Pharmokinetics - Pharmacodynamics

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Pharmokinetics - Pharmacodynamics

• CHAPTER 3 - 4
• Dr. Dipa Brahmbhatt VMD MpH
• dbrahmbhatt_at_vettechinstitute.edu

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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 form by 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)

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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 gt prednisolone

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Drug Interaction - Biotransformation

• Drug interactions desirable/ undesirable
• Multiple drugs
• Metabolized slowly
• Can accumulate gt 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

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ALIENS!

• Drug metabolism different in cats
• Reduced ability to synthesize glucoronic acid
• Glucuronyl transferase activity greatly reduced
  in cats
• Salicylate compounds
• Aspirin used with extended dosage interval
• Bismuth subsalicylate pepto bismal
• NO ACETAMINOPHEN (tylenol)!!
• Liver cant process toxic metabolites

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Age - Biotransformation

• Younger animals (lt 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

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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
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PHARMACOKINETICS RENAL ELIMINATION

• Renal elimination of drugs involves
• Glomerular filtration
• Passive process
• Renal arteriole (smooth m.)gt capillaries
  glomerulus
• Nephron - Bowmans capsule blood protein in and
  water/drugs out
• Tubular reabsorption Passive diffusion
• Tubular secretion Active

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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 gt glomerulus gt bowmans capsule gt
proximal convoluted tubule gt loop of Henle gt
ELIMINATED distal convoluted tubule gt collecting
ducts gt renal pelvis gt urine
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PHARMACOKINETICS RENAL ELIMINATION

• Blood pressure is a factor dec. filtration gt
  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

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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.

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Hepatic Elimination/ Biliary excretion

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

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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 animals
  body

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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?)

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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

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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

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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

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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

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AGONISTS VS ANTAGONISTS
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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
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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
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AGONISTS VS ANTAGONISTS

• Partial agonist/ antagonist
• Drug A receptor gt inc. HR 50
• Drug B receptor gt inc. HR 25
• Partial agonist
• Not as powerful agonist as B
• Partial antagonist
• Drug A receptor gt inc. HR 50
• Drug B receptor gt dec. HR 25
• Not completely reversed effect
• Partial agonist/ partial antagonist
• BUTORPHANOL

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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 gt urine
• Ethylenediamine tetraacetic acid EDTA combine
  with Ca blood gt no clot
• Ca/ Aluminium/ Mg antacid Tums/ rolaid combine
  with acid in stomach gt weaker acid

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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/as
  pirin.pdf