Toxicokinetics II Flashcards
Chronicity Factor
Acute LD50/Chronic LD50
>2 relatively cumulative toxicant
Risk Ratio
Toxicity:Use Level
Ex: urea toxicity = 300 mg/kg, use level = 100 mg/kg
Risk Ratio: 3:1
Henderson Hasselbach Equation
PKa of an acid= pH of the medium + log (N/I)
PKa of a base= pH of the medium + log (I/N)
N= nonionized I= ionized
The ____________ the pKa of a weak acid, the ___________ the N/I; the _________ the pKa of a weak base, the __________ the N/I.
Higher, higher
Lower, higher
Absorption of drugs
The transfer of the drug from the side of admin to the circulation
What factors do we take into account for drug absorption?
Molecular size Lipid solubility Degree of ionization Dissolution of drug in water Concentration of drug at absorptive site Route of administration
The smaller the molecule, the ________ the penetration through pores
Faster
The greater the lipid solubility, the _____________ the absorption
Greater
The higher the ratio between N/I, the ______________ the absorption
Greater
Which is faster: oral absorption of lipid drugs or solid drugs?
Lipid drugs
What does oral absorption of lipid drugs depend on?
Rate of dissolution
What two things does the concentration of a drug at an absorptive site depend on?
Dose and concentration
The higher the conc of a drug, the _________ the absorption
Faster
List the routes of administration and their absorptive rates in order from fastest to slowest?
Sublingual and inhalation- very rapid
IM
SQ
PO
An increase in blood flow causes an increase or decrease in absorption?
Increase
What three things can modify blood flow?
Drugs
Physiological factors
Dz
What two things can decrease blood flow?
Shock
Edema
What is the main site of absorption for drugs given PO?
Duodenum (bc of extensive surface area and rich blood supply)
Rate of absorption depends on what?
Rate of gastric emptying
What 6 factors affect drug absorption from the GI tract?
PO absorption of solid drugs depends on rate of dissolution Activity of the gut Presence of other substances Blood flow Species Individual
Distribution of drugs
Transport of drugs from the plasma to the tissues (site of action, site of storage, side of biotransformation)
What 3 things affect the distribution of drugs?
Physiochemical properties Concentration gradient Plasma protein binding Blood Flow Tissue barriers Affinity of drugs to certain tissues
What are two physiochemical properties of the drug?
Lipid solubility
Degree of ionization
What do acidic drugs bind to?
What do basic drugs bind to?
What do steroids bind to?
Albumin
Acid alpha-1 glycoproteins and lipoproteins
Globulin
Is plasma protein binding reversible or irreversible?
Reversible
What is the significance of plasma protein binding?
It prolongs the half-life of the drug
In plasma protein binding, the bound form is the _________ form, which means it can’t do what 3 things?
Inactive
Can’t be distributed, metabolized, or excreted by glomerular filtration
(PP bound drugs tend to be actively excreted)
The rate of binding of the drugs depends mainly on what?
Amount of drug
Drugs compete where in plasma protein binding?
On the binding sites
True or False. Plasma protein binding depends on the species.
True
What is something that can modify plasma protein binding?
Disease
List the 4 highly perfused tissues.
Brain
Liver
Kidney
Endocrine glands
List the two moderately perfused tissues
Muscle
Skin
List the two poorly perfused tissues
Bone
Adipose tissue
What 3 things are causes of alterations of blood flow?
Physiological factors
Drugs
Disease
What are the 5 tissue barriers?
Brain Eye Testicles Placenta (less effective) Mammary gland
True or False. If the drug can cross the BBB, then it can cross any barrier in the body.
True
Describe the BBB.
Tight capillary endothelial junctions Presence of glial cells Flow of CSF into venous drainage Active transport mechanisms High distribution Lipophillic
What type of transport is used for extrusion of organic acids and bases?
Active transport
What factors influence the BBB?
Age Inflammation (meningitis) Trauma Allergic rxn Severe hypotension Hypoxia High doses of organic solvents (alcohol) High doses of heavy metals (lead, mercury)
Tetracycline has an affinity to ______________ in ______________ tissues.
Calcium; skeletal
Aminoglycosides have an affinity to __________ tissue.
Kidney
Iodine is trapped by what?
Thyroid gland
Redistribution of drugs
The movement of the drug from the tissues to the blood
How do you measure the distribution of drugs?
By the volume of distribution (Vd)
Biotransformation
The chemical alteration of the drug molecule by the cells of the animal
What are the two phases of biotransformation?
Phase 1- oxidation, reduction, hydrolysis
Phase 2- conjugation
If there is a change in physiochemical properties of a drug, the metabolite is more __________, ___________, and __________.
Water soluble, polar, and ionized
If there is a change in pharmacological activity of a drug what occurs?
Bioinactivation or detox of most drugs
Bioactivation or lethal synthesis (few drugs)
True or False. Aspirin is an inactive drug.
What is the active metabolite of Aspirin?
False
Salicylic acid
True or False. Cortisone is an inactive drug.
What is the active metabolite of cortisone?
True.
Hydrocortisone (cortisol)
True or False. Parathion is an toxic drug.
What is the toxic metabolite of parathion?
False. Nontoxic
Paroxon
What are some common sites for biotransformation?
Liver- (SER microsomes; hepatocyte cytoplasm, mitochondria, lysosomes, nuclear envelope, plasma membrane) Nervous tissue Kidney GIT Lungs Skin Plasma
What are the 5 components of hepatic metabolism?
Enzymes lack specificity
Enzymatic rxns are saturable rxns
Drugs can compete on the same enzyme
Enzymes can be induced or inhibited by drugs
Microsomal enzymes cause oxidation, reduction, hydrolysis, and conjugation to glucuronic acid
What are the two types of metabolic rxns?
Which one is synthetic, non synthetic?
Phase 1- oxidation, reduction, hydrolysis (non synthetic)
Phase 2- conjugation (synthetic)
