Pharmacokinetics and Dosage

Pharmacokinetics

• The purpose of administering drugs is to achieve a specific pharmacologic response by using a recommended dose.
• Optimal drug usage depends on a solid understanding of pharmacodynamics and pharmacokinetics, along with knowledge about how the product is formulated.
• Clinical pharmacology hinges on this comprehensive understanding.
• Drugs must reach an effective concentration at their action site to produce their intended effect.
• Variations in drug response occur because of biophasic availability and the inherent sensitivity of the tissue receptors

Biophasic Availability

• Reflects the amount of a drug attained at its action site.
• Dose levels are specified based on mg per kg of body weight.
• Dose rates involve timing the rate of intravenous injections over a specified time period (e.g., mg/kg/hour).

Factors Determining Dosage

• A satisfactory response is contingent upon the drug reaching its action site at sufficient concentration.

Body Size

• Dosage is typically determined based on body weight.
• When administering potent agents, understand the limitations of using body weight for dosage.
• Differences between actual body weight and "true" lean body weight are more apparent when dealing with obesity, starvation, ascites, GIT fill, dehydration, immaturity, old age, or the presence of a large tumor.
• Adjustments should be made for fatness: no increase is needed for drugs that do not penetrate fat, but increased dosage is necessary for fat-soluble drugs that get sequestered in body fat.
• Thiobarbiturate is an example of a fat-soluble drug.

Genetic (Breed) Factor

• Brahman cattle are more susceptible to xylazine effects than European breeds.
• Certain sheep strains lack the necessary enterase enzyme to inactivate haloxon, leading to organophosphate-induced neurotoxicity in lambs.
• Greyhounds often exhibit prolonged sleeping time after thiopental Na administration because of lower body fat.
• Pugs, Pekingese, and Bulldogs may experience syncope after acepromazine due to S.A. block because of vagal overtone.

Species Variation

• Tetracycline, macrolides, and lincosamide cause fatal colitis in horses.
• Xylazine causes extreme sensitivity to depressant effects, and morphine results in excitatory, aberrant behavior in cattle.
• Acetaminophen causes fatal centrilobular hepatic necrosis in cats.
• Aminoglycosides cause neurotoxic effects in cats.

Alimentary Anatomy

• Ruminants, are characterized by a very slow digestion rate and a relatively large gut content volume relative to overall body weight.
• Oral dosages can end up in different compartments based on how the esophageal groove is operated.

Age

• Reduced doses are often required for very old and very young animals because of organ dysfunction: degenerative changes in the liver or kidney in older animals, and underdeveloped function in younger animals.
• A higher rate of drug therapy toxicity is common in neonatal periods.

Sex

• Adverse drug reactions are commonly related to reproductive function, such as purgatives inducing abortion.
• May also cause tetratogenicity in a pregnant animal, like Tetracycline and Aminoglycosides
• A teratogenic agent is a chemical or infectious agent that can alter fetal morphology or subsequent function upon fetal exposure; teratogenicity relies on the agent's capacity to cross the placenta.
• Pharmacotherapeutic concerns for females include potential effects on reproductive organs and their function, possible embryocidal, teratogenic, or abortifacient actions of drugs during pregnancy, potential influence of drugs on the particular process of inducing delaying/inducing parturition
• Also possible effects of drugs used on lactation, and the presence of drugs in the milk residue from lactating animals.

Timing

• Upper digestive tracts absorb orally administered drugs more rapidly when empty, but is often irritant.
• Administer medicine one hour before or after a meal.

Pathology

• Sick animals typically have an impaired ability to detoxify drugs
• Conditions affecting the liver and/or kidney are important.

Tolerance

• When a drug is administered over a period of time, increasing the dose is necessary to maintain a steady response level.
• Tolerance decreases in response to the drug that is repeatedly used and disappears upon drug withdrawal.
• Resistance is the ability to withstand the previously destructive drug effect by microorganisms or tumor cells.
• Drug tolerance examples include alcohol and opioids; one mechanism is accelerated metabolism via induction of hepatic enzymes.
• Can also include a decrease in binding affinity between a drug and a receptor and/or a decrease in the number of receptors.
• Tolerance differs from dependence.
• Dependence is characterized by a desire to use the drug or experience unpleasant withdrawal symptoms when the drug is stopped
• Microorganism strains are resistant when they are no longer killed or inhibited by previously effective antimicrobial drugs
• Resistance begins with a genetic change due to mutation or gene acquisition.

Bioavailability

• Relates to the quantity of drug absorbed
• Used to to express the rate and extent of a drug's absorption.

Resistance

• Drug resistance is the reduction in effectiveness of a drug such as an antimicrobial, anthelmintic or antineoplastic agent in curing a disease.
• It is equivalent to dosage failure or drug tolerance when the drug is not intended to kill or inhibit a pathogen.
• In the context of pathogens the term "acquired" or evolved resistance is commonly used
• Multidrug-resistant describe when an organism is resistant to more than one drug.

Pharmacokinetics

• Refers to the movement and changes that a drug undergoes within the body from administration to elimination.
• Includes absorption, distribution, biotransformation, and excretion.
• Clinical pharmacokinetics applies pharmacokinetic principles to the safe and effective therapeutic management of drugs in an individual patient.
• Drug processes involving absorption and distribution allow drugs to reach their action site to produce a pharmacological effect; biotransformation and excretion terminate the action of the drug.
• Only a tiny portion of drug interacting with receptors and producing effect; effects typically follow after absorption.
• Drug effects are induced only when a certain drug concentration attains a minimum effective drug concentration in the plasma.

Absorption

• The process where drugs or other substances pass from the administration site into the blood circulation.
• Movement of solute from administration site across biological barrier into the blood and/or lymphatic system.
• Drugs must be in solution to be absorbed.
• Drug preparation often requires disintegration and dissolution prior to absorption.
• The endpoint of drug absorption is when the drug is deposited deposition of the drug into the blood or plasma.
• Bioavailability is an important determinant of systemic bioavailability.

Bioavailability

• Indicates the extent and rate at which the active drug enters systemic circulation, reaching its site of action.
• It means the fraction of unchanged drug reaching systemic circulation following administration.

Factors Affecting Bioavailability

• Bioavailability largely depends on the properties of the dosage form, influenced by its design and manufacture.
• Intravenous dose: bioavailability is assumed to be equal to unity.
• Oral drug administration: bioavailability may be less than 100% due to incomplete absorption across the gut wall and first-pass elimination by the liver.
• Chemical equivalence means drug products contain the same active compound in the same amount and meet current standards.
• Bioequivalence means drug products given in the same dosage regimen, and result in equivalent concentrations of drug in plasma and tissues.
• Therapeutic equivalence means drug products in same dosage regimen, have the same therapeutic and adverse effects

Bioavailability Calculation

• To calculate bioavailability, one would compare the amount of drug with an IV dose (AUCIV) to following a non-IV dose (AUC non IV)) and administered dose must be the same
• Formula: % Bioavailability (F) = (IV dose/Non-IV dose) X 100 OR F = AUC (non IV)/AUC (IV)
• Area Under Curve (AUC) represents area under the concentration-time curve.
• The AUC is the area under concentration of drug in blood vs time, typically the area is computed starting at the time administered until the concentration in plasma is negligible.

AUC Interpretation

• Area under the curve represents the total drug exposure over time.
• the AUC becomes useful for reference average concentration over a time interval AUC/t.
• It's also relevant when discussing elimination; amount eliminated = clearance AUC.
• Can be measured in terms of absolute bioavailability (refers to bioavailability when administered via intravenous dosage) or relative bioavailability which compares the bioavailability between two different dosage forms.

Passage of Drug Across Biologic Membrane

• Involves drug transformation between tissue-bound drugs, distribution fluids, site of action, drug-metabolizing enzymes, protein-bound drugs, and excretion.
• Nature of biologic membrane involves phospholipids, proteins, and carbohydrates
• Protein molecules in the membrane can act as hydrophillic carriers, channels, and receptors.

Passage Across Membranes

• Bulk Flow – drug movement within body fluids, with fluids flowing through pores based in response to hydrostatic gradients
• Passive Diffusion – drug molecules moving down concentration and not requiring energy

Drug Molecules

• Diffuse across lipoprotein region or follow through the channel if sufficiently small, can cross the lipid plasma membrane by this mechanism
• They depends on the physico-chemical properties of the xenobiotic substance

Polarity and Solubility

• Inversely related, with the more polarized or charged, the less its lipid solubility.
• Non-polarized or uncharged molecules have more lipid solubility.
• Polar water-soluble can cross lipid membrane by passive diffusion since a water molecule has opposite charges.
• Relative solubility relies on the pH, if the drug being is ionizable.
• Oil/water partition coefficient is the ratio of drug solubility in oil versus its solubility in water
• A high partition coefficient is more soluble in fat thus more absorbable from the gut
• The more unionized a drug is, the more readily it penetrates; the Henderson-Hasselbalch equation predicts ionization.
• Non-ionized forms are lipid-soluble and diffuse readily across the cell, and ionized forms have low solubility.

Non-ionic Diffusion

• Substance pass through the lipid membrane slowly.
• If a drug can exist in anionic and non-ionic form, then the non-ionic can pass through the membrane by passive diffusion.
• Weak acids move readily from acid environments and become ionized and trapped in more alkaline environments. Bases go for alkaline to acidic (vise versa).
• Change in post-diffusible drug happens within 2 pH units of the drug's pKa

Other Factors

• The greater the surface area for diffusion, then the more rapid the net transfer will be.
• The small intestine is most important site.
• Some Drugs alter the fluidity of the membrane and protein channels or pores.

Carrier-Mediated Transport

• Reflective for substance being moved.
• Carrier component moves
• Depends on Saturation
• Facilitated Diffusion: carries substances that cannot go against concentration gradients, and are competitively inhibited.
• Active Transport: moves substances against against high gradients.

Pinocytosis

• Process is not specific, as substances engulf or internalize into to the cell, then often attached
• It is often given by a specific force, and so is not saturated.

Factors That Influence the Rate and Extent of Drug Absorption

• Liberation: Step in which medication enters of the body, followed by which the active ingredient administered.
• It has to separate from mixture manufacture. Some authors have split liberation into three : disintegration, disaggregation and dissolution. Degree for adsorption (pharmaceutical drugs/ions). It happens because they are relatively impermeable. Medical Professionals advise chewing pills/tablets in order to promote liberalization/disaggregation.
• A medication's excipient has role that will be fundamental in creating suitable condition drugs, which means the same dose is in effect, however it might not be of the same type/form at the end.

Solid Dissolution

• In solid form - undergoes dissolution of the drug into the liquid, will then go into the plasma

Solubility

• Lipid-soluble is easier than water-soluble.
• Drug dosage/formulation can have effect of drug absorption( can limit absorption rate parentally, however only does so intravenously). Designs for slow (prolonged ) release exist. Therapeutic plasma may never be reached.
• Dissolution occurs limited to a standard determined in the release drug. Must break apart until dissolved for enhanced rate.

Surface area

• Decreased size will help facilitation ( smaller size). Preparing smaller for medicine = thereby increased administration following oral dose. Different drugs exist due salt level can also manipulated to use to help in taking the right pH
• Also need the agent so that can enhance rates.

Blood Flow At Site For Absorption

• Essentially Movement happens fast (diffusion/instaneous_ or happens slowly (relatively slow)

Absorption In GI

• More important because the drug crosses intestinal cell, and so that it has to be soluble .

Environment

• pH affects drug rate for absorption. Very true for oral dose since the different pH locations, or different animals.

Molecular Size

• Rate depends larger drugs are absorbed slowly , where some large do exist slow as it does occur ( must sterilize).

Surface Area

• Small will more easily absorbed and so less time

Motility/Mixing

• Time/contact and gastric. Emptying/Food will be able to also absorbed. Admintered orally drugs with specific transport
• Barriers (has to get to the blood stream)
• Transformatinos
• By intestinal by absorption at GIT
• dosage form absorportion rapid

Drugs and Body

• Destroyed by enzymes absorbed as
• Proteins absorption and proteins are not absorbed orally, but are.

Gastro

• low bioavailability by parenetal. Most oral drugs/dosage are solid
• has to enter those circulations and there has to be a lot going on until the drug makes it inside the area. Some of those events may lead to decreasing those drugs.

Gastro in Patients

• absorption surface, drugs are are often greatly be able to not be absorbed
• transit Ingesta absorbed more easily in the gut. Digestive/differences can also affect the rate with which occurs. Lipids of the oil ratio

Drugs And GI

• A high partition will usually means it makes soluble to get absorbed to to be what there is. They also absorbed

The first Pass elimination

• Following the absorportion is delivered to liver so the drug crosses all areas before it goes systemic. It might then inactivate the hepatic blood
• Pro drugs that has to be adminerstered via form
• modifying the process can only effect that part. Size shape and degree.

Binding With drugs

• There are protein bound in the protein. Then sequestered outside (Impossible to determine)
• Plasma may be a silent receptior
• Factors affecting are generally are to make.

Intrathecal/Nebulization/Aerosolization

• Some achieve localized. Particle sizes affects where they go. Trachea is over 10 mircons, whereas alveolias are small

Inhalations

• implies rate to absorption and most goes through that with more easily

Some ways and the amount

• Intratoneal. That's where its all at
• Post enteral has to then then must enter the stream

Transfer And Processes

• Diffusion and for non

Solutions In Muscles

• can happen if that stream then go ahead. Increase rate is dependent. It can only go depending rate

Routes Of Injection

• Affected has to go in side and it also has to be with. Absortion Skin

Surface/From Skins

• There is nothing else at that rate .It's highly easily absorbs which means.Certain are easier depending damaged if it can go through it. certain skin level

Drug Level/concentration

• That has to be used so that something to show that the

Plasma

• What about with and it it is with and that

Bito

• Chemical alter. Tend and

Biotopic

• Most and there mostly. And with. Botic

Cytochrome

• The a. A. A.A

Drug

• Most and it has the oxidation but is and and can can