Pharma 02

  Pharmacology has 2 main areas: pharmacodynamics and pharmacokinetics. Pharma: drug

drug is secreted by the kidneys, then it would be excreted as urine. If it was secreted in bile, then it is secreted as feces.

Dynamics: action Kinetic: motion So, pharmacodynamics is the action of the drug on the body, which includes biochemical and physiological effects of the drug, including the mechanism of action, interaction with receptors as well as adverse effects. Pharmacokinetics is what the body does to the drug. The drug is not the master in the body; it acts on the body and the body acts on it. These include absorption, distribution, biotransformation (metabolizing) and excretion of the drug.

Actions of the body on the drug are: 1- Absorption: It is the movement of drug molecules from the site of administration into the circulation. An example of site of administration is in the intestines. When a patient takes a drug orally, the drug is absorbed in the intestines and is moved to the circulation. 2- Distribution: Once in the circulation, the drug goes to the rest of the body. The movement of molecules from the circulation to tissues and between different parts of the body is called distribution. The drug is distributed to its site of action, elimination organs and other tissues. 3- Biotransformation: If a drug reaches to the liver which is a metabolizing agent, it is metabolized. Biotransformation is the biological conversion in the drug from one chemical structure to another by the action of metabolic enzymes. 4- Excretion: It is the movement of drug from the circulation to outside of the body through feces or urine. If the

In explaining the relation between the two concepts: pharmacodynamics and pharmacokinetics, the drug follows the rule of mass action. Rule of mass action can be simply referred to as random diffusion. An example that explains this law is illustrated in adding a drop of blue ink to a large tank of water. The drop diffuses rapidly, and begins to fade out until it fully disappears. At the end, we have a mixture of water and blue ink in which the blue ink is not visible. In the same way, the drug in the circulation is distributed throughout the body, going to the kidneys, liver, heart, intestines, etc… Dosage form is the form of the administrated drug. That can be either in a form of a capsule or a tablet, or as liquid or suppositories. If we take the solid form of a tablet of drug, the drug is not absorbed to the circulation as a tablet. The drug undergoes disintegration. The disintegration of the drug is the job of water. Water in the intestines causes swelling of the tablet, until it disintegrates. After disintegration, the drug dissolves in water. So, before absorption of a drug taken orally to the circulation it must go through two steps: disintegration and dissolution. After this the drug can be absorbed to the systematic circulation. After being circulated, the drug reaches its site of action. It reaches also to the tissue of distribution and elimination organs. The drug is distributed randomly. Some of its molecules go directly to the site of action; some goes to the liver, kidneys, etc… The site of action is the site where the drug performs its pharmacological effect, which

  is either desirable (efficacy) or undesirable (toxicity). Drug in elimination organs excretion or metabolizing.

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Works of drug on the site of action: In order for a drug to work on its site of action only, we should have some selectivity. Drug receptors can grant this selectivity. These receptors are not in the body to receive these drugs originally; they work on substances inside the body such as hormones. Drugs modify body functions, so, they act on the receptor either by stimulating or inhibiting them. A drug receptor is a component of the cell that interacts with a drug and initiates a chain of events leading to drug's action. The binding of the drug alone is not enough to produce the effect; it initiates a chain of events that leads to the effect. The receptors are responsible for the drug selectivity; otherwise, the drug will affect all the body and we will have undesirable results. The receptors also determine the quantitative relation between the drug concentration and pharmacological effect. The effect is proportional to the concentration. A specific concentration leads to specific receptor occupancy, and specific effect. If we raise the concentration to a limit where all the receptors are occupied, then the effect will turn to be constant upon increasing of drug dose. The extra drug molecules that have no receptors will remain free, and will have toxic or no effect, depending on the drug type. Example: When you give a dose of 10 μg of a certain drug, it will occupy 50% of the whole count of receptors on the site of action, and will have 50% effect. If you give 20 μg of the

same drug, it will have 100% occupancy, and 100% effect. If you give the patient 30 μg of that drug, it will still have 100% occupancy, and 100% effect, but the remaining 10 μg will remain in the body in its free form and will have undesirable effect. The receptors function can be modified by agonists and antagonists. If a receptor is stimulated by a drug, we call that drug an agonist. On the other hand, if the receptor is inhibited by a drug, we call that drug an antagonist. The antagonist works by inhibiting the agonist effect. So, the antagonists interfere with the ability of the agonist to activate the receptor. - Receptors in most cases are proteins. 1- The best characterized drug receptors are regulatory proteins, which mediate the actions of endogenous (from inside the body) chemical signals such as neurotransmitters, autacoids and hormones. If we deficiency in hormone activity, we give agonists to stimulate receptors. If we have excessive hormone activity, we give antagonists to inhibit the role of hormone. 2- Some receptors include enzymes that could be inhibited by drugs. (dihydrofolate reductase and trimethoprim). Dihydrofolate reductase is an enzyme involved in folic acid synthesis. Folic acid is a vitamin necessary for cell proliferation by stimulation of DNA synthesis. So, if we inhibit dihydrofolate reductase, we inhibit cell proliferation. We have some drugs that inhibit dihydrofolate reductase such as trimethoprim and methotrexate. Deficiency in folic acid causes anaemia. 3- Some receptors are transport proteins (Na+/K+ ATPase and

  digitalis). Na+/K+ ATPases regulate the amount of potassium and sodium on the two side of the membrane. This ATPase is inhibited by digitalis. 4- Some receptors are structural proteins (tubulin and colchicine). Tubulin is a kind of protein that is polymerized into microtubules. Microtubules are responsible for movement of substances throughout the cell in addition of being the cytoskeleton in the cell. If we inhibit the transformation of tubulin into microtubules, microtubules are not formed. Therefore, this kind of inhibition is used in the cases of inflammation and gout. Gout is caused by the presence of uric acid secreted but inflamed cells. As we inhibit the formation of microtubules, we kill the cells causing pain and we can overcome the situation. Microtubules are also responsible for the formation of mitotic spindle in cell division. If we inhibit tubulin polymerization, we inhibit chromosomal separation and cell division.

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Signaling Mechanisms: (Illustrated in the figure below) 1- The drug molecule can go across the membrane, but it should be lipid soluble to cross the lipid bilayer. The receptor should be intracellular. The receptor is either in the nucleus, or in the cytoplasm. In both ways, the drug

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is transmitted into the nucleus. When the drug binds to the receptor, it stimulates gene transcription, which in turn stimulates mRNA synthesis. mRNA synthesis result at the end in protein synthesis, which is the basis of the drug effect. The drug in this case effects the cell by synthesizing proteins. In this case the drug molecule is not lipid soluble, but it binds to a receptor that traverses through the membrane. So, a part is facing the outside of the cell (receptor portion), and the other is facing the cytoplasm (enzymatic portion). Once the drug binds to its receptor, the receptor performs a catalytic reaction acting as an enzyme; converting A to B. B initiates the pharmacological effect of the drug. This is similar to the second type, but in this case another protein is involved. The drug's interaction with the receptor causes binding of another protein to the receptor which acts as an enzyme that initiates phosphorylation. This is a more complex mechanism, which requires the control of the drug and the receptor and the catalytic protein. This initiates the opening or closing of an ion channel allowing or inhibiting electrolytes to move. This is the most complex mechanism, as it involves control of so many subunits. In this receptor-

  In diagram A below, we realize that: catalyst complex, we have three components. The binding site binds to the drug. The catalytic site is on the membrane but not related to the binding protein. Both components are related to each other through a third component name G-Protein (reGulatory protein). Once the drug binds to the receptor, G-Protein is activated, and relates the catalytic site to the binding site. Finally the complex causes the catalytic site to convert C to D, where D is the molecule that initiates the pharmacological effect of the drug. This is the hardest one to control.

Drug Receptor Interaction Agonist: A drug that binds to and activates the receptor to bring about the pharmacological effect. It can be a full or a partial antagonist, depending on its ability to produce 100% effect. A full agonist produces maximal pharmacological response with full receptor occupancy. A partial agonist produces less than maximal (lower) pharmacological response with full receptor occupancy. Because a partial agonist is not a 100% agonist, it can be considered a partial antagonist.

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Drug effect depends on drug concentration. This is explained by receptors' occupancy. Effect is proportional mainly to receptor occupancy. At 100% occupancy, the drug effect reaches 1.0 unit. The drug here reaches its maximal effect.

Pharmacologists prefer linear curves, so they used logarithm of concentration of drug. The resulting curve is a sigmoid curve, as follows: In diagram B below, we realize that: -

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The diagram is not linear at all parts, but it is linear in a specific region. At a certain concentration, the drug reaches its maximal effect. If we raise the concentration of the drug at that point, no change on effect occurs. In the partial agonist curve, at the 100% occupancy concentration, the response is 40%. That is why it is called partial agonist.

Antagonist: A drug that binds to the receptor but does not activate it. It prevents the agonist from binding to the receptor and prevents its activation and the generation of pharmacological effect. It can be reversible

  or irreversible, competitive or noncompetitive.

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Some antagonists are called "inverse agonists". They reduce receptor activity below basal levels observed in the absence bound ligand (drug). Competitive Antagonist: In the presence of a fixed concentration of agonist, increasing the concentration of a reversible competitive antagonist progressively inhibit the agonist response; high antagonist concentrations prevent response completely. Conversely, sufficiently high concentrations of agonist can completely overcome the effect of a given concentration of the antagonist. Because the antagonism is competitive, the presence of antagonist increases the agonist concentration required for a given degree response, and so the agonist concentration effect curve is shifted to the right. The diagram below shows the competitive antagonist effect: -

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The competitive antagonist decreases the effect of the agonist. At the end, at high concentrations, the two curves meet. That means that the 100% efficiency is not changed. And that can be explained by the definition of the competitive antagonist: the effect of the antagonist can be overcome by increasing the concentration of the agonist.

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If we took the log of the concentration (Slide 24), the sigmoid curve is shifted to the right. That means that there is no change on the full effect of the drug, but there is a change in the concentration of the drug needed for 100% effect. As the competitive antagonist concentration is increased, the curve is shifted to the right further more. (Slide 25)

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