bm213 block E

Question 1

what is pharmacokinetics and a description of its 4 stages

Answer 1

the OBSERVED journey of a drug through the body, split into 4 different stages abbreviated as ADME: absorption, distribution, metabolism, excretion

-absorption: observes how a drug travels from site of administration to site of action
-distribution: observes the passage of a drug through the bloodstream to different tissues in the body
-metabolism: observes the activity that breaks down a drug
-excretion: observes the elimination of a drug from the body

Question 2

what is the importance of pharmacokinetics

Answer 2

to understand how drugs act in the scope of an entire organism instead of in vitro or ex vivo isolated tissue. this is important to gauge dosage, timescale and side effects

Question 3

what is the difference between pharmacokinetics and pharmacodynamics

Answer 3

-pharmacokinetics focuses on what the body does to the drug
-pharmacodynamics focuses on what the drug does to the body

Question 4

what is measured to give readings for pharmacokinetics

Answer 4

typically blood/plasma concentrations as they are easy to access.
an equilibrium with plasma concentration and receptor concentration is used

Question 5

what does a typical PK (pharmacokinetic) profile look like? (graph)

Answer 5

2 curves, one that peaks almost immedietly and at high plasma concentration before lowering over time (intravenous administration) and another curve that starts at 0 and goes up over time before peaking at lower values then intravenous administration and very slowly going down in concentration over time

Question 6

how is PK analysed from a graph?

Answer 6

PK is based on analysis of drug concentration
after one or more doses the drug concentration in the desired matrix is measured.

Question 7

what is the pharmacological respose graph look like for vivo and vitro studies?

Answer 7

in vitro: LOG concentration response curve
in vivo: kind of just the same really.
potency is measured by the ED50 value and where the log dose and effect meet on the log curve.
the maximal effect is correlated to its efficacy

Question 8

what is the therapeutic window?

Answer 8

the area of a graph between the sub-therapeutic and adverse response, with minimised risk and maximised action, a good dose should contain the peak of the effect within the therapuetic window to ensure action and lessen risk
this can look like standard response curve with boundries above and below representing the endges of the window or a TAN graph with the desired therepeutic effect dose curve and unwanted side-effect/toxicity curve side by side, in the latter case the X axis distence between the point both curves reah 50% is the boundries of the therepeutic window, being wider or narrower depending on the distence between them.

Question 9

what is ED50 and TD50

Answer 9

effective dose 50, the dose required to achieve 50% of the disired response in 50% of the population
toxic dose 50 is the media toxic dose of a substance at which toxicity occurs in 50% of cases

Question 10

what are the 3 differet scales a drug’s site of action can be defined at

Answer 10

-anatomical: the compartment the drug has to reach, e.g tissues
-cellular: the cell type the drug has to reach
-molecular: the molecular target to which the drug needs to bind e.g cell surface receptor, intracellular component

Question 11

what are 4 examples of DOACs and their purpose? (and lowkey what is a DOAC)

Answer 11

-DOAC stands for Direct Oral AntiCoagulants
-examples include: apixaban, dabigatran, edoxaban, rivaroxaban
-DOACs are small molecules that can occupy the catalytic site of either FXa or thrombin preventing their ability to cleave and activate their substrates.
-DOACs target the central plasma compartment

Question 12

what receptor does caffeine target and how does it work?

Answer 12

-caffeine targets adenosine receptors
-adenosine A2A reeceptor is mainly present in the heart, brain, lungs, and spleen
-the adenosine A2B receptor has a major distribution in the large intestines and bladder
-the adenosine A3 receptor is present in lungs, liver, brain, BALLS, and heart
-by blocking these receptors, caffeine prevents the neurotransmitter responsible for drowsiness from eliciting an effect, increasing alertness, stimulating stomach acid production, acts as a vascoconstrictor increasing BP and BPM as well as stimulating urine release. cafeine makes you piss harder

Question 13

what is temozolomide

Answer 13

a drug that targets the DNA of brain tumour cells

Question 14

what must be taken into account when gethering PK data of a drug?`11

Answer 14

majority of PK data gained from biological fluids that are good surrogates for systemic drug exposure and are easily accessable such as blood and urine.

THE MAAIIINNN thing to focus on is how deeply the level of interaction is between the monitored compartment (the urine sample) and the drug’s site of action

Question 15

what are the 2 ways a drug is distributed around the body>

Answer 15

-via blood or lymphatic system (perfusion of tissues dictates blood flow (thats fancy talk for they can only move as far as the tubes go and wherever they lead them, hard to reach tissue with low bloodflow or lack of veins) )

-permeability across membranes (permeability is related to the chemistry of the drug as certain structures and sized molecules can pass through easier or harder depending on structure)

Question 16

what 3 biological barriers exist for drugs to cross to reach their target site

Answer 16

-gastrointestinal mucosa (for all orally administered drugs)
-blood brain barrier (real one)
-placenta

Question 17

what influnces the volume of distribution of a drug

Answer 17

the number and nature of biological barriers, carrier mediated transporters at these membranes mediate transport of certain drugs, making it important to understand distribution pathways as well as potential for drug-drug interactions

Question 18

what is the implicit relationship between dose and volume?

Answer 18

higher the volume, lower the concentration, in smaller organisms a lower dose is needed to achive the same effect, for example: propanolol is an anxiety medication in humans and can cause death of L. variegatus worms by far lower concentrations

Question 19

what is the formula for concentration regarding dose and volume

Answer 19

concentration = dose/volume

Question 20

what are the 6 different types of drug molecules that spread throough body compartments differently? from most restricted to least (roughly)

Answer 20

-large molecules stay mainly in plasma witha very small Vd (volume of distribution
-drugs with a volume of distribution at 0.04 L/kg or less are thought to be confined to plasma
-hydrophilic or highly polar small molecule drugs like penicillins distribute into the extracellular fluid (ECF) and have a relitively small Vd
-highly lipid soluble drugs such as tricyclic antidepressants distribute far more widely into tissues and have a large Vd
-drugs with a Vd larger then 0.6 L/kg are thought to be distributed to all tissues in the body, especially the fatty tissue
-some drugs have Vd values greater then 10,000, meaning most of the drug is in tissue with very little remaining in the plasma circulating

Question 21

what are the 6 factors affecting volume of distribution

Answer 21

-molecular size
-lipid solubility
-ionisation
-binding to plasma proteins
-rate of blood flow
-special barriers (blood brain barrier)

Question 22

what are the 4 body fluid compartments

Answer 22

-circulation (plasma)
-intersitial (extracellular) fluid
-intracellular fluid
-intracellular fat

Question 23

what is the % plasma protein binding, lipid solubility/tissue binding, and volume (L/kg) of aspirin, ibuprofen

Answer 23

-aspirin: 80-95% plasma protein binding; low lipid solubility/tissue binding; 0.10 L/kg volume of distribution

-ibuprofen: 99% plasma protein binding; high lipid solubility; 0.15 L/kg volume of distribution

Question 24

what are the two types of human body PK model ad the differences between them

Answer 24

One-compartment models treat the body as a single, rapidly equilibrating unit, assuming instantaneous drug distribution and monoexponential, first-order elimination.

two-compartment models differentiate a highly perfused central compartment (blood/organs) from a slowly equilibrating peripheral compartment (fat/muscle), modeling distribution and elimination phases separately for greater accuracy

Question 25

what specific compartment of the body does tetracycline, amiodarone and chloroquine

Answer 25

-tetracyclin accumulates in bones and teeth with a high affinity for calcium, in high amounts can lead to tooth discolouration -amiodarone can accumulate in the liver and lungs causing causing hepatitis and intersitial pulmonary fibrosis -chloroquine has a high affinity for melanin and can accumulate in the retina and lead to ocular toxicity

Question 26

what % of blood circulation makes it to body fat?

Answer 26

<2%

Question 26

what unique issues arise from partitioning of drugs into body fat

Answer 26

blood circulation to fat is low, around <2% meaning drugs that travel via the bloodstream have difficulties reaching body fat certain drugs can accumulate in body fat such as benzodiazepines and some insecticides since body fat acts as a large source of body mass, obese patients can have far different required dosage to make up for the extra volume presented by their fat. fatty.

Question 27

what types of drugs commonly need dose adjustments in obese patients?

Answer 27

-low molecular weight heparins -aminoglycoside antibiotics -some anaesthetics -monoclonal antibodies -chemotherapeutics

Question 28

what are the 2 ways drugs are transported through the bloodstream

Answer 28

-as free unbound drug -partly reversibly bound to blood components (plasma proteins and blood cells

Question 29

what transportation method do acidic and basic drugs mainly use in the bloodstream

Answer 29

acidic drugs are often bound to albumin basic drugs are often bound more extensively to alpha-1 acid glycoprotein, lipoproteins or both

Question 30

what importance does unbound drug have in the bloodstream

Answer 30

only unbound drug is able to undergo passive diffusion to extravascular or tissue sites where the pharmalogical effects of drug occur this leads the unbound drug concentration to be strongly linked to drug concentration at active site and thus efficacy

Question 31

what is the importance of volume of distribution comparing low Vd (5-10L) and high Vd (50-200L)

Answer 31

the body acts as a reservoir for the drug slowly delivering it to the organs of elimination (liver and kidney) high doses of drugs leads to longer T1/2 and overall drug action with concentration decreasing slower as the body cannot dispel it all at once as it can with regular doses since it has a limited amount of ccatabolic enzymes

Question 31

what is drug elimination and what are the main routes

Answer 31

drug elimination is loss of drug from the body with main routes of the liver and kidneys

Question 32

what is excretion

Answer 32

elimination form the body

Question 32

what is metabolism

Answer 32

conversion of a chemical entity

Question 33

what are 9 different routes of drug excretion

Answer 33

excretion via: -hair -sweat -tears -faeces -bile (liver) -sweat -breath -urine (kidneys) -breast milk

Question 34

what is the mass balance clinical study and its 3 main goals

Answer 34

a study done with the goal of understanding how drugs are absorbed, metabolised, and excreted after dosing. this was done by collecting urine and faeces -to determine mass balance of drug-related material following dose administration -to determine the ratio of parent drug to metabolite(s) in circulation -to determine the primary route of excretion of drug related material

Question 35

what are the two phases of metabolism

Answer 35

phase 1 reactions introduce a reactive group into the molecule phase 2 reactions allow conjugation to the molecule making it hydrophilic and suitable for elimination via the kidney

Question 36

what are the 4 routes for phase 1 drug metabolism and the examples of each (with one route being simply just how most drugs are metabolised)

Answer 36

-parent drug molecule turned to an inactive drug metabolite (route for most drugs) -inactive pro-drug molecule turned to an active drug metabolite (route for codeine, clopidogrel, enalapril) -parent drug molecule turned to active drug metabolite (route for diamorphine, phenacetin) -parent drug molecule turned to TOXIC drug metabolite (route for paracetamol and methanol with some drugs entering as a pro-drug and rely on metabolism to turn it into an active agent

Question 37

what % of drug metabolism pccurs in the liver? what issues does liver disease present for drug metabolism

Answer 37

70-80% of all drugs in clinical use are metabolised in the liver liver disease reduces CYP450 activity in complex and unpredictable ways thus drugs metabolised in the liver should be used with caution

Question 37

what is CYP450 and its relivence to metabolism and drug-drug interactions

Answer 37

CYP450 is a super family of enzymes that are mostly distinct but with overlapping features, typically involved in phase 1 oxidation, reduction and hydrolysis reactions within the liver drug-drug interactions can lead to inhibition or induction of CYP450 leading to undesired clinical effects

Question 38

what is CYP3A4, its importance and common drug-drug interactions that involve it

Answer 38

CYP3A4 is considered the most important drug-metabolising enzyme given its fairly high expression in liver and intestines. there is a high interindividual variability of hepatic CYP3A4 with up to 90% expression difference between individuals. CYP3A4 makes up 15-20% of hepatic CYP content in the liver clarithromycin/erythromycin and simvastatinn results in myopathy or rhabdomyolysis diltiazem/verapamil and prednisone results in immunosuppression caused by increased predniaolone levels AND GRAPEFRUIT FUCKING GRAPEFRUIT CAUSES SEVERE ADVERSE EFFECTS WITH 44 MEDICINES BY BEING A POTENT INHIBITOR OF INTESTINAL CYP3A4

Question 39

what is the purpose of phase 2 drug metabolism

Answer 39

to prepare drug metabolite for excretion by the kidneys as either urine or bile, done by conjugation some drugs are sufficently water soluble allowing immediate excretion via kidney

Question 40

what is first pass metabolism and 4 examples of drugs that undergo first pass metabolism

Answer 40

when drugs are taken orally they enter the intestinal blood stream which goes via the liver before reaching general circulation, this can result in extensive metabolism before any drug reaches site of action -drugs that undergo extensive first pass metabolism: -aspirin -lidocaine -morphine -propanolol

Question 41

what is hepatic extraction ratio and its formula

Answer 41

the fraction of the drug entering the liver in the blood which is irreversably removed during one pass through the liver (amount lost to first pass metabolism) - extraction ratio = (amount in - amount out)/amount in

Question 41

what is bioavalibility

Answer 41

the proportion of a drug that enters circulation when introduced into body

Question 42

what is the gut walls role in drug metabolism and 3 examples of drugs that the intestines contribute to the metabolism of

Answer 42

despite having <1% of P enzymes in the liver it contributes significently in metabolism of several drugs: -cyclosporine -midazolam -verapamil

Question 43

what is renal excretion

Answer 43

the primary mechanism for eliminating water-soluble drugs, metabolites, and metabolic waste from the body via urine, heavily influencing drug dosage and toxicity. It involves three key processes within the nephron: filtration at the glomerulus, active secretion in the tubules, and passive reabsorption back into the blood. however large polar compounds which make up most drug metabolites cannot diffuse vack into circulation and are excreted unless a specific transport mechanism exists for their reabsorption (such as glucose, ascorbic acid and B vitamins

Question 44

what are the 3 phases of renal excretion

Answer 44

-Glomerular Filtration: Blood enters the kidney and is filtered in the glomerulus; only unbound (free) drugs in the plasma are filtered into the renal tubule. Approximately of fluid is filtered daily, though most is reabsorbed. -Active Tubular Secretion: Occurs primarily in the proximal tubule, where specialized transporters move substances (e.g., penicillins, diuretics) from the peritubular capillaries into the tubular fluid. -Passive Tubular Reabsorption: As fluid moves through the tubule, lipids, water, and some solutes are reabsorbed back into the bloodstream. Highly polar compounds are generally not reabsorbed, making them easier to excret

Question 45

wat is the definition of drug clearance and its equation

Answer 45

the volume of plasma cleared of a drug over a specified time period, units are volume/time CL= rate of drug removal/conc of drug in plasma CL= (mg x mL)/(min x mg) w both mg values canceling out to give us mL/min

Question 46

what is the difference between rate of elimination and drug clearance? and both their formulas

Answer 46

rate of elimination is the amount of drug that is eliminated in a unit of time, clearance is the rate of elimination of drug from the body divided by the concentration, this calculation is done assuming clearance remains constant through dosing period rate of elimination: RoE= amount of drug eliminated/time (often mg/hours) drug clearence: clearance/CL=rate of elimination/plasma concentraiton of drug (mg/h)/(mg/L) with both mg canceling to give L/h

Question 47

why does drug clearence matter

Answer 47

those with high rate of elimination have a far smaller T1/2 duration, with T1/2 being the elimination half time, essentially meaning that those with higher drug clearnence expeirence the same drug dosage with lower concentrations and for less time, requiring lower or higher dosage depending on how fast the body can clear drugs out, it'd be bad if someone had verh high drug clearance for anesthetic and values werent ajusted pre-surgury to boil it down: high rate = sharp peaks and troughs with limited accumulation low rate = accumulation over time wiht chronic dosing

Question 48

what are the 8 routes of drug administration

Answer 48

-intramuscular (injected straight into muscle tissue) -inhaled -transderm/topical (absorbed into skin) -subcutaneous (injected into fatty muscle between skin and muscle layers -intravenous (injected into vein) -oral -buccal subllingual (medication placed between cheek and lower gum to bypass digestion and quickly devliver drug to bloodstream thorugh oral mucosa, good for those undergoing seizure or unable to swollow -RECTAL (they put it up ur ass)

Question 49

what is bioavailability

Answer 49

the fraction of drug absorbed into the systematic circulation, the reason why multiple routes of drug administration are needed so drug concentration can be consistent. IV injection goes straight into your bloodstream so has 100% bioavailability topical (rubbed into skin) has the lowest absorption and bioavailability as it is about as indirect a route you can manage for the bloodstream, good for localised medicines to prevent spreading medinine effect to unwanted areas, minimising unessisary side effects, good for localised skin conditions

Question 50

what are the barriers to absorption from: different routes of administration (3), drug factors (5), and patient factors (4)

Answer 50

different routes of administration: -IV has no barriers as it cannot get any more direct -oral administration is hindered by gastrointestinal mucosa breaking down drug and preventing transport of large molecules unaided -topical administration has the skin epithelium and subcataneous tissue to get through before it can act drug factors: -molecular size (too big cant go through membrane unaided) -lipid solubility -ionisation at phyisiological pH -chemical form -pharmaceutical nature of drug patient factors: -surface area of absorptive surface -blood flow to site of absorption -for drugs given orally, stomach emptying and intestinal transit

Question 51

what factors influence penetration rate of drug molecules through intra/extracellular space to the systematic circulation?

Answer 51

-surface area -concentration gradient (more conc more they want to cross the barrier to be in lower conc side) -lipid solubility (higher=better to cross lipid bilayer of cells) -molecular weight -membrane thickness

Question 52

what are the 4 different methods of drug absorption available to low lipid-solubility drugs?

Answer 52

-passive diffusion -carrier mediated transport -pore mediated transport -pinocytosis

Question 53

what are the 6 barriers to oral absorption and their properties

Answer 53

-GIT/gastrointestinal tract: dissolution, degredation, pH, enzymes binding. can slow down or weaken absorption -mucus: diffusion, binding, electrostatic repulsion. can slow down and weaken absorption -epithelium: membrane transport, diffusion, recognition (molecules bind specificly to drug molecules and bring them away from site of absorption and bloodstream, enzymes, brush-border (water barrier slows drug transport and is coated in digestive enzymes which degrade drug structure and is seletively permiable), cytosolic (cytosol contains many phase 1 and phase 2 digestive enzymes). can degrade and slow drug absorption greatly -lymphatics: none :) direct route from epithelium to systematic circulation -portal blood: leads to the liver, primary 'weird ass compound' clearer in your body, contains enzymes in of itself so will degrade drug on the way to liver -liver: enzymes and biliary excretion (sends endo/exogenous compounds into bile to be excreted via fecal matter, any drugs that remain are allowed into systematic circulation to reach target area

Question 54

what are the 4 phases for solid dosage form oral administration

Answer 54

-solid dosage form is taken orally -disintegration of the dosage form occurs (for capsules filled with powder this step is bypassed as drug is already in its disintegrated form) -drug particles dissolve. only soluble material may be absorbed -dissolved drug particles are absorbed across membrane

Question 55

what are the 3 formulations that effect pharmacokinetic profile of oral administration? (all 3 forms are of the same concentration, only their composision is different)

Answer 55

-liquid/solution: fastest form resulting in a sharp spike over a timeframe of minutes (10 in example graph) -tablet immediate release: previously mention capsule administration, thin disolvable packeging around powdered solution, as soon as capsule breaks open absorption occurs, resulting in a peak that is wider then liquid absorption and roughly half the height, with the absorption being spread across both sides of the peak, does not include immediate absorption as capsule must be broken down first (1.5 hour duration till complete drug absorption) -tablet modified release: a straight brick of medicine designed to not immedietly dissolve upon ingestion releasing active ingredients/drugs at specific rates, absorbs slowly as solid form must disintigrate first, giving a graph with less of a peak and more of a hill structure. (time frame of 8-24 hour release, can be modified by pharmacist dependinng on need, that is the benifit of this technique as it allows for more potent drugs to be adminstered giving full day or overnight drug action while a powdered/liquid form of the same concentration would likely cause biological issues and stress upon liver as its higher concentration would be released far quicker overwelming natural clearing methods

Question 56

what are the 5 rough steps in new industry drug production

Answer 56

-new drug hypothesis drawn up, initial testing batch made -extensive cell culture and preclinical animal testing, going through generation lasting effects, seeing if pregnancy is effected as well as any other deleterious side effects that may build up over prolonged use -clinical trial, you got the FDA and clinical funding saying people belive the drug safe enough to test on the real deal, people sign up for clinical trials and are monitored to see if human phisiology responds differently to previous cell culture and animal testing, final steps for seeing if the drug makes side effects too harsh for human exposure -pharmacokinetic data, you look at the vitals and readings of those under clinical trial, this is done to measure the exact effect on human bodies as though you have proven visually that side effects dont occur, there is a lot more factors then outside appearence to drug effect, heart rate spikes recorded aswell as ED50 values and all data surrounding lethal dose and recomended dosage -prescribing instructions, the little leaflet that comes with the cold medine or losengers you buy, they say what you should use the drug for, the side effects they found to occur in some cases, the recomended dosage and timescale to take drug over (3 capsules per day for example), what to do if you see side effect and additional warnings and recomendations to people of specific age, sex, or those on other drugs at the same time. a good instruction sheet should tell you everything you need to know about the drug as a consumer, it wont say how its made but will give you reassurance that it is mostly safe, the circumstances it isnt and when to have it, use as a lifeline as even vitamin D can cause overdoses if not used carefully

Question 56

what is a IND and what does it include?

Answer 56

an investigational new drug document. tells a story about the 'potential' of a new substance, ducumentation covers all disciplinary areas and includes reports dealing with preclinical studies (pen and paper, in vitro, in vivo just not humans) includes chemistry, manufacturing and controls (CMC) information, protocols for clinical studies, investigational plan for clinical development (at minimum of a year)

Question 57

what are the relevent sections of a IND

Answer 57

-all details on pre-clinical animal studies and the pharmacokinetics supporting clinical program -pharmacokinetics that underpin toxicity assessment -justification of clinical testing in humans; extrapolation from animal data to understand how ADME and PK translates into humans -in vitro models that predict specific aspects of PK, such as intestinal cell models that predict intestinal absorption -in silico models that predict overall pharmacokinetics in humans and integrate impact of patiet diversity (eg disease state, paediatrics, pregnancy) on the pharmacokinetics

Question 58

what length is given to pharmacology and drug distribution, and toxicology in a phase 1 trial IND?

Answer 58

pharmacology and drug distribution (<5 pages) includes pharmacological effects and mechanisms and ADME Toxicology (10-15 pages) includes full data table, GLP certification, animal studies and in vitro data