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Pharmokinetics - Pharmacodynamics

Pharmokinetics - Pharmacodynamics. CHAPTER 3 - 4 Dr. Dipa Brahmbhatt VMD MpH dbrahmbhatt@vettechinstitute.edu. PHARMACOKINETICS - BIOTRANSFORMATION. Biotransformation is also called drug metabolism , drug inactivation , and drug detoxification

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Pharmokinetics - Pharmacodynamics

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  1. Pharmokinetics - Pharmacodynamics CHAPTER 3 - 4 Dr. DipaBrahmbhatt VMD MpH dbrahmbhatt@vettechinstitute.edu

  2. PHARMACOKINETICS - BIOTRANSFORMATION • Biotransformation is also called drug metabolism, drug inactivation, and drug detoxification • Biotransformation is the chemical alteration of drug molecules by the body cells into a metabolite that is in an activated form, an inactivated form, and/or a toxic formby enzymes • Primary site of biotransformation is the liver. • Inhibition or induction of Cytochrome P450 • Little in lung, skin and intestinal tract • Goal = metabolite is more hydrophilic (more readily excreted in urine or bile)

  3. PHARMACOKINETICS - BIOTRANSFORMATION • Two step enzymatic process • Phase I metabolism • Oxidation, reduction, hydrolysis of drug molecule • Transform structure of drug molecule • Usually less biological active • Phase II metabolism: CONJUGATION • Metabolite – phase I combined with • Glucuronic acid, sulfate, glycine • Conjugated molecule is more soluble • Prodrugs: more active after biotransformation • Prednisone > prednisolone

  4. Drug Interaction - Biotransformation • Drug interactions: desirable/ undesirable • Multiple drugs • Metabolized slowly • Can accumulate > toxic • Enzyme system: Mixed Function Oxidase System (MFO) • Can increase with repeated exposure to the drug : induced metabolism • Shorter duration of action • Tolerance: barbiturates, narcotics, alcohol • Increase metabolism of other drugs • Phenylbutazone, digitoxin, estrogens, dipyrone, glucocorticoids

  5. ALIENS! • Drug metabolism different in cats • Reduced ability to synthesize glucoronic acid • Glucuronyltransferaseactivity greatly reduced in cats • Salicylate compounds • Aspirin used with extended dosage interval • Bismuth subsalicylate: peptobismal • NO ACETAMINOPHEN (tylenol)!! • Liver can’t process toxic metabolites

  6. Age - Biotransformation • Younger animals (< 5 wks. except foals) • Slower elimination of drugs • NB: ultra-short acting barbiturates, some sulfonamides antibacterial, opioids, salicylates and local anesthetics • Permeable blood-brain-barrier • Less albumin • More volume in ECF • Geriatrics

  7. Pharmacokinetics: Drug Elimination • Out of body: excretion • Major routes • Kidney-urine • Liver – bile - feces • Inhalants – lungs exhaled air • Less common: saliva, milk, sweat; keratin – hair, nails/ hooves • Factors • Dehydration • Age related degeneration kidney/ liver NB: Milk withdrawal time

  8. PHARMACOKINETICS: RENAL ELIMINATION • Renal elimination of drugs involves • Glomerular filtration • Passive process • Renal arteriole (smooth m.)> capillaries – glomerulus • Nephron - Bowman’s capsule: blood protein in and water/drugs out • Tubular reabsorption: Passive diffusion • Tubular secretion: Active

  9. PHARMACOKINETICS: RENAL ELIMINATION • Proximal convoluted tubule: • Active transport: Glucose, drugs, essentials: • Secretion e.g. penicillin actively secreted in u • Loop of Henle • Lipophilic drugs • Urinary acidifiers/ alkalizing drugs Renal arteriole > glomerulus > bowman’s capsule > proximal convoluted tubule > loop of Henle > ELIMINATED: distal convoluted tubule > collecting ducts > renal pelvis > urine

  10. PHARMACOKINETICS: RENAL ELIMINATION • Blood pressure is a factor: dec. filtration > dec. elimination • Urine pH can also affect rate of drug excretion. • Weak acids better excreted in basic urine • Weak bases better excreted in acidic urine • Dehydration, blood loss, shock, inc. Sympathetic NS

  11. Hypoalbuminemia/ Hypoproteinemia • Albumin is the #1 transport protein in circulation and is made in the LIVER. • Animals with liver disease 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 for patients with liver disease. • Also important because most drugs will be metabolized by the liver.

  12. Hepatic Elimination/ Biliary excretion • Drugs secreted (passive diffusion) into bile. • Bile secreted into duodenum: lipophilic form > liver > liver/ systemic circulation • Lipophilic drugs re-enter bloodstream • Eventually return to liver • Hydrophilic drugs eliminated in feces. • Enterohepatic circulation: liver > GI tract > liver • Inc. duration of drug in body • Hepatic lipidosis or cirrhosis: drug dose reduced

  13. PHARMACODYNAMICS • Drugs work in a variety of ways: • Drugs alter existing cellular functions • Secretion • Contract muscle contraction • Depolarizing neurons • Drugs alter the chemical composition of body fluids • Drugs can form a chemical bond with specific cell components on target cells within the animal’s body

  14. Drug Elimination Terminology • Drug residue: amount of drug that can be detected in tissues after administration ceases. • Withdrawal time: period of time after drug administration during which the animal cannot be sent to market for slaughter and the eggs or milk must be discarded because of the potential for drug residues. NB: resistance • Half-life (T1/2): time required for the amount of drug in the body to be reduced by half of its original level • Steady state: point at which drug accumulation and elimination are balanced (takes ~5 half-lives) • If the half life of a drug is 3 hours, how long to steady state? • If half life = 30 hrs., how long to steady state? (How can dose regimen be altered to benefit the patient?)

  15. Half life and clearance: Measures of drug elimination • Clearance or half – life of elimination • How long does the drug concentration in the blood takes to decrease to 50% • Volume of blood cleared over time • Helps with drug interval • Amoxicillin – clavulanic acid ~ 2 hr. hence BID • Phenobarbital ~ 24 hr. hence SID • T1/2 inc. with kidney damage • Excrete through liver • Larger dose will not help reach steady states

  16. RECEPTORS • Receptors are three-dimensional proteins or glycoproteins • Located on the surface, in the cytoplasm, or within the nucleus of cells • Affinity is the strength of binding between a drug and its receptor • High-affinity drugs (hormones) bind more tightly to a receptor than do low-affinity drugs

  17. RECEPTORS • E.g. smooth m. in bronchioles-lung only for receptor A • Receptors: more in some tissues • Cell surface • Organelles • One receptor can have different effects based on different drugs

  18. AGONISTS VS ANTAGONISTS Agonist: drug that binds to a cell receptor and causes action. Intrinsic activity. Antagonist: drug that inhibits or blocks the response of a cell when the drug is bound to the receptors

  19. AGONISTS VS ANTAGONISTS

  20. AGONISTS VS ANTAGONISTS • Competitive Antagonists/ reversible antagonism/ surmountable antagonism • Drug A and B have equal opportunity • Higher conc. Wins • Hydromorphone and naloxone A competitive inhibitor moleculeoccupies the active site andblocks entry of the substrate

  21. AGONISTS VS ANTAGONISTS • Noncompetitive Antagonists/ noncompetitive, irreversible/ insurmountable • Drug A has higher affinity for receptor • Change shape • Reversal by antagonist is slow An allosteric regulatormolecule causes theactive site to changeshape, so the substrateno longer fits allostericregulatormolecule

  22. AGONISTS VS ANTAGONISTS • Partial agonist/ antagonist • Drug A – receptor > inc. HR 50% • Drug B – receptor > inc. HR 25% • Partial agonist • Not as powerful agonist as B • Partial antagonist • Drug A – receptor > inc. HR 50% • Drug B – receptor > dec.HR 25% • Not completely reversed effect • Partial agonist/ partial antagonist • BUTORPHANOL

  23. Non – receptor – mediated reactions • Effect without receptors • Mannitol: osmotic diuresis • Inc. urine w/o receptor • Chelators • Drugs that combine with ions (Ca, Cl, Mg) • Penicillamine – Lb > urine • Ethylenediamine tetraacetic acid – EDTA combine with Ca – blood > no clot • Ca/ Aluminium/ Mg antacid: Tums/ rolaid combine with acid in stomach > weaker acid

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

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