FUN Quiz 4 Flashcards
What are the two types or modes of metabolism?
Catabolic reactions
Anabolic reactions
Briefly describe the two modes of metabolism
Catabolic reactions involve the breakdown of organic matter, ultimately to produce energy by cellular respiration
Anabolic reactions involve the synthesis of complex compounds essential for life but consume energy
What are the 3 steps of anabolism?
- Forming Precursors
- Form complex molecules from simple precursors
- Linking of complex molecules
Examples include proteins, RNA/DNA, lipids, and carbs
What are the 3 steps of catabolism?
- Hydrolysis of complex molecules into monomers
- Conversion of monomers into acetyl CoA
- Oxidation of acetyl CoA followed by oxidative phosphorylation
What are the energy sources of metabolism and where do they come from?
ATP, NADH, NADPH, FADH2
They come from catabolic reactions
How does ATP release energy
Cleavage of ATP into ADP
Describe how the change in free energy predicts whether a reaction is favorable or not
If G is positive => unfavorable => endergonic
If G is negative => favorable => exergonic
What is the first step in glucose metabolism? Is it endergonic or exergonic?
Glucose + ATP -> Glucose-6-Phosphate + ADP
Enzyme used is Glucokinase/Hexokinase
Exergonic
What are the main coenzymes in cellular respiration?
NAD+ and FAD
Differentiate between oxidation and reduction
Oxidation is the gain of oxygen or the loss of electrons or H+
Reduction is the loss of oxygen or the loss of electrons or H+
What is the final electron acceptor in cellular respiration?
O2
What is the role of O2 in the electron transport chain
It is the final acceptor of electrons. NADH and FADH2 are reoxidized.
The TCA cycle is amphibolic. Define Amphibolic
Involved in anabolic and catabolic pathways
Define Gluconeogenesis
Synthesis of glucose from non-carbohydrate precursors.
What are the mechanisms of regulating energy metabolism? Give examples
- Feedback inhibition: NADH can inhibit enzymes involved in it’s production and NAD+ can stimulate
- Phosphorylation/dephosphorylation: Hormones such as insulin and glucagon
- Availability of substrates: Availability of oxaloacetate regulates citrate synthase activity.
- Oxygen availability: Hypoxia - Failure of oxidative phosphorylation
Briefly explain inborn Errors of Metabolism and their consequences
A mutation in a gene can cause the formation of a defective protein with impaired function causing disease/disorder.
In addition to that, these errors can form an alternative product. This would cause:
- Accumulation of substrate
- Deficiency of product
- Diversion to alternate product
How does glucose enter the cell? Describe the energy consumption or lack there of when glucose is transported into the cell
Glucose is carried into cells by one of two active transport mechanisms:
- Facilitated diffusion through GLUT transport proteins in cell membranes
- Na+-dependent co-transport: SGLT
What is meant by the iOS forms of GLUT transport?
GLUT transporters are tissue specific.
Once glucose is in the cell, how is it prevented from leaving?
Once inside, glucose is trapped by phosphorylation converting it to glucose-6-phosphate
Phosphorylation in the first step of glycolysis is carried out by which enzyme(s)?
Hexokinase and Glucokinase
Differentiate between Hexokinase and Glucokinase and describe their regulation
Hexokinase is present in most cells types. Hexokinase has a low Km => high affinity for glucose even at low concentrations as well as a low Vmax => limited capacity. It is regulated allosterically by its product (Glucose-6-P) which inhibits it
Glucokinase is present in liver parenchyma cells and pancreatic islet cells. Glucokinase has a high Km => only kicks in at high glucose concentrations as well as a high Vmax => high capacity allowing it to handle high glucose levels occurring after digesting food. Glucokinase also helps Beta-cells in the pancreas to sense rising glucose concentrations leading to insulin release and allows the liver to break down the high concentration of glucose in the portal circulation after a meal. It is regulated by it’s substrate, glucose, as well as being inhibited by glucose-6-phosphate (it’s product)
What is the end product of glycolysis?
2x Pyruvate, 2 NADH, 4 ATP (2 net)
How much ATP is produced as a result of glycolysis and how much ATP is required for glycolysis to take place?
4 ATP is produced and 2 is required for it to take place
What is the rate-limiting step in glycolysis?
Phosphofructokinase 1 is the rate-limiting step
How is the process of glycolysis regulated?
- Feedback and allosteric inhibition of enzymes: PFK1 (phosphofructokinase 1) is inhibited by ATP; Glucokinase is inhibited by fructose-6-Phosphate
- Hormonal regulation: Insulin and Glucagon control PFK 2 activity
What is more efficient; Aerobic or anaerobic metabolism? Why?
Aerobic metabolism is more efficient as it produced much more ATP
What are the two ways that ATP is produced?
- Directly through substrate-level phosphorylation (glycolysis)
- Indirectly through oxidative phosphorylation (electron transport chain)
How much NET ATP is produced from:
- Glycolysis
- 1 NADH+H+
- 1 FADH2
- Aerobic Respiration
- Anaerobic Respiration
2 3 2 38 2
What are the products of glycolysis in aerobic and anaerobic glycolysis?
Aerobic: 2 Pyruvate, 2 ATP, 2 NADH
Anaerobic: 2 Pyruvate, 2 ATP
Why does Anaerobic glycolysis not form any NADH?
Anaerobic glycolysis does not undergo oxidative phosphorylation and hence the NAD+ is regenerated at the end of glycolysis
Do humans perform anaerobic respiration? Is it normal? What are the consequences?
Yes
Yes
Lactic acid accumulation occurs during vigorous and extended exercise. Excessive buildup can cause lactic acidosis which can cause several CVDs (Cardiovascular diseases)
Where do the following occur?
- Glycolysis
- TCA cycle
- Link Reaction
- ETC (electron transport chain)
Cytoplasm
Matrix (Mitochondria)
Matrix (Mitochondria)
Cristae
The mitochondrial membrane is impermeable to charged molecules. How does pyruvate enter the mitochondria?
Pyruvate Dehydrogenase is a specific Pyruvate Transporter that exists in the inner mitochondrial membrane.
Describe the link reaction. Is it reversible or irreversible?
Occurs in the matrix. Pyruvate Dehydrogenase Complex is a multi-enzyme complex that converts pyruvate into Acetyl-CoA:
Pyruvate + NAD+ + CoA -> Acetyl CoA + NADH + CO2
It is an irreversible reaction
Is it possible to form glucose from Acetyl CoA
Nope lmao
What are the metabolic fates of Pyruvate?
- Conversion to Acetyl-CoA which can either enter the TCA cycle or serve as a precursor for Fatty-acid Synthesis
- Conversion to Oxaloacetate which can enter the TCA cycle or serve as a precursor for Gluconeogenesis
- Reduction to Ethanol (No need to include)
Give 2 Clinical problems associated with Pyruvate Dehydrogenase
- Pyruvate Dehydrogenase Deficiency: Pyruvate converted to lactic acid instead of Acetyl-CoA due to a genetic defect
- Arsenic Poisoning: Inhibits pyruvate dehydrogenase
- Vitamin Deficiencies: Deficiency in vitamins B1,2,3, and/or 5 will impair pyruvate dehydrogenase function
Describe the drug discovery process
Conduct the basic and relevant research for the drug
Customize and synthesize the drug
Screen the drug for it’s efficacy, toxicity, and in vivo efficacy
Explain how diseases are characterized
Diseases are characterized based on how it defines the target disease
Identify commercial factors involved in drug development
Market research is involved in drug development as pharmaceutical companies are for-profit businesses which focus on getting enough market support
What are orphan drugs
A pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance
Distinguish between hit compounds, lead compounds, and candidate compounds
Hit compound: A compound from high-throughput screen with activity on the target
Lead Compound: The most promising hit compound selected for further work. Derivatives of these compounds can be screened to be optimized
Candidate compound: Best compound selected for clinical development
Define QALY
QALY is a key pharmacoeconomic measure but not the only one
1 QALY is a year of life with perfect health
What is pharmacoeconomics mainly focused on?
Pharmacoeconomics looks at the value of pharmaceuticals and total cost
Define Drug Toxicity
A drug where it’s specific target produces toxic effects
What are unwanted effects for OPIATES and ANTI-HISTAMINES?
When using opiates to treat pain, constipation is an unwanted effect
When using anti-histamines to treat allergies, drowsiness is an unwanted effect
Explain the difference in detecting predictable/pharmacological adverse effects vs. unpredictable/non-pharmacological adverse effects?
Predictable: These effects occur when you see excessive pharmacological action, which is seen with a class of drugs
Unpredictable: These effects are seen with only a specific member of a drug class
Explain how idiosyncratic/dose-independent adverse effects are shown
These effects will only be shown in drugs that are dose-dependent and can be immunological. These effects can occur due to polymorphism
Give 1 example of a drug that expresses the following effects:
- Predictable/pharmacological adverse effects
- Un-predicatable/nonpharmacological adverse effects
- Idiosyncratic/dose-independent effects
- Thalidomide
- Diethylstilbestrol or paracetamol
- Coumarin
Give 4 types of drugs that show predictable adverse effects
Antibiotics
Anticoagulants
Opioid Analgesia
Insulin
What are the main sources of adverse drug effects?
- Active pharmaceutical ingredients (toxicity is due to metabolites and species-specific effect)
- Contaminants
- Excipients
Why does coumarin produce dose-independent effects in rats?
Toxicity is dose dependent and coumarin is shown to produce high levels of hepatotoxicity in rats
Define Pharmacovigilance
This occurs when patients undergoing treatment provide a large source of information on adverse effects
Explain contaminants and how its effects degrade over time
Contaminants are very pure forms of active pharmaceutical ingredients that may be produced by by-products from drug synthesis. This causes it to degrade based on storage condition which has two major effects:
- Reduced dose of API
- Increased presence of toxic by-products
Define Bioequivalence
Absence of significant difference in the rate and extend to which the active ingredient or moiety in pharmaceutical equivalents or alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study
How is bioequivalence measured?
Measured by comparing Cmax and AUC between two products
Explain the concept of risk management plans. Give one example of a drug being used in the plan?
Risk management plans are used to allow the use of a drug but reduce the risk of an adverse effect
- Natalizumab
- Thalidomide
Explain the types of studies used in Preclinical, Clinical, and Post-market Study Designs
Preclinical: Discovery followed by preclinical studies are used. The patent is then granted to allow the investigation of new drugs
Clinical: Phase 1-4 are included. New drug applications are assessed in phase 4
Post Market: Post market studies are conducted. When the patent expires, generics are branded
Describe the drug discovery process:
Basic research is conducted, followed by customizing and synthesizing the drugs. It is then screened for its efficacy, toxicity, and in vivo efficacy
Explain how diseases are characterized
Diseases are characterized based on how it defines the target disease
Identify commercial factors involved in drug development
Market research is involved in drug development because pharmaceutical companies are for-profit businesses and focus on getting enough market support
What are the stages in clinical development?
Phases 0-IV
How are the stages of clinical development classified in the design of clinical studies?
The phases are classified by function
In Phase 0 studies, describe the doses used, the sample size, and its importance in clinical studies
The doses used has no biological effect. There are a small number of volunteers. Phase 0 studies are used to assess pharmacokinetics/pharmacodynamics and is used to identify potential candidates for clinical development
What’s another name for Phase 0 studies?
Microdosing studies
When Identifying volunteers for Phase 1 studies, what are the requirements?
Healthy male volunteers
Why are females not included in phase 1 studies?
Females can’t take part because they need to undergo developmental toxicology studies first
What is measured and assessed in Phase 1 studies?
Tolerability through measuring drug concentrations. The results from this can assess pharmacokinetics, pharmacodynamics, metabolism, and potency
What type of patients are recruited for Phase 2 studies?
Patients with the appropriate disease, all gender, generally older population
Differentiate between the two types of Phase 2 studies
Phase 2a repeats much of phase 1
Phase 2b monitors the surrogate endpoint (measure of effect of specific treatment that correlates to a clinical endpoint), where the estimate dose is required
What is a surrogate endpoint? Where is it used in clinical studies?
It is a measure of the effect of a specific treatment that correlated to a clinical endpoint. Used in phase 2b
In phase 3 studies, describe its function and sample size. What can be concluded from Phase 3?
Therapeutic confirmation is the main focus of Phase 3 studies. Large patient populations are assessed.
Phase 3 establishes efficacy, safety, the dose-response relationship, and the benefit-risk relationship
What kinds of studies are used in Phase 3 studies?
Pivotal studies
Explain the function and conclusions that are drawn from phase 4 studies
Function: Determine therapeutic use of drugs and studies approved drugs
Conclusions after approval: Refine benefit/risk, pharmoeconomics, adverse effects (i.e. low incidence, long term use)
What are the different types of names drugs can have?
Chemical name, drug name, brand name, generic names, trade names
What are the two trade names for the drug Sildenafil?
Viagra and Revatio
Define drug distribution
Drug distribution is the process by which a drug reversible leaves the blood stream and enters the extracellular fluid and/or cells of the tissue (intracellular fluid)
Define Volume of Distribution Vd, what it indicates, and what it determines
Definition: Theoretical volume of fluid a drug would occupy if the total amount of drug in the body was in solution at the same concentration as in the plasma.
Indication: Measure of the extent of distribution of a drug from plasma into tissues
Determines:
- The relationship between plasma concentration and total amount of drug in the body
- The amount of a drug that has to be administered in order to produce a particular plasma concentration
Define Loading Dose and give it’s function or use case
Loading dose is a high dose a drug given to reach therapeutic levels faster
Compare the clinical usefulness of Vd for:
Large Vd drug
Low Vd drug
Vd reflects the size of distribution space. A large Vd indicated that we will need a higher dose to load and a small Vd needs a lower dose to load.
How is the loading dose calculated?
LD = Vd x Desired plasma concentration
What are the 2 processes the body uses for drug elimination?
Metabolism and Excretion
In Drug elimination, metabolism usually converts ___ into ___
Lipid soluble chemical
Water soluble species
Drug Metabolism primarily occurs in the _____ and involves two types which are ______ that deals with the ____, ____, and ____ of drugs as well as ____ which involved ____
Liver Phase 1 Oxidation Reduction Hydrolysis Phase 2 Conjugation
Outline the types of excretion that the body utilizes for eliminating drugs
- Renal: Fluids (Urine, sweat, tears, milk)
- Biliary/Gastrointestinal: Solids (Feces, hair)
- Pulmonary: Gases (Expired air)
- Mammary
- Salivary, Skin, and Hair
Can excretion of an already metabolized drug occur?
Yes
What are the 3 renal processes accounting for renal drug excretion?
Glomerular filtration
Active tubular secretion
Reabsorption
What is the main importance of Urinary/Renal Excretion
Elimination of low molecular weight polar substances
What is the main function of glomerular filtration
Only allows molecules under 20 kDa to enter the filtrate in the nephron
Why can’t protein-bound drugs not enter the filtrate?
Many drugs bind to plasma proteins while circulating which increase their molecular weight hence preventing them from entering the filtrate of the nephron
Explain the process of Urinary Excretion
Urinary excretion is crucial for low molecular weight polar substances. It involves 3 main processes:
1. Glomerular Filtration: Filters molecules in the blood only allowing for molecules less than 20 kDa to enter the filtrate of the nephron. Protein bound drugs are not filtered in.
- Tubular secretion: Active carrier mediated elimination involving secretory mechanisms for both acidic and basic compounds against their concentration gradient
- Reabsorption: Passive re-absorption of lipid-soluble un-ionized drug.
Lipid soluble drugs are more likely to be reabsorbed and hence last longer in the body whereas water-soluble drugs are more likely to be excreted in urine.
How are lipid-soluble, ionized, and high molecular weight drugs excreted?
Biliary/Gastrointestinal Excretion
Explain the process of Biliary Excretion and the concept of Entero-hepatic Circulation
Hepatocytes in the liver uptake lipid-soluble drugs, metabolize them, and excrete them into bile. This process does not sufficiently excrete the drug as it is then reabsorbed through the Entero-hepatic Circulation once the drug is released into the intestine through the bile duct. Here, drug conjugates are Hydrolyzed mainly by bacteria in the lower intestine. This causes the active drug to be released once more.
What is the most signification route of excretion for Glucoronide Conjugated
Bile Excretion
Briefly explain Pulmonary Excretion of drugs
Excretion occurs via the lungs and breath. It is a significant route for some volatile molecules such as anesthetics and ethanol
Compare concentration of molecules in breast milk to that off free concentration in maternal blood
Concentration in milk is similar to the free concentration in maternal blood
What is the clinical relevance for the effect of a drug on a breast-feeding baby? Give one example
Babies should not be exposed to the same levels as mother and hence the drugs the mother takes should be at a safe concentration for the baby.
Tetracyclines for example when incorporated into the baby’s teeth will weaken them
Most drugs are eliminated through which order process
First
Compare and contrast First order and zero order kinetics giving one example for each
First order elimination is where the amount of drug eliminated is directly proportional to the serum (blood plasma) concentration. The fraction of the drug eliminated and not the amount of the drug eliminated is constant. Example: Glomerular Function
Zero Order Kinetics: Elimination occurs at a fixed maximum rate that is independent of drug concentration. Example: metabolism of ethanol and protein mediated reaction
What is meant by the half life and which order of elimination kinetics does it follow?
The half life is the time for plasma concentration of a drug to fall by 50%. It follows the 1st order elimination kinetics
What is the plasma half-life determined by?
- Activity of metabolizing enzymes or excretion mechanism clearance
- Distribution of drug between blood into tissues => High Vd (drugs mainly located in tissue) results in prolonged half life
What is the general rule for Plasma Half life when administering surgery?
4 or 5 half lives
Briefly explain what is meant by Steady-State of a drug as well as it’s aim
With infusion and first order elimination, at a certain point in therapy, the amount of drug administered during a dosing interval exactly replaces the amount of drug excreted.
When this equilibrium occurs, (rate in = rate out), steady state is achieved
The aim is to maintain the steady-state concentration of a drug within therapeutic range