Pharmokinetics CHAPTER 3 3 Dr Dipa Brahmbhatt VMD

Pharmokinetics CHAPTER 3 - 3 Dr. Dipa Brahmbhatt VMD Mp. H dbrahmbhatt@vettechinstitute. edu

Drug Absorption • Drug absorption is the movement of a drug from the site of administration into the fluids of the body that will carry it to its site(s) of action (IV is directly in blood) • Drug factors include bioavailability, route of administration, lipophilic/ hydrophilic, p. H of the environment, ion trapping, dissolution, first pass effect, perfusion • Patient factors include the animal’s age, health, metabolic rate, genetic factors, sex, and species

p. H and Ionization • p. H – the measurement of the acidity or alkalinity of a substance and environment (scale 0 -14) • # of available hydrogen ion • More hydrogen ions lower the p. H – Lower numbers (1 -3) = acid/acidic – Higher numbers (10 -12) = alkaline/basic (fewer hydrogen ions available) – Neutral = 7 – Relative: p. H 6 is more acidic than p. H 9

0 100 1 10– 1 2 10– 2 3 10– 3 p. H value 10– 4 5 10– 5 H+ 6 (H+ > OH–) 10– 6 7 10– 7 8 10– 8 increasingly acidic neutral (H+ = OH–) 10– 9 10 10– 10 11 10– 11 (H+ < OH–) 12 13 10– 12 10– 13 drain cleaner (14. 0) 1 molar sodium hydroxide (Na. OH) oven cleaner (13. 0) household ammonia (11. 9) washing soda (12) phosphate detergents chlorine bleach (12. 6) toothpaste (9. 9) seawater (7. 8– 8. 3) baking soda (8. 4) water from faucet milk (6. 4) pure water (7. 0) blood, sweat (7. 4) normal rain (5. 6) urine (5. 7) black coffee (5. 0) orange (3. 5) tomatoes beer (4. 1) vinegar, cola (3. 0) stomach acid (2) lemon juice (2. 3) 1 molar hydrochloric acid (HCl) • The p. H scale 4 9 14 10– 14 increasingly basic concentration in moles/liter Fig. 2 -11

Comparison of I/NI for 3 drugs at Different p. Hs ASPIRIN (acidic) SULFADIMETHOXINE (acidic) LIDOCAINE (basic) p. H I/NI 1 1: 100000 1 100: 1 2 1: 10000 2 10: 1 3 1: 1000 3 1: 1 4 10: 1 4 1: 100 4 1: 10 5 100: 1 5 1: 100 6 1000: 1 6 1: 1000 7 10000: 1 7 1: 10000 8 100000: 1 8 1: 100000 RATIO • Hydrophilic (ionized) molecules : lipophilic (nonionized) molecules, p. H of the liquid environment • Depended on drug’s acid/base nature and p. Ka

p. H and Ionization • Aspirin: weak acid – Stomach (p. H 2): Acidic environment , mostly nonionized/uncharged, lipophilic (1: 10) – Duodenum (p. H 6): : More alkaline environment, mostly ionized/charged form, hydrophilic (1000: 1) – Absorbed better in stomach than SI to go through plasma membrane

Acid/ Alkali Drug and p. Ka • Nature of the drug: p. H of drug – Weakly acid drugs = hydrophilic form in alkaline environment, ionized e. g. aspirin and sulfamethoxine – Weakly alkaline drugs = hydrophilic form in acid environment, ionized e. g. lidocaine Increasing acidic environmental p. H Increasing alkaline (basic) environmental p. H Acidic drug Becomes more ionized nonionized (lipophilic) (hydrophilic) Alkaline (basic) drug Becomes more ionized Becomes more (hydrophilic) nonionized (lipophilic)

p. Ka • p. H at which drug has 1: 1 ratio of ionized drug: nonionized drug e. g. aspirin p. H 3 and sulfadimethoxin p. H 6. • p. Ka bridges the drug with the location in which it is best absorbed • Acid drugs > lipophilic > more readily absorbed across the membrane : p. H more acidic than p. Ka • Alkaline drugs > lipophilic: p. H more alkaline than p. Ka

p. Ka • Henderson – Hasselbalch equation – p. H = p. Ka + log ([I/NI]) – E. g. aspirin has p. Ka = 3 at what p. H 10: 1 – p. H = 3 + log ([10/1]) = 4 E. g True or False • An alkaline drug with p. Ka of 9 is mostly nonionized after being placed in a medium with p. H of 8

Ion Trapping • Definition – when a drug changes from an ionized to nonionized form as it moves from one body compartment to another • Shift between nonionized and ionized forms traps and moves drug around the body • e. g aspirin – Stomach lumen - p. H 2: nonionized > stomach wall: p. H 7. 4 (most fluids and body cells): ionized in stomach cell membrane, some nonionized > blood: other ionozed > nonionized to maintain ratio – Net effect: slower absorption of drug and mild GI upset as it accumulates in stomach cells

Ion Trapping • This process is important in overdose of drug/ toxic agents – Change in urine p. H: urinary acidifiers and alkalizers > change nonionophilic lipophilic drug/ toxin to hydrophilic molecules: kidney cannot reabsorb > renal tubules > urine “Alkalization of the urine with intravenously administered sodium bicarbonate will enhance renal excretion of salicylate (aspirin) by decreasing tubular reabsorption of the drug. This effect may be enhanced by instituting an osmotic diuresis with mannitol solution. Peritoneal dialysis is effective in removing salicylate from the plasma “

Dissolution - PO • PO: lipophilic and broken to smaller particles: dissolution e. g. tablets, granules, powders • Solutions and elixirs: Don’t need dissolution – E. g. digoxin elixir more rapidly absorbed and higher bioavailability than tablet • SR medication: – Adv: sustained release over time – Dis. Adv: lower peak conc – Harder to get to target tissue from blood pg 64 Fig 3 -9

Oral vs. Parenteral • ORALLY ADMINISTERED DRUGS – Must be disintegrated and dissolve before they are absorbed • Inert substances: size/shape and dissolution of drug • K / Na add to drug increase absorption of drug: penicillin • This may be sped up by administering fluids with solid drugs – Speed may be hindered by decreased gastric motility, large drug size, and they must be lipophilic in form • PARENTERAL DRUGS – Tissue blood flow affects drug absorption • Also, drugs must by hydrophilic

First pass effect • First-pass effect: Intestinal lumen > hepatic portal v. > liver: xenobiotics e. g. diazepam not effective PO – Liver: Metabolized/biotransformed to inactive form for excretion – Reduces bioavailability – Lidocaine and nitroglycerine are not given orally due to firstpass effect

Getting in: DRUG ABSORPTION

Patient Factors • Affect drug absorption – Blood flow – Pain/Stress/Food: slow gastric emptying, increases absorption – Hunger – Fasting – p. H

Perfusion • Few capillaries/ further away than absorbed slowly • Perfusion: IM > SC > fat • Inactivity – Atrophy, sedation/ anesthesia > absorbed at slower rate • Hypothermia: vasoconstriction > dec. absorption of drug • Inc. temp: hyperthermia, exercise > inc. absorption Exception SNS vasodilation but vasoconstriction in SC so dec. absorption of drug

GI motility – PO Patient factor • Stomach contractions/ GI motility: mix; stomach > SI – Condition/ dz. That decrease > delay absorption – Spasm of pylorus > dec gastric emptying > delay absorption – Inc > drug absorbed faster • Intestinal motility – Hypermotile diarrhea > dec. absorption most in feces – Constipation/ antidiarrheal drugs: inc. absorption

Drug Absorption • Age – Young animals may not have well developed gastrointestinal tracts/ liver and less active enzyme systems • Health – Sickness will affect the rate of absorption of certain drugs

Drug Absorption • Metabolic rate – Animals with a high metabolic rate may eliminate drugs from their system quicker • Genetic factors – Individual variation in response to drugs may occur because of genetic differences between animals

Drug Absorption • Sex – Male and females have different body compositions – These specific compositions may affect the action and distribution of the drug • Species – Cats have a reduced ability to biotransform certain drugs and thus eliminate certain drugs slowly

DRUG MOVEMENT • PHARMACOKINETICS is the physiological movement of drugs. • 4 Steps: – Absorption – Distribution – Biotransformation (drug metabolism) – Excretion – Drug properties determine this: hydrophilic

Drug Absorption: Distribution

Drug Distribution • Drug distribution is the physiological movement of drugs from the systemic circulation to the tissues • Goal of distribution is for the drug to reach the target tissue or intended site of action • Factors affecting drug distribution: – – Membrane permeability Tissue perfusion Protein binding Volume of distribution

Barriers to drug distribution • Capillary fenestrations • Places hard to reach – Blood- brain barrier – Prostate – Eye globe • Placenta

Membrane Permeability • Capillary fenestrations (holes between cells) allow movement of small molecules in and out of them • Large molecules usually cannot pass through them -Exception: Only lipophilic drugs can pass through the bloodbrain barrier because capillaries have no fenestrations and it has an extra layer of cells surrounding them (astrocytes and glial cells). However, fever/inflammation can make the membrane more permeable to other drugs - Exception: The placenta has the ability to block SOME drugs from affecting the fetus with its barrier. Capillary has fenestrations.

Tissue Perfusion • Definition – the relative amount of blood supply to an area or body system. It affects how rapidly drugs will be distributed • Well perfused: exercised skeletal m. , liver, kidney, brains • Poorly perfused: non exercised skeletal m. , adipose – Thiopental : barbiturate, short acting, lipophilic, not in sighthounds • Drugs travel rapidly to well perfused tissues (brain) if given IV. May initially have high levels of drug and cause sedation. • Few minutes of injection animal recovers because of distribution of drug. • IV > brain > fat and inactive muscle : low blood levels hence more leaves from the brain • REDISTRIBUTION: blood > tissue (brain) > 2 nd tissue (fat) • Can also be affected by blood flow rates that are altered via vasoconstriction or vasodilation • Decreased rates decrease the amount and rate of the drug that’s delivered to the tissues.

Protein Binding • Proteins are large in size and many drugs bind to them when they are in the body. This makes them too large to pass through capillary fenestrations and stuck in the circulatory system. – INCREASED PROTEIN BINDING = less free drug available to the tissues – DECREASED PROTEIN BINDING = more free drug available to the tissues • Albumin is the main protein in circulation and is made in the LIVER. • Animals with either liver disease or protein-losing enteropathies/nephropathies will have less protein in their body, thus more drug will be UNBOUND and available to the tissues. – DECREASED dosages or different medications should be chosen as the patient may be exposed to high levels of the drug in it’s tissues. Also important because most drugs will be metabolized by the liver. – E. g. barbiturate case on pg. 69 terrier –X with chronic diarrhea

Volume of Distribution = Vd • How well a drug is distributed throughout the body based on the concentration of drug in the blood (penetrability and distribution of drug) • Assumes that the drug concentration in the blood is equal to the drug concentration throughout the rest of the body • Obese dog: less drug in tissue and more in blood > lower Vd > use lower [drug] • Dose may need to be increased in cases of larger volumes of distribution e. g. dog with ascites • Exception: drug is clustered/ sequestered/ accumulated: digoxin • Vd is misleading. Vd high hence well distributed. • Highly bound to proteins in skeltal m. and heart most is distributed

Volume of Distribution

References • Romich, J. A. Pharmacology for Veterinary Technicians, 2 nd edition. 2010. • Bill, R. L. Clinical Pharmacology and Therapeutics for the Veterinary Technician, 3 rd edition. 2006. • Ahearn Gregory, Life on Earth, 5 th edition, 2008. • http: //vetmed. tamu. edu/common/docs/publi c/aavpt/aspirin. pdf