pharmokinetics - pharmacodynamics

Pharmokinetics - Pharmacodynamics

CHAPTER 3 - 4CHAPTER 3 - 4

Dr. Dipa Brahmbhatt VMD MpHDr. Dipa Brahmbhatt VMD MpHdbrahmbhatt@vettechinstitute.edudbrahmbhatt@vettechinstitute.edu

PHARMACOKINETICS - PHARMACOKINETICS - BIOTRANSFORMATIONBIOTRANSFORMATION

• 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)

• 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

PHARMACOKINETICS - PHARMACOKINETICS - BIOTRANSFORMATIONBIOTRANSFORMATION

Drug Interaction - Drug Interaction - BiotransformationBiotransformation

• 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

• 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 can’t process toxic metabolites

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

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

PHARMACOKINETICS: RENAL PHARMACOKINETICS: RENAL ELIMINATIONELIMINATION

• 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

PHARMACOKINETICS: RENAL PHARMACOKINETICS: RENAL ELIMINATIONELIMINATION

• 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

– 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

PHARMACOKINETICS: RENAL PHARMACOKINETICS: RENAL ELIMINATIONELIMINATION

Hypoalbuminemia/ Hypoalbuminemia/ HypoproteinemiaHypoproteinemia

• 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.

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

PHARMACODYNAMICSPHARMACODYNAMICS• 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

Drug Elimination TerminologyDrug 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?)

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

RECEPTORSRECEPTORS• 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

RECEPTORSRECEPTORS• 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

AGONISTS VS ANTAGONISTSAGONISTS 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

AGONISTS VS ANTAGONISTSAGONISTS VS ANTAGONISTS

• Competitive Antagonists/ reversible antagonism/ surmountable antagonism– Drug A and B have equal

opportunity– Higher conc. Wins– Hydromorphone and

naloxone

AGONISTS VS ANTAGONISTSAGONISTS VS ANTAGONISTS

A competitive inhibitor moleculeoccupies the active site andblocks entry of the substrate

• Noncompetitive Antagonists/ noncompetitive, irreversible/ insurmountable– Drug A has higher

affinity for receptor– Change shape– Reversal by antagonist is

slow

AGONISTS VS ANTAGONISTSAGONISTS VS ANTAGONISTS

allostericregulatormolecule

An allosteric regulatormolecule causes theactive site to changeshape, so the substrateno longer fits

AGONISTS VS ANTAGONISTSAGONISTS 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

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

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