General pharmacology third lecture

Dr. Khaleel Makki

Done by : Azal Masaood Amshoosh.

At the end of the last lecture I was discussing with you the subject of Protein Binding and I said that drug bind to protein in the form of a reversible reaction so there are free drug fractions and protein bound drug fractions the important point is that only the free unbound drug fractions can pass the cell membrane ,so the free fraction is the metabolizable , absorbable and excreted fraction. Know examples of Drugs which are highly protein bound Warfarin, Phenylbutazone and Diazepam. (do not worry about the names of these drugs we will
talk more about them more in the future) what I mean by highly protein bound drug

that the bound drug fraction is more than the free one ,and usually its protein binding capacity is more than 95% that means 95% of the drug is attached to protein and only 5% or less is in free fraction. Digoxin , Gentamicin and Theophylline are Drugs which has low protein bound so the free fraction is very high here about 50%. This figure shows you protein binding:

Only the free drug fraction can produce an effect

Plasma protein reversibly bind to the drug and then the free drug is the only fraction of the drug bind to the receptor to be effective, metabolizable, and excreted.

Another figure to show you protein binding :

Drug bind to protein in a reversible reaction=bound drug can not bind to receptor. receptor

Free unbound fraction of drug =the only fraction that can bind to receptor producing an effect.

Protein binding displacement:

A
These star shape molecule represent another drug=drug A given to patient who is taking drug B

Is one of the processes which can explain drug interaction .You can see that we add drug A to patient who is taking drug B , notice that drug A is high protein

binding drug too ,so it displace the original drug B ,by this drug B free fractions
increase ,so its effect will increase "without any addition of drug B".

Example: A patient is taking Warfarin (anti- coagulant). Normally this patient

has an effect of warfarin. Without increase the dose of warfarin and if we add another drug which is highly protein binding drug this drug will displace warfarin so that the free fraction of warfarin will increase also its effect will increase this may lead to the toxicity of warfarin is that patient might start bleeding at any time . (we will discuss this in more details later)
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Effect of hypoproteinemia:
Here protein level is low such in case of renal and hepatic diseases protein level will decrease so the free drug fraction will be more than the bound drug fraction, by this the drug effect will increase . So in case of renal or hepatic disease there will be hypoproteinemia + hypoalbuminia + increasing free drug fractions increasing drug effect. That's why in case highly protein binding drug in case of renal or hepatic disease we should reduce the dose of these drug in order to prevent toxicity.

Apparent Volume of Distribution:

It is the volume that would be required to contain the entire drug in the body at the same concentration as in the plasma. Assuming the body as a single compartment. Explanation we assume the body as one barrel containing a fluid the dose of drug will be dissolved in this barrel. If the drug is given IV : Cp = plasma concentration of the drug at zero point of time

Vd = Dose/ Cp

at zero point of time If drug is given by another routs : Bioavailability

Vd=F X Dose / Cp
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"If we got low volume of distribution means we have high plasma concentration so we will get low fraction" and vise versa . Low plasma concentration drug means that the drug is not limited to plasma compartment. Haemodialysis is useful in drugs have low volume of distribution = have high plasma concentration ((the blood is moving through membrane separated it from dialyzing fluid so that the metabolites , urea , creatinine or any drug limited to plasma compartment can move to the dialyzing fluid this is the principle of the artificial kidney)).

Selective distribution
Some drugs are selectively distributed for example: Iodide not uniformly distributed in the body it has been found that its concentration on the thyroid gland 25 times more than in the plasma. Another example Thyopentone is intravenous general anesthetic concentrated in CNS and adipose tissues that is why it has a rapid onset of action and short duration of effect ," rapid onset because it will be trapped by central nervous system" . Blood brain barrier (BBB) also can provide selective distribution, some drugs cannot pass BBB and some drugs cannot pass the placental barrier. This barriers are protective barriers protect CNS and the newly developing fetus from the entry of some toxic drug.

This figure shows you BBB:

In normal blood vessel of the body as in the liver the endothelial is not tightly joining to each other there are gaps in between.

In the CNS there is tight junction between the endothelial cells producing BBB can prevent movement of toxic drugs from blood to CNS.

Metabolism :
Usually (in any

represented by m in ADME

Q Why drug is metabolized?

biological, medical and clinical sciences there is no always so if you see a sentence

with always you can say it is wrong) drug

is metabolized to:
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1. Reducing lipid solubility. 2. Alteration (decrease or increase) of biological activity e.g. detoxification or deintoxication.
This is a nephron: Drugs pass to glomerulus, proximal tubule by process of filtrations and execration. Glomerulus permit the passage of lipid and water soluble molecules. While the drug is passing through renal tubule only the lipid soluble is reabsorbed back to the circulation. And only the water soluble drug will be execrated The main aim of drug metabolism is to increase water solubility and decrease lipid solubility to enhance renal excretion.

Sites of drug metabolism

Most of drug metabolize in liver and some drug such as Succinylcholine is metabolized in plasma by the enzyme cholinesterase , also GIT mucosa metabolizes female sex hormone of Contraceptives as first pass metabolism. Some Sympathetic amines "adrenaline and nor adrenaline are metabolized by synapses of Synaptic neurons".

Pathways of drug metabolism

Usually drugs are metabolized by what called phase1 metabolism reaction either oxidation, reduction and/or hydrolysis. If oxidation ,reduction or hydrolysis are not enough to reduce lipid solubility of the drug then phase2 reaction take place to increase water solubility or to more decrease lipid solubility.phase2 reaction usually called conjugation reaction it produce conjugated products which are highly water soluble and very low lipid soluble conjugations could be with glucoronic acid ,sulfate group, methyl group , acetyl group and so on. Let us see this example:

Benzene is highly lipid soluble metabolize by phase1 reaction oxidation (hydroxylation)to produce phenol which is still highly lipid soluble we need phase 2 reaction where phenol conjugate with glucoronic acid to produce

phenol glucoronide which highly water soluble so it will be highly eliminated by

the urine it will not be reabsorbed back to the circulation.

Factors Affecting Drug Metabolism:

1. Genetic factors: people are classified into two groups according their rate of metabolism = Fast and slow metabolizers. According to studies Eskimo have fastest metabolism rate and Egyptian have the slowest. 2. Age, (neonates and very old are slowly metabolize drug because the

metabolizing enzymes are immature in neonates and aged in old people

"geriatric). 3. Pathological factors: e.g. People with liver cirrhosis are slow metabolizers, therefore, drugs which metabolized mainly by liver should be given in lower doses to patients who have advanced liver diseases. 4. Enzyme induction and inhibition: The endoplasmic reticulum composed of (smooth part called microsome use to metabolize drug) and (rough with ribosome used for protein synthesis.) The microsomal enzymes are the main system for drug metabolism and they called induction enzyme .Induction is increase activity and /or quantity of the microsomal enzymes after chronic or repetitive intake of certain drug. The inducer: is the drug that can produce these increments of activity and /or quantity of the microsomal enzymes. So drug metabolizing enzymes might be (microsomal = Inducible) Or (nonmicrosomal =not inducible). Inhibition: is decreasing the activity and/or quantity of microsomal enzymes after chronic or repetitive intake of certain drug. We discussed two Mechanisms of drug interactions:
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*Protein binding displacement interaction. *microsomal enzymes induction or inhibition.

Drugs Affecting Microsomal Enzymes: (by the end of the course it will be very easy
to memorize these drugs, do not worry we will repeat it a lot )

ME Inducers Rifampicin Carbamezepine Phenobarbitone Phenytoin

ME Inhibitors Cimetidine Erythromycin Ciprofloxacin Isonizid

e.g. patient is taking warfarin (for any reason) this patient need Rifampicin (is an antibiotic mainly use to treat tuberculosis which is a
chronic disease) we give him Rifampicin for 2 or 3 weeks what will happen to ME? they will induced so the concentration of warfarin in the plasma will decrease that means when we give Rifampicin to patient who is taking warfarin we should increase the dose of warfarin.

So please follow this idea and try to conclude the effect of any ME inducer or
ME inhibitor in warfarin plasma level.

Concentration Dependent Metabolism (please pay attention to this part of

the lecture)

We have two types of kinetics FOK and ZOK FOK: first order kinetic (most drugs follow it)
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ZOK: zero order kinetic (only few drugs follow it such as aspirin, phenytion and theophylline).

First Order Kinetics means always there is fixed fraction of drug eliminated
per unit of time e.g. if we have 100mg at time 0 after 1h there will be 10% of the 100mg is eliminated in 10 min then after another 10min there will be another 10% (of the remaining 90%) eliminated and so on. by that you will get this curved line:

Concentration- time curve

By taken logC you will get this straight line

Concentration versus dose curve: there is a direct relation between concentration and dose of the drug that is why concentration can be predicted from the given dose, so you will get straight line:
e.g. If D is 100 and the C = 1O. by doubling the D to 200 the C =20 by tripling the D to 300 the C=30..SO ON.

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Zero Order Kinetics: there is fixed amount of drug eliminated per unit of
time. If we got concentration versus time we will get straight line:

By taken logC you will get this curved line Notice that the decrease in concentration of the drug at very high concentration is (flat) slower than the decrease in concentration of the drug at low concentration (more steep).

Why the decrease in concentration of the drug at very high concentration is slower ? Because of the enzymes responsible for drug metabolism at high concentration are saturated that is why another name for ZOK is saturation kinetic. Or according to names of scientists who explain it Michaelis-Menten kinetic. Concentration versus dose in ZOK= curly linear line
Here if D=100 and C=10 By doubling D=200 C=50 OR 60 So doubling dose of ZOK might be toxic.

. That is why increasing the dose of ZOK drug should be taken carefully and increasing gradually not suddenly.
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Excretion: represented by E in ADME

The main site of excretion is the kidney *Glomerular filtration * Passive tubular reabsorption (pH &pKa) dependent . *Active tubular secretion (all drug actively secreted by renal tubules have very short t as penicillin).so it should be given frequently. * Respiratory (general anesthetics= taken by inhalation and excreted by lungs). * Other minor routes as milk, sweat, saliva sometimes ,tears by lacremal gland Let us have an idea about entero- hepatic cycle:

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The drug taken orally , is absorbed through the intestine to the portal circulation then to the liver .It metabolized by both phase1 and phase2. And then the conjugated products is eliminated through the bile from the bile to the intestine at the intestine the bacteria will deconjugate the conjugated drug product so it will be free again absorbed through the intestine to the portal circulation then to the liverand so on this cycle is called entero-hepatic circulation . *Drugs subjected to entero-hepatic circulation have long half lives.

Drug Half Life (T )

The time taken for the conc. To fall to half its original value. Or the time taken for all the concentration. To be halved. e.g. 100 50 50 one half life 25 another half life

25 12.5 12.5 6.25 6.25 3.125 so drug need 5 half lives to reach 3% of original

concentration *you will never reach zero concentration = we cannot get rid of drug totally and it has been regarded that 3 of drug means nearly complete elimination. Clinical importance: - Determine dose frequency: drug with short half life should given more frequently. In contrast, drug with long half life should be administered less frequently.

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- Determine the time for nearly complete elimination of the drug from the body. (4- 5) t

QUESTION:
What is the time needed for nearly complete elimination of Digoxin if its half life is 35 hours? 5 X 35=175hours nearly a week. 35 hours or 1hours or 1 week or 1month

-Determine the time to steady state serum drug concentration (4- 5) t How can we measure half life ?

We can measure half life from this log concentration - time curve give us straight line in case of FOK the slope of this line is tan = Ke (constant of elimination ) and by getting the constant of elimination . t = 0,693 / Ke Ke =slope of the line or rate of elimination &. 0,693= natural log of 2=Ln2

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This diagram shows concentration versus time curve after drug administration the concentration gradually moved up , we have peaks of concentrations of different heights and troughs of concentrations of different depths until we reach state where all peaks have the same height and all troughs have the same depth this state called the steady state serum drug concentration . Our aim therapeutically is to reach steady state serum drug concentration. The time needed to reach it is (4- 5) t In case of Digoxin 35X(4- 5) = around 1 week In case of Penicillin 4 to 5 hours

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Drug clearance (Cl)

Clearance is defined as the volume of the biological fluid such as blood and plasma which is cleared from the drug in unit of time.

Be careful for this :

The unit of clearance Unit of volume per unit of time. Unit of volume.

The unit of volume of distribution The unit of drug half life

Unit of time.

Finally

THE END Please forgive me for any mistake.

Wish you all the best in the third year .

Now away from pharmacology , free short journey in 7 minutes only :
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Azal Amshoosh

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