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Pharmacology has 2 main areas: pharmacodynamics and pharmacokinetics .

Pharma: drug

Dynamics: action

Kinetic: motion

So, pharmacodynamics is the action of thedrug on the body, which includes biochemicaland physiological effects of the drug,including the mechanism of action, interactionwith receptors as well as adverse effects.

Pharmacokinetics is what the body does tothe drug. The drug is not the master in the

body; it acts on the body and the body acts onit. These include absorption, distribution,

biotransformation (metabolizing) andexcretion 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. Anexample of site of administration is inthe intestines. When a patient takes a

drug orally, the drug is absorbed in theintestines and is moved to thecirculation.

2- Distribution: Once in the circulation,the drug goes to the rest of the body.The movement of molecules from thecirculation to tissues and betweendifferent parts of the body is calleddistribution. The drug is distributed toits site of action, elimination organsand other tissues.

3- Biotransformation: If a drug reaches

to the liver which is a metabolizingagent, it is metabolized.Biotransformation is the biologicalconversion in the drug from onechemical structure to another by theaction of metabolic enzymes.

4- Excretion: It is the movement of drugfrom the circulation to outside of the

body through feces or urine. If the

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

In explaining the relation between the twoconcepts: pharmacodynamics and

pharmacokinetics, the drug follows the ruleof mass action. Rule of mass action can besimply referred to as random diffusion. Anexample that explains this law is illustratedin 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 circulationis distributed throughout the body, going tothe kidneys, liver, heart, intestines, etc

Dosage form is the form of the administrateddrug. That can be either in a form of acapsule or a tablet, or as liquid or suppositories. If we take the solid form of atablet of drug, the drug is not absorbed to thecirculation as a tablet. The drug undergoes

disintegration. The disintegration of the drugis the job of water. Water in the intestinescauses swelling of the tablet, until itdisintegrates. After disintegration, the drugdissolves in water. So, before absorption of adrug taken orally to the circulation it mustgo through two steps: disintegration anddissolution . After this the drug can beabsorbed 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. Thedrug is distributed randomly. Some of itsmolecules 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

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is either desirable (efficacy) or undesirable(toxicity).

Drug in elimination organs undergoesexcretion or metabolizing.

Works of drug on the site of action:

In order for a drug to work on its site of actiononly , we should have some selectivity. Drugreceptors can grant this selectivity. Thesereceptors are not in the body to receive thesedrugs originally; they work on substancesinside the body such as hormones. Drugsmodify body functions, so, they act on thereceptor either by stimulating or inhibitingthem.

A drug receptor is a component of the cell thatinteracts 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 theeffect; it initiates a chain of events that leadsto the effect.

The receptors are responsible for the drugselectivity; otherwise, the drug will affect allthe body and we will have undesirable results.

The receptors also determine the quantitativerelation between the drug concentration and

pharmacological effect. The effect is proportional to the concentration. A specificconcentration leads to specific receptor occupancy, and specific effect. If we raise theconcentration to a limit where all the receptorsare occupied, then the effect will turn to beconstant upon increasing of drug dose. Theextra drug molecules that have no receptorswill remain free, and will have toxic or noeffect, depending on the drug type.

Example: When you give a dose of 10 g of acertain drug, it will occupy 50% of the wholecount of receptors on the site of action, andwill have 50% effect. If you give 20 g of the

same drug, it will have 100% occupancy,and 100% effect. If you give the patient 30 g of that drug, it will still have 100%occupancy, and 100% effect, but theremaining 10 g will remain in the body in

its free form and will have undesirableeffect.

The receptors function can be modified byagonists and antagonists. If a receptor isstimulated by a drug, we call that drug anagonist. On the other hand, if the receptor isinhibited by a drug, we call that drug anantagonist. The antagonist works byinhibiting the agonist effect. So, theantagonists interfere with the ability of the

agonist to activate the receptor.

- Receptors in most cases are proteins.

1- The best characterized drugreceptors are regulatory proteins ,which mediate the actions of endogenous (from inside the body)chemical signals such asneurotransmitters, autacoids andhormones. If we deficiency inhormone activity, we give agonists

to stimulate receptors. If we haveexcessive hormone activity, we giveantagonists to inhibit the role of hormone.

2- Some receptors include enzymes that could be inhibited by drugs.(dihydrofolate reductase andtrimethoprim). Dihydrofolatereductase is an enzyme involved infolic acid synthesis. Folic acid is avitamin necessary for cell

proliferation by stimulation of DNA

synthesis. So, if we inhibitdihydrofolate reductase, we inhibitcell proliferation. We have somedrugs that inhibit dihydrofolatereductase such as trimethoprim andmethotrexate. Deficiency in folicacid causes anaemia.

3- Some receptors are transportproteins (Na +/K + ATPase and

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digitalis). Na +/K + ATPases regulatethe amount of potassium and sodiumon the two side of the membrane. ThisATPase is inhibited by digitalis.

4- Some receptors are structuralproteins (tubulin and colchicine).Tubulin is a kind of protein that is

polymerized into microtubules.Microtubules are responsible for movement of substances throughoutthe cell in addition of being thecytoskeleton in the cell. If we inhibitthe transformation of tubulin intomicrotubules, microtubules are notformed. 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 theformation of microtubules, we kill thecells causing pain and we canovercome the situation. Microtubulesare also responsible for the formationof mitotic spindle in cell division. If we inhibit tubulin polymerization, weinhibit chromosomal separation andcell division.

Signaling Mechanisms: (Illustrated in thefigure below)

1- The drug molecule can go across themembrane, but it should be lipidsoluble to cross the lipid bilayer. Thereceptor should be intracellular. Thereceptor is either in the nucleus, or inthe cytoplasm. In both ways, the drug

is transmitted into the nucleus.When the drug binds to the receptor,it stimulates gene transcription,which in turn stimulates mRNAsynthesis. mRNA synthesis result atthe end in protein synthesis, whichis the basis of the drug effect. Thedrug in this case effects the cell bysynthesizing proteins.

2- In this case the drug molecule is notlipid soluble, but it binds to areceptor that traverses through themembrane. So, a part is facing theoutside 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. Binitiates the pharmacological effectof the drug.

3- This is similar to the second type, but in this case another protein isinvolved. The drug's interactionwith the receptor causes binding of another protein to the receptor which acts as an enzyme thatinitiates phosphorylation. This is amore complex mechanism, whichrequires the control of the drug and

the receptor and the catalytic protein.

4- This initiates the opening or closingof an ion channel allowing or inhibiting electrolytes to move.

5- This is the most complexmechanism, as it involves control of so many subunits. In this receptor-

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catalyst complex, we have threecomponents. The binding site binds tothe drug. The catalytic site is on themembrane but not related to the

binding protein. Both components arerelated to each other through a thirdcomponent name G-Protein(reGulatory protein). Once the drug

binds to the receptor, G-Protein isactivated, and relates the catalytic siteto the binding site. Finally thecomplex causes the catalytic site toconvert C to D, where D is themolecule that initiates the

pharmacological effect of the drug.This is the hardest one to control.

Drug Receptor Interaction

Agonist: A drug that binds to andactivates the receptor to bring about the

pharmacological effect. It can be a full or a partial antagonist, depending on itsability to produce 100% effect.

A full agonist produces maximal pharmacological response with full

receptor occupancy.

A partial agonist produces less thanmaximal (lower) pharmacologicalresponse with full receptor occupancy.Because a partial agonist is not a 100%agonist, it can be considered a partialantagonist.

In diagram A below, we realize that:

- Drug effect depends on drugconcentration. This is explained byreceptors' occupancy. Effect is

proportional mainly to receptor occupancy.

- At 100% occupancy, the drug effectreaches 1.0 unit. The drug herereaches its maximal effect.

Pharmacologists prefer linear curves, sothey used logarithm of concentration of drug. The resulting curve is a sigmoidcurve, as follows:

In diagram B below, we realize that:

- The diagram is not linear at all parts, but it is linear in a specific region.

- At a certain concentration, the drugreaches its maximal effect. If weraise the concentration of the drug atthat point, no change on effectoccurs.

- In the partial agonist curve, at the100% occupancy concentration, theresponse is 40%. That is why it iscalled partial agonist.

Antagonist: A drug that binds to thereceptor but does not activate it. It preventsthe agonist from binding to the receptor and

prevents its activation and the generation of pharmacological effect. It can be reversible

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- If we took the log of theconcentration (Slide 24), thesigmoid curve is shifted to the right.That means that there is no changeon the full effect of the drug, butthere is a change in theconcentration of the drug needed for 100% effect.

or irreversible, competitive or noncompetitive.

Some antagonists are called "inverseagonists". They reduce receptor activity below

basal levels observed in the absence boundligand (drug).

Competitive Antagonist: In the presence of afixed concentration of agonist, increasing theconcentration of a reversible competitiveantagonist progressively inhibit the agonistresponse; high antagonist concentrations

prevent response completely.

- As the competitive antagonistconcentration is increased, the curveis shifted to the right further more.(Slide 25)

Yours Always,Wael ToukanConversely, sufficiently high concentrations of

agonist can completely overcome the effect of a given concentration of the antagonist.

Simply The Best

Because the antagonism is competitive, the presence of antagonist increases the agonistconcentration required for a given degreeresponse, and so the agonist concentrationeffect curve is shifted to the right.

The diagram below shows the competitiveantagonist effect:

- The competitive antagonist decreases

the effect of the agonist.- At the end, at high concentrations, the

two curves meet. That means that the100% efficiency is not changed. Andthat can be explained by the definitionof the competitive antagonist: theeffect of the antagonist can beovercome by increasing theconcentration of the agonist.

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