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Questions and Answers
What is the primary mechanism by which Phase I reactions increase hydrophilicity?
What is a consequence of Phase II metabolism?
Which of the following can inhibit drug metabolism?
How long does the induction process typically take to reach its maximum effect?
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Which route of administration is primarily affected by First Pass Metabolism?
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What effect can metabolic induction have on a drug's action?
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What role does grapefruit juice play in drug metabolism?
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What are the two main types of Phase I reactions?
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What primarily determines the efficiency of drug passage through cell membranes?
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Which factor is NOT mentioned as influencing the rate of drug distribution?
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How does high plasma protein binding affect drug availability?
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In which type of tissue is drug distribution expected to be the most challenging?
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What effect does saturable binding sites have on drug interaction?
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Which of the following organs is least likely to have high drug concentration after administration?
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What characterizes low plasma protein binding drugs?
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Which two factors primarily impact the distribution of drugs to various organs?
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What is a characteristic of liposoluble drug distribution?
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How does hydrosoluble drug distribution primarily affect drug access in the body?
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What role does the blood-brain barrier (BBB) play in drug distribution?
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Which condition can increase the volume of distribution (VD) of a drug?
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What effect does liver failure have on drug distribution?
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Which factor primarily hinders hydrosoluble drugs from entering the central nervous system?
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What mechanism is primarily involved in the transport of liposoluble drugs into the CNS?
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Which of the following statements is true about drug distribution in special areas like the eye or fetal circulation?
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What is one of the main roles of cytochrome P450 monooxygenases in drug metabolism?
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Which phase of drug metabolism is primarily responsible for conjugation reactions?
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Which of the following conjugation reactions occurs primarily in the liver and produces water-soluble metabolites known as glucuronides?
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What is the product of a hydrolysis reaction involving an ester and water?
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Which group is commonly involved in phase II drug metabolism reactions for conjugation?
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What does acetylation in drug metabolism typically involve?
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Which metabolic process converts phase I metabolites into highly polar conjugates for excretion?
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Which of the following describes the nature of phase I reactions in drug metabolism?
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What is the primary site for drug excretion in the body?
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Which process can limit the systemic circulation of orally administered drugs?
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Which parameter is NOT considered in excretion kinetics?
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How does the pH of urine affect the re-absorption of drugs?
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What is one of the ways drugs are eliminated from the body through means other than excretion?
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Which of the following is considered a route of excretion for drugs?
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What factor heavily influences the passive diffusion of lipophilic drugs during kidney excretion?
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Which of the following describes the total kidney excretion formula?
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Study Notes
Comparing Phase I & Phase II Enzyme Reactions
- Phase I reactions are oxidation, reduction, and hydrolysis reactions.
- Phase II reactions are conjugation reactions.
- Phase 1 increases hydrophilicity slightly.
- Phase 2 increases hydrophilicity significantly.
- Phase I exposes a functional group for a new reaction.
- Phase II adds a polar functional group.
- Phase I can lead to metabolic activation.
- Phase II facilitates excretion.
Metabolism Inhibition
- A drug can inhibit the metabolism of another drug if it uses the same enzyme or metabolism cofactors.
- This is rare since different drugs typically use different isoforms of the CYP (P-450).
- Inhibition can lead to toxicity effects due to a lack of drug elimination.
- Some foods, like grapefruit juice, can inhibit drug metabolism.
- Grapefruit juice is metabolized by an isoform of CYP450, thus preventing metabolism of the drug, leading to prolonged pharmacological effect.
Metabolism Induction
- A drug can induce the metabolism of another drug by increasing the synthesis of metabolic enzymes.
- Inductor drugs are highly selective for certain isoenzymes of the CYP (P-450).
- Induction takes 4-14 days to reach maximum effect and lasts for 1-3 weeks.
Metabolism Induction Results
- Metabolism induction can lead to lower or higher intensity and duration of drug effect.
- Tolerance occurs when the drug itself induces its own metabolism.
First Pass Metabolism (PRE-systemic)
- First Pass metabolism is the metabolism of a drug during its passage from the absorption site to systemic circulation.
- Oral administration exposes drugs to metabolism in the intestine wall and liver.
- Transdermal administration exposes drugs to metabolism in the skin (low relevance).
- All routes expose drugs to metabolism in the lungs (low relevance).
Distribution
- Distribution is the passage of a drug from the blood to different tissues and organs.
- Important to consider when treating diseases located in specific areas, such as the CNS, and during pregnancy and lactation.
Factors Influencing Drug Distribution
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Plasma protein binding: Many drugs have an affinity for plasma proteins, the most important of which is albumin.
- The less bound a drug is, the more efficiently it can cross cell membranes.
- Unbound drug fraction is available for pharmacological effects, metabolism, and excretion.
- Bound drug is not available.
- Plasma protein binding can influence the drug's biological half-life.
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Regional blood flow: The rate of distribution to organs after absorption depends on the amount of cardiac output the organs receive.
- High vascularization (e.g. heart, kidney, liver) leads to faster drug distribution.
- Low vascularization (e.g. skin, adipose tissue, bone, skeletal muscle, brain) leads to slower drug distribution.
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Liposolubility: Determines how quickly a drug is absorbed, crosses membranes, and settles in tissues
- Liposoluble drugs distribute well in highly irrigated organs (brain, heart, liver, kidneys) and more slowly to muscle, fat, and poorly irrigated tissues.
- Hydrosoluble drugs don't distribute well and struggle to access the CNS.
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Distribution in Special Areas: CNS, eye, fetal circulation, and exocrine secretions (tears, saliva, milk, prostate fluid)
- The blood-brain barrier restricts the distribution hydrophilic drugs to the brain.
Volume of Distribution
- Volume of distribution (VD) describes the extent of drug distribution between plasma and the rest of the body after oral or parenteral dosing.
- VD can be increased by renal failure (fluid retention), liver failure (altered body fluid and plasma protein binding), and decreased in dehydration.
- VD is typically involved in cytochrome P450 monooxygenase, NADPH, and oxygen activity.
Phase I Reactions
- Oxidation: Most important, typically involves cytochrome P450 enzymes.
- Reduction: Addition of hydrogen or removal of oxygen.
- Hydrolysis: Molecule degradation by addition of a water molecule.
Phase II Reactions - Conjugation
- Glucuronidation: Most important, mainly in the liver, catalyzed by UDP-glucuronyltransferase enzyme.
- Acetylation: Involves acetyl-CoA conjugates.
- Methylation: Addition of methyl groups forming conjugates.
- Sulfation: Formation of sulfonates conjugates.
- Glycine conjugation: Conjugation with glycine.
- Glutathione conjugation: Involves glutathione disulfide and glutathione reductase.
- Ribonucleosids and nucleotids synthesis: Conjugation of purine and pyrimidine antimetabolites.
First Pass Effect (Route of Orally Administered Drugs)
- Drugs absorbed in the gastrointestinal tract pass through the portal venous system to the liver where they are exposed to first pass effect.
- First pass effect can limit systemic circulation.
- Once in systemic circulation, drugs interact with receptors in target tissues resulting in a pharmacological effect.
Excretion
- Expulsion of a drug and its metabolites to the outside.
- Essential process in all forms of life to eliminate non-useful materials from the organism.
- Accumulation of foreign substances can negatively affect normal physiological functions.
Sites of Excretion
- Kidney (most important, urine)
- Biliary excretion (faeces)
- Air expiration
- Saliva and sweat
- Breast milk
- Important during lactation as it can transfer drug metabolites to the baby.
- Low molecular weight and lipophilic drugs can easily pass through to the milk, but the amount that reaches the maternal milk is usually low.
Kidney Excretion
- Responsible for water-soluble compounds.
- Total kidney excretion = (Glomerular filtration + Active tubular secretion) - (Tubular re-absorption)
- Glomerular filtration of unbound drug.
- Tubular re-absorption of lipophilic and non-ionized drugs by passive diffusion.
- Affected by pH modifications.
- Basic drugs are more ionized and less re-absorbed in acidic urine.
- Acidic drugs are more ionized and less re-absorbed in alkaline urine.
- Active secretion of free and protein-bound drug by transporters.
Excretion Kinetics
- Important pharmacokinetic parameters to consider:
- Bioavailability (F)
- Volume of distribution (V)
- Clearance (CL)
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Description
Explore the critical differences between Phase I and Phase II enzyme reactions in drug metabolism. Understand how these phases affect hydrophilicity and the implications for drug interactions and metabolism inhibition, including the unique case of grapefruit juice. Test your knowledge on these essential biochemical processes.