Chapter 1 Principles of Drug Absorption, Drug Disposition and Drug Action

Pharmocology = study in all of chemicals matter in order to used as drug in therapeutic purposes Pharmacology has 2 main focuses: Pharmacokinetics = in drug absorbtion, distribution, biotransformation and excretion Affect the administration route, doses, doses interval and toxicities of drug

Pharmacodinamics Drug Absorbtion and Disposition: General Principles = involve drug journey in body start in administration of drug itself Drug Action Passive Diffusion cell has bimolecular lipoprotein layer as a barrier for the drug come accross the cell membrane depend on pKa and the pH of medium carrying the drug. pKs=pH when 50% drug is ionized while other not. Calculating ionized drug accross membrane is using Henderson-Hasselbaclch equation. Thera two acid or base. If Acid = If Base = pKa=pH+log pKa=pH+log = crosses several biological membranes to reach the site for action

In monogastric animlas weak acid (e.g. aspirin which pKa=3,5) has better absorbed than weak bases because the acidity in stomach. In ruminant pH varies with feeds and often not low. Weak base is poorly absorbed in stomach because the exist in mostly in ionized state (low lipid solubility) because Acidity condition in that stomach. Weak base is easier absorbed in intestine because the pH is higher than stomach. Filtration Some drug matter has low molecular weight (e.g. water urea, ETC) is easier to absorbed than predicted on their solubility In the glomerular filtrationprocess in kidney has large pores that can help the large molecular weight substance except retain albumin that has mw ~60,000 Facilitated difution No cellular energy needed, doesnt go against concentration gradient

Involves attachment to carrier e.g. macromolecul (example reabsorbtion of glucose in kidney and absorbtion B12 in intestine in higher environmental pH Active transport Need cellular energy Chemical structure is important in attaching in carrier Pinocytosis Rare in drug absorbtion but important for some polypeptides, bacterial toxin, antigen and food protein by the gut

Routes of Administration Except intravascular, all administratiomn involve an absorbtion process that drugs must cross one more one membrane before reach the blood Alimentary routes Routes Oral Advantages Safest, convenient, economical, but difficult in some animal Require to mixed in food Food stimulate secretion which help dissolve lipophilic drug to increasing absorbing Can be used in unconscious animal or vomiting animal Slowwer absorbtion than oral Disadvantages Acid environment in stomach can destroy drug In ruminant several bacteria enzime become inactive Some drug irritate GI mucosa Some presence food probably prevent drug absorbtion

Rectal

Parenteral routes Intravenous (IV) Intramuscular (IM) Subcutaneous (SC) Intraperitoneal (IP) Spinal and subdural used regional anestesia Rapid onse3t useful for unconscious animal or vomiting animal, more uniform and predictable IM and SC injection sites is mostly determined by the amount of blood flow to the destination Asepsis Pain Probably penetrate blood vessel during IM injection Speed of onset is so rapidas IV administration Discolorization in meat or abscess may occur and can make carcass devalue

Other routes: dermal and inhalation Drug distribution

Refers in reversible transfer in two sites Commonly, the junction between the cappilary endothial cells are not tight thereby free drug reach equilibrium fast on both vessel wall Distribution drug to CNS and cerebrospinal fluid (CSF) is restricted due Blood Brain Barrier (BBB) Plasma binding protein of drug can affect drug distribution, since only the free drug is able to freely across membrane Drug+ free protein =drug-bound protein Aciditic drug are bound primary to albumin and and basic drug bounded to 1-acid glycoprotein. Steroid and thyroid hormone are bounded in spesific globulins with high affinity. Drug redistribution Can terminate drug respone usually by metabolism and excretion Drug redistribution is mechanism of the cell in reducing drug concentration in action site Drug metabolism Definition: the mechanism of alteration in chemical drug (xenobiotics) same as the other normal substance inside the body Principle Follow the renal glomerulus filtration the most liphopilic drugs are reabsorbed in this site Biotransformation of more water-soluble will found difficulties to be reabsorbed again in kidney. Liver is the most important organ for biotransformation then the second lung, kidney and GI ephitelium Drug transformation gradualy reduce the biological activity in drug Not same with drug inactivation as the parent chemical may be transformed to a chemical with greater biological activity

Enzymathic reaction is occur in 2 phases: Phase 1 : found in smooth endoplasmic reticulum at hephatic cells o Oxidation o Mixed function oxidation o Nonmicrosomal oxidation o Oxidative methabolism o Reduction o hydrolysis Phase 2: occur in mithocondria o Have greater solubility and readily to excretes by kidney o It depend on species variation for the phase 2 proccessess o Enterophatic recirculation

Bioinformatic by GI microflora

Drug excretion Definition: processes of eliminating drug from the body. Kidney is primarily organ Renal excretion o Glomerula filtration, active tubular secretion, passive tubular secretion Other excretion routes o Billiary secretion: Glucuronide drug is gone by via the bile, renal excretion proccess o Milk o Saliva o Expired air o Other minor route: tears and sweat

Pharmacokinetics Definition: equational of drug concentration in the body Plasma concentration at time zero The apparent volume of distribution Half Life Total body clearance Total body clearance Bioavailibility F= Determination dosage Clb=.Vd= t1/2=.Vd=
( )

Species variation Different species and breed need different drug or concentration of drug Effect on Disease Fever, Liver and Kidney disease Effect on stereoisomers to prevent the stereoisomers need reducing activity racemates Pharmacodynamics: Mechanism Of Drug

Receptor bind a drug amd give signal Similar with chemiacl bond Has two indicator: affinity and intrinsik activity Dose-response relationship The response is measured in deividual tissue or animal Drug concentration effect relationships has for important characteristic: Potency, Slope variability and Maximum Effect Quantal Dose-response relationship Therapeutic index