

responsible for drug metabolism at high concentration, therefore the rate

of the elimination of the drug will be slower. While when the

concentration decreases, the rate of elimination will be speeded up due to

the non-saturation of the enzyme system responsible for drug

metabolism.

Thats why sometimes Zero order kinetic is called saturation kinetic.

Most drug fortunately follow first order kinetics, and minority of drug

such as aspirine follows zero order kinetics , by plotting concentration

versus dose in FOK we can highly predict the concentration from the

dose, dose 1 will give us concentration 1 , if we double the dose we can

double the concentration, tripling the dose we can tripling the

concentration, so we can easily predict the concentration from the dose.

While in ZOK if we plot concentration versus dose we can not predict

concentration from the plot, why? Dose one give us concentration one, if

we double it we might not have double concentration but we might have

more than double of the concentration, if we triple the dose the

concentration will shot up to a toxic level. This is due to the saturation of

the enzyme responsible for drug metabolism.

Drugs which are metabolized with ZOK if we want to increase there

doses , the dose increment should be gradually not suddenly, for example

we don't change the dose from 100 directly to 200 but gradually 100 to

125, then to 150 to 175 until we reach the therapeutic dose .

Pharmacodynamics: It means the mechanisms of action of the drug.

The common mechanism of drug action is called

Transmembrane signaling mechanism or Drug-

receptor (DR) interaction.

This mechanism means that for any drug, there is a

specific receptor so the drug can bind to it and

produce an effect.


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** Mechanisms of action of the drugs:

1. Drug receptor interaction:well discuss it after few

minutes.

2. Physical or physiochemical properties: for

example:

- Magnesium sulfate acts as purgative and Mannitol

acts as diuretic.

3. Chemical interactions: the simplest example is the

antiacids; we can neutralize the hyperacidity of the

stomach by giving alkaline preparation that will interact

with acid of the stomach leading to the formation of salt

and water and neutralization of the acidity.

4. Chelation:

It is the formation of a complex of the chelators (B) with

the drugs (A) to make unabsorbable substances by the

intestine and if the drug is already absorbed, the chelator

can make a complex with this drug which could be easilyeliminated from the kidney.

For example: BAL which is a chelating factor that is used

for the chelation of heavy metals poisoning such as

poisoning with Lead or As.

5. Blockade of active transport system:

Examples: Digoxin which inhibits Na-pump and

Omeprazole which inhibits H-pump and it is the drug that

is used for the treatment

of peptic ulcer.

6. Enzyme inhibition:

Neastigmine: it is an inhibitor of the enzyme choline

esterase

7. Blokade of ion channels:


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Such as Local anesthetics by blocking Na-channels and

Ca-channels blockers which block Ca channels.

8. Inhibition of cell wall and protein synthesis:

It is a major mechanism of actions of antibiotics or drugs

which are used for treatment of infections.

9. Effects on nucleic acids synthesis or function:

Cytotoxic drugs or anti-cancer drugs produce their effect

by the inhibiotn of RNA or DNA synthesis.

10. Replacement therapy as hormone and vitamins:

For example: - Diabetes type I is treated by replacing

deficient insulin.

Anemic patient (deficiency in vit-B12) is treated by

the replacement of this deficient vitamin.

Lets go back to the first and main mechanism, the drug-

receptor interaction:

For any drug, there is a specific receptor as for every

lock, there is only one specific key to open ( key-lock

theory ).

Lets have an idea about these terms:

1. Affinity: the ability of the drug to combine to its

specific receptor.

So when the drug binds to its specific receptorproducing an effect we call this process Affinity and we

say that this drug has affinity.

2. Intrinsic activity: the ability of the drug to produce

an effect (pharmacological action) after binding to its

receptor.

**According to these two definitions, drugs are classified

into three main types:


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Agonist: it means that drugs have powerful affinity

(+++) and can produce a powerful effect (+++).

Antagonist: it means that drugs have very high

affinity but can NOT produce any effect. It is usefultherapeutically because it displace the agonist effect.

A common example of the agonist is the acetyl

choline binding to cholinergic parasympathetic

receptors. On the other hand, Atropine is acetyl

choline antagonist that prevents acetyl choline from

binding to its receptor.

Partial agonist:it is between the agonist and the

antagonist; it can bind to the receptor and producing

an effect. So it has high affinity but with partial

intrinsic activity.

Briefly:

All agonist, partial agonist and antagonist have high

affinity, but the difference between these three classes is

in their intrinsic activity.Agonist High intrinsic activity.

Antagonist No intrinsic activity. (e.g: Atropine).

Partial agonist In between. (e.g: Nalorphine,

Pindolol).

AffinityIntrinsic activityAgonist++++++Partial agonist++++Antagonist+++-

** Therapeutic ratio or index:


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It is the ratio between therapeutic dose 50(TD

50) to the effective dose 50 (ED 50).

What does #50 mean ?

* If we give the drug to 100 patients or 100

experimental animals, the dose which can produce

therapeutic effect in 50% of patients or the

experimental animals is called TD 50 and by the

same definition the ED 50.

* In other books, you might see the definition of TD

50 as toxic dose 50.

- Keep in mind:

*TD 50 means toxic dose 50 and toxic means the

dose which can produce side effect of toxins.

* ED 50 means effective dose 50 (sometimes it is

called therapeutic) and effective means producing an

effect whether it is minor or major effect.

- Example: 20 tablets of 500mg of Paracetamol mightbe toxic in most patients while the therapeutic dose of it,

is from 500mg to 1g.

So its therapeutic index will be 20 tablets/ 1 tablet = 20

while for example, therapeutic dose is 0.1mg and the

toxic dose is 0.2mg, its therapeutic index will be

0.2/0.1=2.

we can conclude that drugs with low therapeutic index

are usually more toxic than drugs with high therapeutic

index. Thats why we can say that Paracetamol is a very

safe drug while Digoxin is relatively a toxic drug.

Drugs of therapeutic index of (1) called poisons

because the toxic dose equals the therapeutic dose.

Now, lets have an idea about these terms:


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Potency: it is the effect of the drug per unit of

weight.

Here we can see that drug A is more potent than drug B

because drug A produces an effect at lower dose than

drug B.

Efficacy: it is the maximal or ceiling effect of the

drug after which there is no increase in response

even when the dose is increased.


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Here, drug A has higher affinity than drug B, because

drug A has higher maximal effect.

The end

Done by :

Haneen zuhdi al-kawamleh

&

Wala2 khdour

Eman : "Friends are the sunshine of life." :)

Lecture 4, Drug metabolism (Script)

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