week 19 p1 Flashcards
- Stages of drugs in the body
• Absorption, distribution, metabolism and excretion
Define drug metabolism
• Chemical alternation of a drug by the body
• Metabolism consists of anabolism and catabolism
Ie build up and breakdown of substances by enzymatic conversion of one chemical entry to another
- What is the primary objective of drug metabolism
• Facility a drug excretion by increasing water solubility (hydrophilicity)
- What issues does drug metabolism cause
• Metabolism decreases he pharmacological activity of the drug \but also some causes metabolism to increase
- What is a prodrug
- Inactive [precursors that are metabolised to active metabolites
- Inactive competent that is active in the later stage of another drug
E.g of prodrugs
- beclomethasone dipropionate à beclomethasone nonproportionate
- Diacetyl morphine (heroin) is a prodrug that penetrates the bbb even faster than its active metabolites which is morphine
- Another one is beclomethasone dipropionate used for asthma ( shown in the diagram)
Advantage of prodrugs
• Improves the digestive of metabolism and excretion
- What kind of issues can be solved by using prodrugs
• Instability of drugs in the gastric pH
• Failure for the drug to cross bbb
Prevent direct gastric irritation
- Where does metabolism take place\
- Mostly in the liver, but every biological, tissue has some abilities to metabolise drugs
- Such as kidneys, skins, epithelial cells of GT
- Why is the liver mostly metabolising drugs
- Largest organ
- First organ that perfused by chemicals absorbed in the gut
- Has high concentration of most drug metabolised enzymes such as CYPs
- What does first metabolism mean (Also known as pre systemic metabolism
• Fraction od the drug that is lost during there process of absorption which is related to the liver and gut wall
• Reduces bioavailable too
• Mostly occurs in liver but can occur in lungs.GT etc
The concentration of the drug administrated is reduced before irt reaches there systemic circulation
- What factors effect first pass mechanism
• Enzymatic activity • Plasma concentration • Gastrointestinal motility • Repair enzymes • Bacterial enzymes Gut wall enzymes
- How does first pass metabolism occur
- After injection of a drug
- The drug is absorbed in the digestive system,
- And enter hepatic portal system
- The drug is carries through he portal vein into the liver then reach to the rest of the body
- What is the role of gut microbiome in pharmacology
• Action of the gut microbiome effect on the drug metabolism is an recent discover
we aim to integrate the contribution of the gut microbiome in health and disease to xenobiotic metabolism focusing on therapeutic interventions, pharmacological drug action, and chemical biotransformation’s that collectively will have implications for the future practice of precision medicine
• Traditionally, clinical studies evaluating the pharmacokinetics of new drugs have mostly ignored the important direct and indirect effects of the gut microbiome on drug metabolism and efficacy
• The significance of both microbial metabolism of xenobiotics and the impact of the gut microbiome on host hepatic enzyme systems is nonetheless gaining traction and presents a further challenge in drug discovery efforts, with implications for improving treatment outcomes or counteracting adverse drug reactions.
- What Is first pass metabolism important
• If the drug is severely effected by FPM , it will not be able to reach concentration
• in the plasma high enough to promote its threptic effect
Less amount of drug reaches to rhe liver then the heptal vein
• This means alternative routes need to investigated for drugs such as rectal s, sublingual( under tongue)
- An example of drug that causes FPM levels
- Remdesivi cannot be given orally because the entire does would be trapped in the liver
- Little will then reach the systemic circulation
- It requires IV infusion by passing the portal vein
- However herpetic extraction is required in the second pass metabolism
- Whereby a fraction of venous blood travels thought hepatic portal vein an hepacytes
- Describe the two ways of drug metabolism pathways
• reactions are catabolic and products are more chemically reactive thus toxic
• Phase one reaction is with reactive group e.g. hydroxyl
• This combination is known as functionalisation
• Liver is important for this phase hepatic drugs metabolises eg CYP
• Drugs must cross there plasma concentration
Passes through
- Describe the two ways of drug metabolism pathways
- reactions are catabolic and products are more chemically reactive thus toxic
- Phase one reaction is with reactive group e.g. hydroxyl
- This combination is known as functionalisation
- Liver is important for this phase hepatic drugs metabolises eg CYP
- Drugs must cross there plasma concentration
- Passes through
- What is included in phase one of drug metabolism
• Hydrolytic reaction
• Oxidation
Reduction
- What is included in phase 2 for drug metabolism
• Sulphate conjugation
• Glucuronic acid conjugation
Methylation
- What is the differences in phase one and phase two in drug metabolism
Phase I • Functionalisation phase • Involves only the metabolised molecule • Can either activate or deactivate drugs Reactions usually convert the parent drug to a more polar metabolite via the formation of — OH, -NH2, or —SH groups • Modifications may facilitate Phase Slide 17 of 31 Il reactions Notes Comments Phase Il • Conjugation phase Involves the formation of a covalent bond with a second endogenous molecule Almost invariably inactivate drugs The most frequent reactions are conjugation with glucuronic acid (glucuronidation) Drugs can be also conjugated with lutathione or glycine, or modified y the transfer of methyl, acetyl, or sulpha groups from donor compounds 93%
- What is the enzymes that are involve sin drug metabolism
• Cytochrome P450 (CYP) enzymes are considered the major enzyme family that catalyses oxidative niotranformation (phase 1 metabolises) of most drugs
• CYP enzymes bind to membrane within the cell (cyto)
• Contain heme pigmentation (chrome and p)
That absorbs light at wavelength of 450m when exposed to carbon dioxide
Where is CYPs located
• Are associated proteins located in the inner membrane
or endoplasmic reticulum of cells
- What is the role and function of CYPs
- Metabolises thousands of endogenous and exogenous chemicals
- Some CYPs metabolises one or more substrates such as CYP19
- Most common reaction catalysed by CYPs is a monooxygenase reaction
- What is the reaction for CYPs
- Most common reaction catalysed by CYPs is a monooxygenase reactions
- Requires drug,P450 enzyme, molecular oxygen, NADPH and NADPH-P450 reductase
- Outcome is one atom of o2 to the drug that hydroxylated product
- The other atom of oz ic converted yo h20
- RH + O2 + NADPH + H+ → ROH + H2O + NADP+
- What is the importance of CYP450s
- enzymes can be induced or inhibited by many drugs
- and substances resulting in drug interactions where one drug affect the metabolism (and hence the PK profile) of the other
- What is non CYP in metabolism
- Approximately one third of the top 200 prescribed drugs which undergo drug metabolism are substrates for enzymes other than CYPs.
- The most prevalent are UDP-glucuronosyl transferases and esterases accounting for approximately 8% and 5% of the metabolised drugs respectively.
- What are the pathways involed in non-cyps
- flavin monooxygenases (FMO)
- monoamine oxidases (MAO)
- aldehyde oxidases (AO)
- aldehyde dehydrogenases (ALDH)
- aldo-keto reductases (AKR)
- alcohol dehydrogenases (ADH)
- hydroxysteroid dehydrogenases (HSD)
- sulphotransferases (SULT)
- How can Cyps lead to inter-indivdual varriable in drug metabolism
- Genetic mutations play an important role in determining the variable enzyme activity observed for many CYPs at population level.
- Genetic polymorphism is defined as a stable variation in a given locus of the genetic sequence, which is detected in 1% or more of a specific population.
- common genetic mutation in human CYP genes
• is single-nucleotide polymorphisms (SNPs).
