What tissues will be enriched in lipophilic drugs?
fat tissues
Vd= equation?
Amout of drug in body (DOse)
Drug plams concentration
What does cellular distribution depend on?
Tissue permeability
Perfusion rate
What does the rate of tissue permeability depend on?
Physiochemical properties of the drug: molecular size, pka. partition coeficient
Physiological barriers that retrict the diffusion of drug into tissues
T/F ONLY unionized/lipid soluble drugs rapidly cross the cells membrane
T
Example: thiopental, a lipophilic drug, largely unionized at blood and ECF pH readily diffuse into the brain where as pen vk which are polar and ionized do not pass b3
What are the factors that make it difficult to cross the b3
A stealth of endothelial cells lining the capillaries
Tigh jxns
Neural tissues cover the capillaries
How can you promote the passage of drug pass the b3?
Permeation enhancers: Dimethyl sulfoxide
Osmotic disruption of the b3 infusing the internal carotid artery with mannitol
USing dihydropylridine redox system
What makes up the placental barrier?
Trophoblast basement membrane and the endothelium
T/F only highly lipid soluble drugs can cross the CSF barrier
T
Drug dispositon
distribution
what is a major determinant of drug disposition
Drug binding to plasma protein and tissue
Why is drug binding an important effect on drug dynamics?
Because only the free drug can interact with the receptors
Why is plasma binding seldom has clinical relevance?
Because few drugs are used as displacers
Fu
Drug plasma protein binding
expressed as a percent free fraction
Free []total []
Lipophilic drugs
Pasage through lipid membranes, access to site of acition but hinders excretion
What metabolites are excreted from the body?
MOre polar, water soluble, inactive metabolites
T/F MEtabolites may have potent biological activity or toxic effects
T
Phase I
functionalization reactions
Phase II
Conjugation reaction
Where are phase I enzymes located?
ER
Where are phase II enzymes located?
Cytosol
What are some factors affecting drug metabolism?
Environmental determinant: inhibition, induction
disease factors
age and sex
genetic variation
How does environmental affect metabolism?
Activity of most drug metabolizing enzymes can be modulated by certain exogenous compounds
enzyme induction is the process by which exposure to certain substrates results in accelerated biotranformation with a corresponding reduction in ummetbolized drug
results in the drug getting metabolized faster
Can drug induce their own metaolism?
Yes Phenobarbital carbamazepine
What are four consequencces of drug induction?
Increased rate of metabolism
Decrease in drug plasma concetration
Reduced bioavailability
If the metabolite is active or reactive increase in drug effects or toxcity
What is the therapeutic implications of drug induction?
MOst drug will decrease efficacy due to rapid metabolism but if the metabolite is active would increase the efficacy
Will have to change dosing
What kind of process is drug metabolism?
enzymatic process which can lead to the enzymes being ihibited therefore can an effect of the metabolism of drugs
What are the types of drug enzymes inhibition?
Competitive
Irreversible inactivation of enzyme, destruction of the active site like breaking the heme group in a cyp enzyme
What are the consequence of enzyme inihibtion?
Increase the plasma concetration of the parent drug
Reduction in metabolite concentration
Exaggerated and prolonged pharmacological effects
Increased likelihood of drug-induced toxicity
What are the therapeutic implications of enzyme inhibition?
May occur rapidly without any warning
How can liver disease effect drug metabolism?
Impaired drug metabolism decreased enzyme activity
How can genetic variation affect drug metabolism?
Can lead to therapeutic failure or and adverse drug reactions
Genetic variation amoung enzyme can result in three phenotypes:
Extensive metabolizers
INtermediate metabolizers
Poor metabolizers
What are actively excreted into the bile?
Some organic acids and bases
some drugs
Glucuronides of steroids and morphine
What is the route of the enterheptatic cycle?
Liver --> common bile duct --> small intestine --> portal vein --> liver
What are the factors that affect pulmonary excretion?
PLamsa solubility of the drug
Cardiac output
Respiration
What is the rate of pulmonary excreation proportion to?
Drug alveolar tension of the gaseous, and inversily proportional to its plasma solubility
How is urine is distilled from blood plasma in what ways?
Filtration
Re-absorption
Active secretion
Where does active secretion of uric acid, organic acid, organic bases take place in the kidneys?
Proximal convoluted tubule
Where does reuptake of glucose aa bicarbonate tak eplace in the kidneys?
Proximal convoluted tubule
Where does reuptake of na and water?
Thin descending limb
Distal convoluted tubules
Collecting duct
what is the major determinant in the rate of excretion of polar solutes?
