Pharmacokinetics and Pharmacodynamics: How Drugs Move and Produce Effects

1. PharmacokineticsandPharmacodynamics CHAPTER 3

2. ______________________: the study of how a drug moves into, through, and out of the body • How is it absorbed into the body, where is it distributed to, how it is metabolized, how is it eliminated • _____________________: the study of how the drug produces its effects on the body • What tissues are effected/what changes are made because of the drug

3. Therapeutic range • Therapeutic Range/Window: IDEAL RANGE of drug concentration in the body. • Too much drug will make concentrations in the body exceed the top of the therapeutic range (______________ effective concentration) • Insufficient drug amounts will cause the concentration of drug in the body to be below the therapeutic range (______________ effective concentration) • To maintain a drug’s therapeutic range, the amount of drug entering the body must be balanced with the rate that the drug leaves the body.

4. Therapeutic index • Therapeutic index: the comparison between a drug’s ability to produce the desired effect and its tendency to produce toxic effects. Also called the Margin of _______________. • Expressed as a ratio between the LD50 and the ED50 • LD50= dose of a drug that is lethal in 50% of animals receiving the dose • ED50= dose of a drug that is effective in 50% of animals receiving the dose • TI= LD50/ED50

5. EXAMPLE: -Drug A is designed to lower heart rate. The drug is given to a group of mice. -Drug A causes 50% of the mice to have a lower heart rate a dose of 2 mg per pound. This is the effective dose. -Drug A is then given at 100 mg per pound and 50% of the mice die. This is the lethal dose. TI = LD50/ED50 TI = 100 mg per lb/2 mg per lb TI = .

6. Drug B is also used to lower heart rate and is given to a group of mice. • Drug B causes 50% of the mice to have a lower heart rate at 10 mg per pound (effective dose). • When Drug B is given at a dose of 20 mg per pound, 50% of the mice die (lethal dose). TI = LD50/ED50 TI = 20mg per lb/10mg per lb TI =

7. Which drug is safer? • DRUG A ) TI = • DRUG B) TI =

8. Dosage regimen and routes of administration • ____________________ Dose: amount of drug designed to raise the drug concentration to the therapeutic range in a short time. • Administered as either a large amount once or small amounts frequently. • Used in situations where achieving the effect of the medication quickly is critical • ____________________ Dose: maintains therapeutic concentrations established by the loading dose.

9. Dosage regimen and routes of administration • ________________ _______________: time between administrations of separate drug doses • SID produces a wide swing in drug concentrations (high concentration after the drug is absorbed, possibly toxic, and a low concentration right before the next dose, possibly subtherapeutic). • More frequent dosing results in less of a difference in drug concentrations throughout the day. This option would also be more likely to result in concentrations in the therapeutic range. • ___________ ___________ ______: combined amount of drug (in mass) administered in a given day • 100 mg would be the total daily dose of a 25mg tablet was given QID. The total daily dose would be the same if it was a 50mg tablet given BID.

10. Dosage regimen and routes of administration • Route of administration: the means by which a drug is given. • ___________: drug given by mouth- most common route • ___________: drug administered on the surface of the skin • ___________: drug is administered in an inhaled mist or gas and absorbed into the airways • ___________: a route that does not involve the GI tract (ex: injection)

11. ___________________: drug is injected directly into a vein. It is carried toward the heart where it is diluted before being distributed throughout the body. • IV ___________- single, large volume injected at once • IV _______________- drug is slowly injected (dripped) into a vein over time. Results in accumulation of drug concentrations in the body until the drug concentrations plateau (steady state) • Accidental injection of an IV drug outside the vein is termed extravascular or perivascular. • ___________________: drug is injected directly into an artery. It is carried toward a specific organ or tissues at high concentrations (accidental)

12. _________________: drug is injected directly into a muscle • _________________: drug is administered beneath the skin • _________________: drug is administered within the skin • _________________: drug is administered within the abdominal cavity

13. Movement of Drug Molecules • PASSIVE DIFFUSION: the movement of drug molecules from an area of high to low concentration • __________ the concentration gradient. • The majority of drug movement occurs this way. Drug moves from the site of administration (________ concentration) to other areas of the body (________ concentration). • Once equilibrium is achieved, the drug molecules may still move evenly throughout the tissues. • Energy is _______ used. • For a drug to diffuse across the phospholipids of a membrane, it must be able to dissolve in fat (since cell membranes are made of phospholipids).

14. MovementofDrugMolecules • FACILITATED DIFFUSION: diffusion across a cell membrane that involves a carrier molecule within the membrane. • __________ with receptor sites for drug molecules • When a drug molecule fits into the receptor, the carrier protein changes to allow the drug to pass across the membrane • Energy is ______ used (passive process) • __________ the concentration gradient

15. Movement of Drug Molecules • ACTIVE TRANSPORT: Carrier protein assists in moving the drug molecules across the membrane without the limitations of a concentration gradient. • Energy is _____________. • Does not result in an equal amount of drug molecules on each side of the membrane • Uncommon method of drug movement

16. Movement of Drug Molecules • _______CYTOSIS: Part of the cell membrane forms an invagination to take in drug molecules (cell drinking) • _______CYTOSIS: Part of the cell membrane surrounds/engulfs the drug molecules (cell eating) • Both are forms of active transport that are not often used • Slow processes because the cell membrane has to change its shape

17. MovementofDrugMolecules • Factors that affect rate of drug molecule transport: • Diffusion: • A __________ concentration gradient makes drug molecules move quickly • __________ drug molecules will move faster than larger ones • _______________ molecules will be able to dissolve within the membrane quickly. Hydrophilic molecules will require a carrier protein. • The ____________ the temp, the faster the diffusion rate • The ____________ the cell membrane, the faster the diffusion rate • Facilitated diffusion and active transport: • Number of carrier proteins available

18. Movement of Drug Molecules: Hydrophilic vs. Lipophilic • ________________ drugs travel well in aqueous environments. • They are __________________________, allowing them to interact well with water molecules, which will dissolve them. • _________________ molecules travel well across the phospholipid bilayer of the cell membrane. • They are __________________________. • A drug can exist as a ratio of hydrophilic (ionized) molecules to lipophilic (nonionized) molecules. • Hydrophilic molecules can become lipophilic and vice versa

19. PHARMACOKINETICS studies how drug movement and concentrations in the body are affected by physiology or drug characteristics. ________________________________________________ All can be altered by disease or physiologic conditions. This can affect the drug dose that the animal needs.

20. ABSORPTION: the movement of drug molecules from the site of administration to the systemic circulation. Rapid, total absorption of the drug is desired unless the drug acts locally. • _________________________: the degree to which an administered drug is absorbed and reaches the general circ. • If 100% of the drug is absorbed, the bioavailability is 1 • If 50% of the drug is absorbed, the bioavailability is 0.5

21. Effect of route of administration on absorption • _____ route skips the absorption phase since the drug is placed directly into the circulatory system. The bioavailability is 1. • They also begin excretion immediately. • _____ drugs are absorbed rapidly and almost completely so bioavailability is only slightly less than 1. • Inactive muscle absorbs slower than active. • _________________ drugs have a bioavailability significantly less than 1. • Longer distance for drugs to travel before they get to the systemic circulation.

22. Effect of route of administration on absorption • If a drug is absorbed rapidly, it will rapidly have high plasma concentrations. Signs of toxicity could show at this time. A slowly absorbed drug (oral or SQ) will take more time for its plasma levels to peak and will do so at a lower blood concentration.

23. Effect of lipophilic and hydrophilic properties on absorption • Whether a drug is hydrophilic or lipophilic can affect the drug's ability to dissolve in water or pass through a cell’s membrane. • The ___________________ that the drug is placed in plus the ________ of the drug (hydrophilic/lipophilic) affects absorption. • SQ or IM drugs are placed in extracellular fluid when injected. They must diffuse through the fluid to get to the circulation. Drug molecules in the hydrophilic form will diffuse more readily through the fluid and be absorbed faster than those in the lipophilic form.

24. Effect of lipophilic and hydrophilic properties on absorption • PO drugs must pass through cellular membranes to be absorbed through the lumen of the GI tract. These cells are tightly adhered to their neighbor cells so ____ drugs MUST be in ____________ form to be absorbed. Hydrophilic drug molecules may remain in the lumen and exit in the feces. • Dewormers exist mainly in the hydrophilic form so that they effect the parasite and not the host animal • Some IM or SQ drugs are purposely made to be primarily in the lipophilic form to slow absorption

25. Effect of ph of the environment on absorption • The ratio of hydrophilic to lipophilic drug molecules in a medication can be affected by the pH of the environment that the drug is in. This ratio can change as the drug moves through different environments. • Chart on page 59 • The characteristics of drugs that determine their ratio of ionized to nonionized molecules at any given pH are the drug's acid/base nature and its pKa.

26. Acidic drugs vs. Alkaline drugs • The acidic or basic nature of a drug molecule determines the shift in a drug’s hydrophilic or lipophilic form as the environmental pH surrounding the drug changes. • An acidic drug has a chemical structure that causes it to release a hydrogen ion as the environment becomes increasingly alkaline. • By releasing a hydrogen ion, the drug becomes ionized as it now acquires a charge.

27. Acidic drugs vs. Alkaline drugs • An acidic drug becomes more hydrophilic as it is placed into a more alkaline environment. • As an acidic drug is placed in an increasingly acidic environment, the drug will exist more in the lipophilic form. • Basic drugs become more hydrophilic as they are placed in an increasingly acidic environment and more lipophilic as they are placed in increasingly alkaline environments.

28. pKa • pKa of a drug is defined as the _______ in which the ratio of a drug‘s ionized to nonionized molecules is ______. • Knowing whether a drug is an acid or a base and knowing its pKa will allow someone to know which form (hydrophilic or lipophilic) that drug will exist in at any pH.

29. pKa • The ratio of ionized to nonionized molecules can be more precisely determined if the drug’s acid/base nature, its pKa, and the environmental pH are known. • The ratio of ionized to nonionized molecules changes by a factor of ten for each incremental change of pH. • Acidic drugs become more lipophilic at pH values to the acidic side of a drug's pKa, whereas basic drugs become more lipophilic at pH values to the alkaline side

30. ION TRAPPING and absorption of drugs • The many compartments of the body have different pHs. • Stomach = pH _______ • Duodenum = pH ______ • Intracellular environment and bodily fluids = pH ______ • As a drug molecule passes to different compartments with varying pHs, the ratio of ionized to nonionized molecules changes. • A drug molecule in the lipophilic/nonionized form crosses a cell membrane. There is a pH difference between the intracellular and extracellular environments. The new pH causes the molecules to shift to hydrophilic/ionized. This molecule may now be trapped in their new environment because lipophilic/nonionized is the form that crosses the membrane easily. • The state of this molecule being “stuck” in the cell is called _____________________.