pharma sheet #5

بسم الله الرحمن الرحيم


- Albumin (plasma protein) is very important in determining drug level in the blood.
- Free drugs are active drugs , but drugs that bind to albumin aren't active and they work as a reservoir.
- Drugs that bind to protein ( Albumin ) have longer time of action. It is known that there is equilibrium between free drugs and binding drugs. So if the concentration of drugs decreases in the blood they separate from Albumin.
- The equilibrium changes in the case of addition of another drug, that compete with the first drug toward the Albumin and this will cause an increase in the amount of the free first drug.
- Some lipophilic drugs go toward adipose tissue and are stored there. When the concentration of drugs in the blood decreases they are released from adipose tissue.


Metabolism (biotransformation)

- Many lipid soluble drugs are not readily eliminated from the body and must be conjugated or metabolized to compounds that are more polar and Less lipid soluble drugs before being excreted.
- Metabolism often, but not always, results in inactivation of compounds
- ex. salicylic acid (aspirin) works well for awhile and when it reaches to its half-life, it goes to the liver and is metabolized there and then eliminated from the body.

- The liver is the major organ for metabolism for many drugs , but other organs ,such as lung and kidney can also metabolize drugs.

 Drugs metabolism occurs in 2 phases:
Phase I metabolism

Phase I. Reaction function (ex. oxidation, reduction, hydrolysis) after chemical reactivity and increase water solubility.

* Cytochrome P450 enzymes are found in a liver.
*There are 12 unique isoforms of this enzymatic system (CYP2D6, CYP3A4). These enzymes play a very important role in human drug metabolism.

- Every drug has a special isoenzyme that metabolizes it.
- If one of this isoenzyme changed, the drug that metabolized by this isoenzyme would accumulate in the body and there will be toxic effect.

- People are divided into 4 types (according to cytochom p450):

1. Extensive metabolizer ( fast metabolizer )
–these people need higher dose of the drug .

2. Intermediate metabolizer ( normal metabolizer)
–we don't need increase the dose or reduce it .

3.Poor metabolizer –metabolism is very slow .
And drug concentration In the body is high.

4. Ultrarapid metabolizer – in these people copy of genes more
than normal and we need to increase the dose much more.


- Every enzyme is translated from a special gene in our body. Every gene has 2 copes (this copes called alleles) . If this copes are inactive, then a patient is poor metabolizer.

- How can we know the type of a metabolizer?
By a phenotype analysis.
We give a drug to the patient and see how much metabolized drugs are eliminated with urine and how much of them remain in a body. If the amount of eliminated drugs is little ,then it means that
there is no metabolism and all drugs are building up in the body.
Another way is genotyping way .
We extract DNA from a patient and study genes on it and see Is active or not.

- A DNA length is 3 billion nucleotides, 5 million nucleotides differe between people. Small change in one or more nucleotide - if it happen in place where the gene is translated to special enzyme from cytochrome P450- will give different function. And this may cause ultrarapid or rapid or poor metabolism .

- 9 cytochrome p450 isoenzymes that are identified and have special functions. Every isoenzyme is specialized to metabolize a certain drug

ex. 1A2 metabolizes caffeine
- testosterone is metabolized by 3A4
- 2C9 metabolizes warfarin

Phase II metabolism

- If the metabolite from phase I is polar enough it will be execreted by the kidney. But if it is still lipophilic to be retained in the kidney, a phase II metabolism will take place.
- Phase II consists of conjugation reaction with endogenous substances, such us, glucuronic acid, sulfuric acid, or an amino acid
- Results in polar and usually more water soluble compounds.


 Cytochrome P450 system dependant enzymes can be induced or inhibit by a certain drug.
- Ex: 1.If a patient takes Erythromycin and varapamil at the same time, erythromycin will accumulate becase 3A4 inhibited by varapamil . If the patient takes rifampin, Erythromycin decreases and we need to increase the dose.
- 2.If a patient takes midazolum and ketoconazole at the same time, midazolum will be more active. But if he takes a rifaprin the activity will decreases.

- Poor metabolizer can be a good thing because there will be building up in a patient body .So, we need to give him less dose of drugs and the chance to have toxicity will be less. But this is true only when the patient knows that he is poor metabolizer ,but if he doesn't know the toxicity will increase.



Elimination.
- Occurs via a number of routes, the most important being through the
kidney into the urine.
- Other routes include the bile, intestine, lung, milk in nursing mother (so if the mother takes a heroin or morphine the baby may poison by this drugs)

- Drugs eliminated through these routes (bile, intestine lung, milk) tend to be lipid soluble and unionized.

Drug- drug interaction

When two drugs are taken together, there is a possibility that drugs will interact with each other causing unanticipated effect. Usually increase or decrease in the desired therapeutic effect.

Drug- drug interaction occurs in the following sites:

1. At the site of action, drag antagonism

2. During biotransformation (metabolism) (CYP450)

3. At the site of absorption,(ex. amino acid and levodopa compete to bind in the same site of the intestine in order to absorb them) Another example –tetracycline drug is not absorbed from the GI tract if calcium product is present in the stomach.

4. During excretion, digoxin and quinidine are both excreted from the same sites in the kidney. The quinidine will be excreted first because it is more competitive for these sites, resulting in increased serum levels of digoxin.

5. During distribution, aspirin competes with methotrexate for protein binding sites, and because aspirine is more competitive for the sites, resulting in increased release of methotrexate and so increase toxicity to tissues.




Adverse effect

What is the difference between side effect and adverse effect?

-Adverse effect is a major bad effect ( ex . if a patient takes a penicillin ,an anaphylactic shock may occur)

-Side effect is a minor bad effect (ex. A patient takes a penicillin and then has diarrhea)

- Adverse effect can occur for many reasons:

1. Drug- drug interaction (if the drug accumulate in the body adverse
effect will happen.)

2. The patient is taking too much or too little of the drug.
3. The patient has allergic reaction to the drug ( if a child is given Aspirin he may die from allergic reaction).
4. The patient is sensitive to the drug.(If a patient who is a poor
metabolizer (cytochrome P450 system is not active) is given high dose of drug he will be more reactive to the drug.



Ex. A normal patient is given morphine to decrease pain perception. If he is given overdose of morphine he will have drug toxicity.
Another patient is sensitive to morphine . He may have asthma or another respiratory disease. He is given normal dose of morphine but his state changes for the worse.

Risk: benefit ratio

- Benefit: intended biological activity
- Risk: adverse effect
- With every drug use, unwanted effects must be taken into account. Before prescribing a drug, the physician should therefore assess risk: benefit ratio.
- Therefore ,knowledge of principal and adverse effects is a prerequisite.
- Prophine and aspirin are non steroid anti-inflammatory drugs .
- An Asthma patient shouldn't be given non steroid anti-inflammatory drugs ,but if it is necessary, we can give him prophine but not aspirin.







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DONE BY:Nataliya Komashynska
3/10/2010
LEC #:5