Molmed Pharmacology

Question 1

Key directive of the 1906 Pure food and drugs act:

Answer 1

Requires correct labelling of ingredients of drug

Question 2

What immediately followed the Pure food and drugs act?

Answer 2

Sulphinamide tagedy:
Ingredients may have been listed, but they didn’t have to be safe and added sweet diethylene glycol was toxic
Ensuring lawsuit because of incorrect naming, not toxicity

Question 3

Key directive of the 1938 Cosmetic and drug safety act?

Answer 3

Safety:

Pre market safety testing, requirement of clinical data for compound approval

Question 4

What is a downside of the 1938 Cosmetic drug and safety act?

Answer 4

Automatic approval of compounds if FDA doesn’t give active rejection within 180 days

Question 5

Key directive of the 1962 amendment to the Cosmetic and drug safety act:

Answer 5

Drug actually needs to work
Drugs need active approval from FDA
Evidence of effectiveness of compounds needs to be supplied
Clinical trials need to be conducted and adverse reactions recorded
Trial patients need to give consent

Question 6

First German drug registration act:

Answer 6

1961: First time new drugs need to be officially registered

Question 7

Problem with Contegran?

Answer 7

Teratogenic drug given to treat morning sickness: many stillbirths and disabled babies born
Drug approved despite clinical testing required bc it was never tested on pregnant people

Question 8

Key directives of the 1976 German drug approval act?

Answer 8

Drug needs to be high quality, actually show efficacy
Restrictions on labelling, manufacturing, distribution and marketin in place to ensure safety
Liability of pharma companies if shit goes worng
Advertising only for over the counter drugs
Safety precautions for participants in clinical trials

Question 9

Key directives of current Arztneimittelgesetz:

Answer 9

Defines what drug is
Labelling criteria: info and structure
Drug manufacturing standards: including transport and distribution
Safety precautions for clinical trials
Approval required for drugs (simplified if very similar to existing compound, not nec when homeopathic)
Homeopathic stuff needs to be traditional, no proof of efficacy
Pharmacovigilance post market release

Question 10

What approvals is the BfArM responsible for?

Answer 10

Approval of new small molecule drugs
Regulation of controlled substances
Risk evaluation of drugs and medical products in use
Permissions for studies/research

Question 11

What does the Paul Ehrlich institute do?

Answer 11

Approval of vaccines and biomedicines
Evaluation of allergens for therapy and diagnostics
Evaluation of antibodies, blood and tissue products

Question 12

What is under the jurisdiction of the EMA?

Answer 12

Harmonisation of EU lawscape regarding drugs
Give evaluation of drug application, but not approval
Compulsory for approval of biomedicinces, antiviral and orphan drugs
Anti HIV, cancer, diabetes, neurodegenerative and autoimmune diseases (for severe diseases)

Question 13

Outline the process of drug discovery

Answer 13

Identification of biological target -»
Screen for compounds interacting with target with high-throughput bioassay -»
Score for hits (compound actually does thing)-»
Refine compound through addition of functional groups-»
Identify lead compound to carry on to in vitro testing of pharmacodynamics-»
Test compound in cell culture and in animal model (coincides with Phase 0) -»
Optimised compound with idea of starting dose

Question 14

Outline the steps of drug development:

Answer 14

Aim is to provide proof of therapeutic effect and safety
Phase 0: in vitro and vivo determination of drug safety and starting dose, test Pkinetics, Pdynamics and potential toxicity effects
Investigational new drug application (IND)
Phase 1: compound tested in healthy humans, open label no control; test for safety, possible adverse effects with increasing dose, Pkinetics
Phase 2: treatment vs control group, randomised blinded; determiantion of effectiveness and optimal dosage for greatest effect, define most frequent side effects; observation of drug-drug interactions
Phase 3: evidence of efficacy and safety in diseased patients, treatment vs control, randomised blinded; profitability decision
New drug application (NDA) summary of findings
Regulatory body approval if effective in intended use and benefits outweigh risks
Phase 4: Pharmacovigilance of drug on market (open label no control real life people) asess long term effects, stability, compare how drug performs vs already existing drugs; see rarer side effects and long term adverse effects

Question 15

Criteria for good clinical trials:

Answer 15

Participants randomised to remove bias
Even matching of treatment and control groups
Blinding (preferably double to remove placebo effect on study objects and bias on study conductors)
Defined endpoints clinically relevant (or good surrogate endpoints chosen that don’t easily change based on sth outside trial eg blood pressure, mortality LDL content, major adverse events stroke etc)
Study planned ahead and conducted accordingly
Data analysis potentially blinded, including dropout trial patients to make sure trial doesn’t look safer than it is
Cohort number to be sufficiently large

Question 16

What are the failings of clinical trials:

Answer 16

Sample size not reliable for whole population extrapolation
Rarer side effects unobserved due to small smaple size
Long term effects not observed
No comparison of drug effectivity to drugs already on market till phase 4 in most cases
Unintetional bias enrolling healthy patients in early trials, comorbidities irl much more frequent

Question 17

What do Pharmacodynamics measure?

Answer 17

What drug does to the body

Includes drug and receptor interaction, signal transduction and biological response

Question 18

What is the difference between a Pkinetics and a Pdynamics graph?

Answer 18

P dynamics graph measure the effect of the drug agaisnt log of drug concentration
p kinetics graph measure concentration of drug within body

Question 19

Define potency:

Answer 19

How good a drug is at evoking an effect
EC50: how much drug there needs to be to evoke 50%of total response, comparing different drug potencies by this number
The more lft on P dynamic graph the more potent

Question 20

Define Efficacy:

Answer 20

The maximum efect magnitude of a drug
Depends on receptor drug interaction and their intrinsic activity inducing response
Measured as amplitude (y axis) on P dynamic graph

Question 21

Compare an antagonist to an inverse agonist:

Answer 21

Antagonist can compete with agonist or block evocation of effect via another receptor binding site, even covalent binding inactivation possible -» R makes no effect
Inverse agonist evokes opposite effect from R as agonists, usually in competition with agonist -» actually shows less effect than zero/ pushes into opposite direction

Question 22

Compare 3 types of agonists!

How do you tell them apart on a graph?

Answer 22

Full agonist: Binding to receptor stabilises activated state to 100% of biological activity
Partial agonist: less activity produced than biological full agonist of R; lower amplitude on P dynamic graph
Super agonist: Activation of receptors with higher efficacy than biological agonist; reaches maximum plateau faster (higher potency) than full agonist, but 100% is 100% for a reason

Question 23

What do Pharmacokinetics measure?

Answer 23

What body does to drugs

Absorption, Distribution, Metabolism, Excretion (ADME)

Question 24

Define Bioavailability:

Answer 24

How much active compound is circulating in body, fully available for tissues
P kinetic graph shows exactly that, measured as fraction of drug administered vs same amount of drug admitted intravenously -» this is why Pkin graph is = drug in bloodstream by IV
Depends on body’s ability to liberate, absorb, transport drug and how fast it gets cleared and excreted and by which enzymes

Question 25

Define volume of distribution:

Answer 25

Describes the amount of drug carried around by circulation
The higher volume of distribution means the lower the concentration at a signle location is
The lower the Vd the more local (when measured from blood, the more intravenous)
The higher the Vd the more distributed to tissues
Measured tissue administered vs administered IV

Question 26

Define Therapeutic index

Answer 26

The range of concentration at which drug elicits positive effect
Above causes toxicity
Below causes no effect
TI is fraction of max non-toxic dose and min effective dose

Question 27

Name methods of administration and their major up and downsides:

Answer 27

Oral: high compliance and safety; slow absorption and high susceptibility to first pass metabolism and complicated uptake pathway problems

Sublingual/buccal: direct adsorption avoiding first pass metabolism; local toxicity

Intravenous: Highest bioavailability and fastest possible, easy to control dose; Irreversible and unsuitable for lipophilic drugs

Intramuscular: long term slow release administration with high bioavailability; low compliance and local pain and tissue swelling

Inhalation: Rapid delivery to lung and bloodstream; kind of localised and can be exhaled just as fast as well

Topical transdermal: Good for slow sustained delivery of lipophilic drugs; ONLY for lipophilics, may not reach deeper target structures or cause allergy

Rectal: avoids GI tract damage; doesn’t fully avoid first pass metabolism, low compliance

Question 28

What is the prodrug concept?

Answer 28

Using the natural metabolism in the liver to turn drugs administered as inactive forms into their active form
Increases bioavailability and avoids first pass metabolism clearance, reduces unwanted systemic side effects
Eg codeine to morphine; valocivir to aciclovir

Question 29

What is monkshood? What is its effect and how do you treat it?

Answer 29

Plant in central Europe
Contains aconite which causes cardio and neurological problems
First sign: vomiting and gastro problems
Treat symptoms

Question 30

What is Hemlock/Hogweed? How do you treat it?

Answer 30

Plant causing blistering burns when touched

Phototoxic reaction, keep away from sun

Question 31

What is death cap? Why has it become a problem? How do you treat it?

Answer 31

Mushroom, ingested by untrained foragers
Ammatoxin in mushroom causes diarrhoea after 8-12h and attacks liver
Only solution is liver transplant

Question 32

What are signs of body packing gone wrong? What to do then?

Answer 32

Seizures,
Test urine for cocaine metabolites, X ray to identify packs in body and perform laprotomy

Stuffers could get away with gastric lavage

Question 33

What are single nucleotide polymorphisms?

Answer 33

Single base exchanges found with a frequency of over 1% in the population
Appear biallelic: either you have an exchanged base or you don’t
Effect: can change AA encoded or not, or promoter activity if localised in promoter
Different SNPs can appear together or completlely independnet from each other
Tested for with PCR-RFLP, SNP microarray, prominent: CYP2D6, VKORC1

Question 34

What can the idenitfication of SNPs be used for

Answer 34

Different SNP combination determines eg susceptibility to asthma, or different eye colours
Genetic similarity between individuals

Question 35

What influences SNP inheritence:

Answer 35

Closeness of SNP loci: distance between SNPs, the lower the more likely they will be inherited together during crossing over
Natural haplotype hotspots: sometimes SNPs just appear in one genetic loci more than others
Linkage Disequillibrium: several SNP ALWAYS appear together, no random chance of inheritance

Question 36

What is a haplotype:

Answer 36

Set of linked SNP alleles that tend to occur together

Question 37

What is linkage equillibrium:

Answer 37

When SNPs are inherited completely independend from each other
Low D/r2

Question 38

What are copy number variations?

Answer 38

Large sequences erroneously replicated by DNA polymerase when the reading is impacted
Up to a megabase affected
Multiallelic as depending on sections and number of replication more than two options possible
Found in CYP2D6
Detectable by SNP microarray

Question 39

What are variable number tandem repeats?

Answer 39

DNA micro and minisatellites that are just repeating segments
Used in DNA fingerprinting, paternity and linkage analysis
Not biallelic as replication amount individual (hence why so identifying)
Tested for with PCR

Question 40

How does an SNP affect drug clearance?

Answer 40

Polymorphisms in genes for clearance pathway components can mess with the available dose of the drug making people poor or ultrametabolisers
Example: CYP2D6 and warfarin -> poor metaboliser, too much in blood
VKORC1 and warfarin -> same problem
OCT1 hepatic import channel and ?