At the end of the last lecture I was discussing with you the subject of drug metabolism and we discussed

why drug are 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 drug metabolism. Drug metabolism is affected by the following factors: 1. genetic factors people are classified into bad or slow metabolism due to genetic factor, for example isoniazid(drug is used for TB) in some people will be slowly metabolized in other people will be rapidly metabolized, the consequences of this fast and slow metabolism will be discussed later, isoianzid, hydralazine, cobinamide could be metabolized rapidly 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 metabolize the drug slowly why ?? because in neonate the drug metabolizing enzymes are immature , and in very old aged drug metabolizing enzymes will be not so effective or what is called aged enzyme therefore in neonate and in very old ages we should give small doses, why?? Because drug elimination will be slow. 3. Pathological factor: can determine the rate of drug metabolism, because drug metabolism is slow and elimination is also slow, for example a patient with liver disease should be given low doses because the rate of drug metabolism is low. 4. enzyme induction and inhibition : most drugs are usually metabolized within by the liver by a set of enzymes called micromsomal enzymes you know the Microsome we have intracellular organelles called microsomes and ribosomes , we have the endoplasmic reticulum smooth one and rough: Rough ribosome protein synthesis Smooth Microsome drug & chemical metabolism

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 Phenobarbitone (antibiotic) Rifamicin Carbamazepine Phenytoin Inhibiting agent Isoinazid Ciprofloxacin Erythromycin 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 inducer so 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.

Therapeutic effect is direct proportional to the In this case we use drug B as concentration inhibitor , therefore the rate of drug metabolism will slow down so the serum concentration will increase so the therapeutic activity will increase .

Therapeutic activity will decrease or therapeutic failure might be produced if we use microsomal inducer enzymes.

Toxicity might be produced if we add microsomal inhibitor enzymes to certain drug.

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 .

Main order of metabolism is the liver

Main order of execretion is the kidney.

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: 1glomuleral filtration . 2tubular reabsorbtion (is a ph and Pka dependent as we have already explained according Hassel-balch Henderson equation) 3Tubular secretion.

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 be absorbed 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

The other routes of drug secretion : Sweat milk lung bile : drugs might be secreted by the .

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 and the 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-hepatic cycle 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.

Pharmacodynamics Drug half-life Drug half-time: the time taken for the concentration to fall to half it's original concentration.

CLINICAL IMPORTANCE OF KNOWING HALF-LIFE : To determine the drug frequency: drug with long half-life should be given less frequently, while the drug with short half-life should 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.
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Drugs with long half-life they are called accumulative drugs. 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. 3To 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 measure the half life ?? By plotting a log concentration time curve

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 :

t 1\2 = 0.693\ke Ke : is the slop of the line Ke = tan Constant of the elimination indicate 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.

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 have First order and Zero order kinetics:

First order: fixed fraction of the drug is eliminated per unit of time. Zero order: fixed amount of 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

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 If is high t1/2 will be very long. t1/2 will be very short.

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 Drugreceptor (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.

** 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 easily eliminated 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:

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 drugreceptor 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 receptor producing 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:

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 useful therapeutically 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 Antagonist Partial agonist Pindolol). High intrinsic activity. No intrinsic activity. (e.g: Atropine). In between. (e.g: Nalorphine,

Intrinsic activity +++ + -

Affinity +++ +++ +++

Agonist Partial agonist Antagonist

** Therapeutic ratio or index:

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 might be 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:

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.

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

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