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What tissues will be enriched in lipophilic drugs?
- 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
- 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
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
- Drug plasma protein binding
- expressed as a percent free fraction
- Free total 
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
Where are phase I enzymes located?
Where are phase II enzymes located?
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
- Dietary micronutrients (food preservative)
- Environmental factors pesticides industrial compounds
What is induction of drug metabolism?
- 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?
- 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
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?
- 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?
Glomular filtration rate
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