Pharmacokinetics and Pharmacodynamics -Sandeep

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Principles of Pharmacokinetics and PharmacodynamicsSandeep KandelInstitute of Medicine Maharajgunj Medical Campus, Nepal

Presentation layoutPharmacokinetics AbsorptionDistributionMetabolismExcretionPharmacodynamicsSignal TransductionDose Response RelationshipAgonist and AntagonistOcular PharmacologyOcular Drug AbsorptionDrug Delivery System

Pharmacokinetics and pharmacodynamicsThe purpose of studying pharmacokinetics and pharmacodynamics is to understand the drug action, therapy, design, development and evaluation

Pharmacokinetics is what the Body Does To The Drug like how the drug is Absorbed, Distributed, Metabolized, and Excreted by the body Drug disposition

Pharmacodynamics is what the Drug Does To The Body which may be the therapeutic effects or the adverse side effects - Drug action

Pharmacokinetics

PharmacokineticsRefers to what body does to the drugDefined as the study of the time course of drug absorption, distribution, metabolism, and excretionThese four pharmacokinetic properties determine the:

AbsorptionDrug absorption from the site of administration permits the entry of the therapeutic agent into the plasmaDistribution The drug may then reversibly leave the bloodstream and distribute into the interstitial and intracellular fluidsMetabolismThen the drug may be biotransformed by the metabolism in liver, or other tissues

Elimination Finally, the drug and its metabolites are eliminated from the body in the urine, bile, or feces.

I. Absorption of drugsIt is the transfer of a drug from its site of administration to the bloodstream via one of the several mechanismsThe rate and efficiency of absorption depend upon following factors:

The environment where the drug is absorbed

The drugs chemical characteristics

Route of administration (which influences the bioavialability)

For IV drug delivery, absorption is complete . Total dose of drug administered reaches the systemic circulation ie. 100% bioavialability10

Mechanism of absorption of drugs from the GI TractPassive Diffusion:

The driving force for passive diffusion is the concentration gradient across a membrane separating the two body compartments

Water soluble drugs penetrate the cell membrane through the aqueous channels or pores

The lipid soluble drugs gain access to the cell across the biological membranes due to their solubility in the membrane lipid bilayers

Facilitated Diffusion:

Drugs enter the cell through specialized trans-membrane carrier proteins that facilitate the passage of large moleculesIt requires carrier molecules and can be saturated

Active Transport:

This mode of drug entry involves specific carrier proteins that span the membrane and energy-dependent active transport is driven by the hydrolysis of ATP

It is capable of moving the drugs against the concentration gradient ie. from low concentration to high concentration

Endocytosis and Exocytosis:

Transports the drug of exceptionally large size across the cell membrane

Endocytosis involves the engulfment of a drug molecule by the cell membrane and transport into the cell by pinching off the drug filled vesicle.

Exocytosis is used by cells to secrete many substances by similar vesicle formation process

For instance, Vitamin B12 is transported across the gut by endocytosis and neurotansmitters like nor-epinephrine are released by exocytosis

DRUG DISPOSITION

Factors affecting drug absorptionEffect of pH on drug absorption[Most drugs are either weak acids or weak basesAcidic drugs (HA) release a proton (H+), causing a charged anion (A-) to form HA H+ + A

Weak bases (BH+) can also release an H+ and loss of a proton produces the uncharged base (B)BH+ B + H+

pKa is the measure of the strength of the interaction a compound with protonHigher the pka the more basic the drug is and lower the pka the more acidic the drug

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A drug passes through membranes more readily if it is uncharged, thus for weak acid, uncharged protonated HA can permeate through the membranes and A- cannot

For weak bases, the uncharged B can permeate through the membranes but the protonated form BH+ cannot

The ratio between the ionized and the non ionized forms is determined by the pH at the site of absorption and by the strength of the weak acid or base, represented by the ionization constant, pKa

2. Blood flow to the site of absorption

Because the blood flow to the intestine is much greater than that of stomach, the absorption of drug from intestine is more favored

3. Total surface area available for absorption

With surface rich in brush border containing micro-villi, the intestine has a surface area about 1000-fold that of the stomach, making absorption of drug across the intestine more efficient

4. Contact time at the absorption surface

If the drug moves across the GI tract very quickly, as can happen with severe diarrhea, it is not well absorbed

5. Expression of P-Glycoprotein

P-glycoprotein is a multidrug trans-membrane transporter protein responsible for transporting various molecules including drugs

BioavailabilityBioavailability is the fraction of administered drug that reaches the systemic circulation

Is important for calculating drug doses for non-intravenous routes of administration

It is determined by comparing the plasma levels of a drug after a particular route of administration with the plasma drug levels achieved by IV injection, in which the total agent rapidly enters the circulation

Factors influencing the BioavailabilityIn contrast to IV administration, which confers 100% bioavailability, the oral administration of drug involves the first-pass metabolism A. First-Pass hepatic metabolismWhen the drug is absorbed across the GI tract, it first enters the portal circulation before entering the systemic circulationIf the drug is rapidly metabolized in the liver or gut wall during the initial passage, the amount of unchanged drug in the circulation is decreased

B. Solubility of the drug

Very hydrophilic drug are poorly absorbed because of their inability to cross the lipid-rich cell membranes

Paradoxically, drugs that are extremely hydrophobic are also poorly absorbed, because they are totally insoluble in the aqueous body fluids

For a drug to be readily absorbed, it must be largely hydrophobic, yet have some solubility in aqueous solutions

Thats why many drugs are either weak acids or weak bases

BioequivalenceTwo related drug preparations are bioequivalent if they show comparable bioavailability and similar times to reach the peak blood concentrations

THERAPEUTIC EQUIVALENCE

Two similar drugs are therapeutically equal if they are pharmaceutically equivalent with similar clinical and safety profiles

II. Drug DistributionProcess by which a drug reversibly leaves the blood-stream and enters the interstitium (extracellular fluid) and then the cells of the tissues

A. Blood Flow: The rate of blood flow to the different tissue capillaries varies widely as a result of the unequal distribution of cardiac output to the various organs

Blood flow to the brain, liver and kidney is greater compared to that of adipose tissue, skin and viscera.

B. Capillary permeability:

In the liver and spleen, a large part of the basement membrane is exposed due to large, discontinuous capillaries through which large plasma proteins can pass

While in case of brain, the capillary structure is continuous that constitute the blood-brain barrier

So, to enter the brain, drugs must pass through the endothelial cells of the capillaries of the CNS or be actively transported

Lipid soluble drugs can readily penetrate into the CNS because they can dissolve in the membrane of the endothelial cells

C. Binding of drugs to plasma proteins and tissues:

Binding to the plasma proteins:Reversible binding to the plasma proteins sequester drugs into the non-diffusible form and slows their transfer out of the vascular compartment

Plasma albumin is a major drug binding protein and may act as a drug reservoir

Binding to the tissue protein:Numerous drugs accumulate in the tissues, leading to the higher concentration of drug in the tissues than in the ECF and blood

Drugs may accumulate as a result of binding to the tissue proteins, lipid, or nucleic acids

Volume of DistributionThe apparent volume of distribution, Vd, can be thought of as the fluid volume that is required to contain the entire drug in the body at the same concentration measured in the plasma

Where, C0 = Plasma concentration at time zeroOnce the drug enters the body, it has the potential to distribute into any one of three functionally distinct compartments of body water or to become sequestered in a cellular site

Vd= (Amount of drug in the body)/C0

Plasma compartment:

If a drug has a very large molecular weight or binds extensively to the plasma proteins, it is too large to move out through the endothelial slit junctions of capillaries, thus is trapped within the plasma

Extracellular Fluid:

If a drug is of low molecular weight but is hydrophillic, it can move through the endothelial slit junctions of the capillaries into the interstitial fluid.

However, the hydrophillic drugs cannot move across the lipid membrane of cell to enter the water phase inside the cell

Hence these drugs distribute into a volume that is sum of plasma water and the interstitial fluid which constitute about 20% of total body