Drug Disposition Flashcards
What is drug disposition ?
Study of the movement of drugs in the body across biological membranes from the time of absorption until elimination
What are the stages of drug disposition?
Absorption
Distribution
Biotransformation
Excretion
How can drugs be transported across cell membranes?
Passive diffusion
Facilitated diffusion
Active transport
Pinocytosis
What are the two types of passive diffusion?
Transmembrane- passive through aqueous protein channels or hydrostatic/osmotic differences across the membrane
Paracellular - intercellular aqueous pores
Bulk flow of water can carry small water soluble substances
What are the 3 factors what will affect simple diffusion?
Concentration gradient
Lipid solubility (measured by lipid partition coefficient)
Degree of ionization
The (higher/lower) the lipid solubility of the drug the faster the drug crosses cell membranes
Higher
Drugs pass cross biological membranes in their (ionized/nonionized) forms
Nonionized -> lipid soluble
What is the rate of diffusion dependent on?
Ratio of ionized (I) to nonionized (N)
- > pH of drug
- > pka of drug
- > pH of medium
What is pka of a drug?
PH at which a weak electrolyte is 50% ionized and 50% non ionized
_________ drugs are ionized in an alkaline medium
Acidic
__________ drugs are ionized in an acidic medium
Basic
Henderson hasselbalch equation for a weak acid?
Pka = pH + log (N/I)
Hendreson Hasselbalch equation for a weak base?
Pka = pH + log (I/N)
The (higher/lower) the pka of a weak acid, the higher is N/I, and the (higher/lower) the pka of a weak base, the higher is N/I
Higher; lower
_____________________ compounds such as d-tubocurarine are mostly ionized
Quaternary ammonium
What is facilitated diffusion??
Carrier-mediated transport that does not need energy
How can facilitated diffusion protect the cell from toxic substances ??
Transporters move substance from inside the cell to outside
What is active transport?
Drug moved from low to high concentration requiring energy
- > primary- directly use ATP
- > secondary- use gradient generated by ATP
Can be saturated, is selective, and competitive inhibition
What is pinocytosis ?
Endocytosis were cell engulfs drug molecules dissolved in water
Eg aminoglycoside antibiotics by renal tubular cells
What is drug absorption?
Transfer of drug from site of administration to the circulation
What drug factors can affect absorption??
Molecular size: smaller=faster
Lipid solubility
Degree of ionization (N/I ratio)
Dissolution of drug in water (oral liquid after than solid)
Concentration at site (dose and concentration): higher=faster
Route of admin: subliguinal and inhalation > intramuscular >subcutaneous > oral
What factors related to the animal can affect drug absorption?
Blood flow Absorbing surface area Connective tissue Species Individual
How does blood flow alter absorption?
Increased blood flow= increase absorption
How can blood flow be altered
Drugs, physiological factors, and disease
Heat/massage increase blood flow
Sympathetic stimulation: increase flow to muscles but decrease to GI and subcutaneous sits
Shock/edema decrease flow
What part of the intestine is the main site of absorption for all drugs given orally
Upper small intestine (high surface area)
What factors affect drug absorption from the GI tract
Oral absorption of solid drug dependent on dissolution rate Activity of gut Presence of other substances Blood flow Species Individual
Rate depends on gastric emptying
What is distribution of drugs?
Transport of drugs from the plasma to the tissues
What factors can affect distribution of drugs?
Physiochemical properties of the drug Concentration gradient Plasma protein binding Tissue barriers Blood flow Affinity of drugs to certain tissues
________ drugs mainly to albumin in the plasma
Acidic
_______ drugs bind mainly to acid a1-glycoproteins and lipoproteins
Basic
What affect does plasma protein binding have on drug distribution
Bound form of drug is inactive -prolongs half-life
Cannot be distributed, metabolized, or excreted by globular filtration
Binding is reversible and competitive
The rate of plasma protein binding depends mainly on ____________ of drug
Concentration
Competitive binding
Binding can be modified by disease
Alteration of blood flow will have what affect on distribution
Altered delivery to drug to tissue
Physiological factors/drug/disease
What components of the blood brain barrier prevent drug entry to the brain?
Tight capillary endothelial junctions
Glial cells
CSF flow to venous drainage
Active transport (organic acid/base)
What factors can alter the blood brain barrier?
Age Inflammation Trauma Allergic rxn Severe hypotension Hypoxia High dose of organic solvents (alochol) High does of heavy metals (lead, mercury)
____________ can be sequestered by calcium in skeletal tissues
Tetracycline
What is sequestered/accumulates in kidney tissue
Aminoglycoside
_______ is trapped in the thyroid gland
Iodine
Movement of drug fro the tissue to the blood
Redistribution of drugs
Eg thiopental vs phenobarbital
What is biotransformation
Chemical alteration of the drug molecule by the cells of the animal
What are the two main results of biotransformation ?
Change in physiochemical properties
Change in pharmacological activity
Inactive drug-> active metabolite
Bioactivation
Eg. Cortisone-> hydrocortisone
Nontoxic drug -> toxic metabolite
Lethal synthesis
Eg Parathion -> paroxon
What is the most important tissue involved in biotransformation
Liver
What are the phase I types of biotransformation reactions?
Oxidation
Reduction
Hydrolysis
What is the phase II type biotransformation reaction
Conjugation
The majority of drug metabolism is by _____________ reaction biotransformation
Oxidative
Where can oxidation reactions occur?
Microsomal Non microsomal ( cytosol and mitochondria)
What is an example of an non microsomal oxidation reaction
Alcohol and aldehyde dehydrogenase to ethanol and acetaldehyde
What enzymes are involved in oxidation reactions ?
Xanthine oxidase (eg xanthine to uric acid) Tyrosine hydroxylase (eg tyrosine to dopa) Monoamine oxidase (eg catecholamines and serotonin metabolism)
What type of reaction adds hydrogen groups? Where can these reactions occur?
Reduction
Microsomal and non-microsomal
What type of reaction requires water
Hydrolysis
What enzymes are involved in hydrolysis?
Hydrolases
Eg
Esterase
Amidases
Peptidases
What is the combination of a drug or metabolite with an endogenous substance
Conjugation
What is the most common conjugation reaction
Conjugation to glucuronic acid
What is the only microsomal conjugation reaction
Glucronidation (glucuronic acid)
All others are non- microsomal (sulfuric acid, acetyl groups, methyl group, glycine, methionine, and glutathione)
Conjugation is deficient in the ____________
Neonate
Conjugation of __________ to _______________ leads to hepatotoxic products
Acyl glucroonic acid to NSAID
What are factors that alter biotransformation? (Long list)
Species Individual Route of admin Enzyme inducers/inhibitors Liver disease Hepatic blood flow Plasma protein binding Distribution and storage Age Sex Diet and nutrition Body temp Environmental factors
What species are deficient in glucuronyl transfereases and are unable to conjugate phenols and aromatic amines?
Cats
What species are deficient in hydroxylation and dealkylation?
Cats
What species lacks acetylating enzymes?
Dog
What species has less plasma pesudocholinesterases?
Ruminants
What species have hight levels of oxidative enzymes ?
Ruminant and horses
What species are deficient in methylases
Equine
What species are deficient in sulfate conjugating enzymes?
Pigs
What species lack oxidative enzymes?
Birds
What species have low levels of drug metabolizing enzymes?
Fish
How can route of administration alter drug biotransformation ?
First pass effect for oral, rectal, intraperitoneal routes, and skin
Drug goes through liver and is metabolized before it is distributed
Eg. Lidocaine, propranolol, and morphine
What are drugs that stimulate production of more metabolic enzymes in the liver? Where are they found?
Enzyme inducers
Microsomal enzymes
What are drugs that inhibit the liver to produce metabolic enzymes??
Enzyme inhibitors
What are examples of enzyme inhibitors?
Chloramphenicol
Cimetidine
Ketoconazole
How does biotransformation in newborns and geriatrics compare to adults?
Less in newborns and geriatrics
Diet and nutrition can alter biotransformation. ______________ foods can induce enzymes and ___________ can be an enzyme inhibitor
Charcoal broiled foods
Grapefruit juice
Removal of clearance of drug from the body??
Drug excretion
What are the routes of drug excretion? (Another long list)
Renal Hepatic Feces Milk Semen Saliva Eggs Hair Feathers Sweat glands Expired air
3 ways drugs are excreted in the kidney?
Glomerular filtration
Active tubular secretion
Tubular reabsorption
What factors affect glomular filtration
Glomular filtration rate- arterial BP -> hydrostatic pressure
Molecular size- less than 7000Da is freely filtered; 7000-70,000Da filtered at a rate proportional to molecular mass
Molecular charge- large negative molecules are not filtered
Plasma protein binding- only unbound are filtered
Where does active tubular secretion take place? And what provides the energy?
Proximal convoluted tubule
Sodium pump ->. ATPase
Secondary/tertiary active transport (concentration dependent)
(Organic anion and organic cation system)
Organic cation transporters carry organic _________
Bases/basic drugs
-cimetidine, procaniamide, or nictotine
Organic anion transporters transport organic ________
Acids/acidic drugs
Eg penicillin, thiazide diuretics, or loop diuretics
Where does passive tubular reabsorption occur in the kidney?
Proximal and distal convoluted tubules (non-ionized forms of weak acids and bases)
What are factors that can affect tubulular reabsorption of drugs?
Physiochemical drug properties (soluble/ionized/polar)
Degree of ionization (acidification/ alkalinization of urine pH)
Rate of glomular filtration
Active tubular reabsorption
__________________ of the urine pH enhances renal excretion of weak basic drugs
Acidification
Ammonium chloride or methionine
____________________ of the urine pH enhances renal excretion of weak acidic drugs
Alkalinization
Sodium bicarbonate
What is the second most important organ for drug excretion??
Liver (bile or blood)
How can drugs be excreted in bile ?
Molecular weight greater than 300Da and presence of a polar group increase biliary absorption
Can be unchanged to as glucuronides
Acid/basic/neutral
What are examples of drugs that are significantly excreted in bile?
Steroid hormones Erythromycin Nafcillin Digitoxin Glucuronides of chloramphenicol and morphine
What is enterohepatic circulation?
Conjugated of lipophillic drugs are excreted in bile -> hydrolyzed in the intestine -> lipid soluble drug is reabsorbed
=> prolonged half life of the drugs
What types of drugs are excreted in the feces?
Orally administered; non absorbed
Drugs excreted in bile and not reabsorbed
Drugs from plasma to GI tract by passive diffusion
(Acid/basic) drugs are excreted in milk in large amounts because of ion trapping. What is the significance of drugs in the milk?
Basic
Drug residues
Systemic treatment of mastitis
Adverse effects on newborn
Volatile compound like inhalation anesthetic are excreted in ?
Expired air
