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Chemistry and Disease > Intro to med chem > Flashcards

Intro to med chem Flashcards

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1
Q

What are the two stages of pre-clinical testing?

A

In vitro studies (in lab tests against target tissue/simple model to test pharmacodynamics), animal studies (determines toxicity and safe dosage, if good then is tested for its activity against disease, must be tested in at least 2 animal species before humans).

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2
Q

What would be the difficulties in eliminating pre-clinical animal studies?

A

Would be difficult to predict a max safe dose and likely that no one would volunteer for Phase 1 trials due to high risk.

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3
Q

How many phases of clinical testing are there?

A

4

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4
Q

What is the aim of phase 1 trials and why is it sometimes skipped?

A

Testing on HEALTHY HUMAN VOLUNTEERS to evaluate the drug’s safety/pharmacokinetics/dose levels and to determine interactions with other drugs/food, takes about a year. If drug is a bit toxic/used against life-threatening ilnesses (think HIV/AIDS) then phase 1 is skipped and drug tested on volunteer PATIENTS.

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5
Q

Describe phase 2 clinical trials

A

Testing on patients suffering from the relevant condition to see the therapeutic value, at first a limited number then a larger group. Trials are double blind and compared with a placebo/established treatment (HIV/AIDS), takes about 2 years.

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6
Q

How do phase 3 trials differ from phase 2?

A

Tests more dose levels on a larger number of patients (still double blind), aims to show statistically significant efficacy and safety (takes about 3 years). MAY then get approved.

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7
Q

Why are phase 4 trials necessary?

A

Performed after drug has been approved for market; monitors drug safety and identifies rare side effects/unexpected interactions with other drugs. Also notes how different populations react to the drug. ONGOING.

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8
Q

What did we gain from Ancient Egyptian medicine?

A

EBERS PAPYRUS- critically, they left written records (including oldest written prescription). Example treatments: SENNA, honey, thyme, aloe, garlic, peppermint, pomegranate root.

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9
Q

Who was Emperor Shen Nung?

A

Founder of Chinese medicine, developed 365 herbal remedies (mild/moderate/severe effects), eg ginseng (stimulant) BUT left no written records.

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10
Q

What was developed from Emperor Shen Nung’s work?

A

A pharmacopiea was compiled (200BC-300AD) which was refined to the Handbook of traditional drugs (1941AD).

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11
Q

What was a key anti-malarial discovered from traditional Chinese medicine/

A

Artemisin.

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12
Q

Name an example traditional drug from each of the following cultures: Indian, South American, Native North American, Aboriginal Australian

A

Neem tree
Quinine, cocaine
Mescaline
Tea tree oil

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13
Q

Who was Hippocrates, and what was he know for?

A

Father of Greek medicine (500ish BC), developed medical practice (Hippocratic oath), use of willow bark for pain (which was later developed into aspirin).

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14
Q

What is the De Materia Medica?

A

Essentially an updated version of the Ebers papyrus, Dioscorides.

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15
Q

Which Ancient Greek physician developed the idea of anatomy (particularly arteries/veins)?

A

Galen

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16
Q

How did the development of medicine in Western Europe get affected in the Dark Ages?

A

Medicine didn’t evolve and descended to folklore and oral tradition (unlike the Arab world which became the centre of global development).

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17
Q

What was the importance of the Middle Ages (1500) in Western medicine?

A

Rise of alchemy–> SYNTHESIS.

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18
Q

What did Paracelsus believe and advocate?

A

Believed diseases were poisons which could be treated with other poisons (Hg/arsenic/Sb), advocated simple prescriptions and proof of efficacy.

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19
Q

What effect led to the ‘anything goes’ route of medicine in the 18th century?

A

Placebo effect (inert treatment appears to work)- why always need to compare medical treatments to a placebo.

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20
Q

What century did organic synthetic chem begin in and what did this lead to?

A

19th century- birth of modern medicine.

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21
Q

What increased the popularity and hence use of morphine in 1850?

A

Intro of the hyperdermic syringe- increased home use therefore popularity (morphine not very orally active).

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22
Q

What was the first truly synthetic drug and how was it developed?

A

Aspirin: originally from willow bark but direct extract caused gastric bleeding due to SALYCYLIC ACID- esterified the phenolic OH group to decrease side effects (doesn’t change activity).

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23
Q

How was heroin developed from morphine?

A

Esterified phenolic OHs (aspirin)- enhanced ability to cross blood-brain barrier.

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24
Q

How was codeine developed from morphine/heroin?

A

2x methyl ethers instead of esters- decreased addictiveness.

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25
Q

What are the most numerically significant bacteria?

A

Streptococcus and staphylococcus

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26
Q

Why was salvarsan selective for syphilis bacteria over human cells?

A

Syphilis bacteria contains more thiol-containing enzymes than human cells.

27
Q

What is the active pharmacophore of Prontosil red?

A

Sulfonamide

28
Q

Why was the use of sulfonamide drugs suspended?

A

Poor solubility- crystallized in kidneys, also low activity.

29
Q

What did Salvarsan replace?

A

Toxic mercury salts

30
Q

What is the therapeutic index, and who was it defined by?

A

LD50 / ED50

Ehrlich

31
Q

Who originally discovered penicillin?

A

Fleming

32
Q

What were the 2 potential structures for penicillin, and how was the correct structure proven?

A

Oxazolone (chemically sensible) and beta-lactam (looked crazy). Proven by Dorothy Hodgkin using X-rays in 1945.

33
Q

Why is the amide not as stable in a beta-lactam ring?

A

Because it is in a strained 4-membered ring hence the resonance is unstable leaving the C=O prone to Nu attack.

34
Q

How do bacteria stabilize their cell walls?

A

By cross-linking between termini of adjacent glycopeptides.

35
Q

What is the mode of action of penicillin?

A

Interferes in cross-linking of bacteria by mimicking D-Ala-D-Ala. The beta-lactam reacts with the Nu in transpeptidase and permanently blocks the active site so cell walls can’t cross link and bacteria die.

36
Q

What are the limitations of penicillin?

A

Low acid stability (needed injection), narrow spectrum of use (only treated gram + bacteria), large % of patients allergic, RESISTANCE.

37
Q

How did bacteria develop evolutionary resistance to penicillin?

A

Bacteria evolved a beta-lactamase enzyme to break the lactam and inactivate the drug.

38
Q

What is MRSA?

A

Bacteria resistant to methicillin (penicillin analogue).

39
Q

What is Augmentin?

A

Combo of amoxicillin and clavulanic acid- overcame resistance and extended patent life.

40
Q

Where was Vancomycin originally found, and why was it an important drug?

A

Japanese soils, was the antibiotic of last resort for a very long time.

41
Q

How did bacteria become resistant to vancomycin?

A

Bacteria replaced D-Ala-D-Ala with D-Ala-D-Lac (4 H-bonds rather than 5)- weakened binding so bacteria could still cross-link hence survive

42
Q

Why are some viruses difficult to vaccinate?

A

Because they subtly change their external coat to evade the immune system.

43
Q

Why is HIV/AIDS normally treated with a combination therapy?

A

To try and prevent resistance occurring.

44
Q

What enzyme allows the flu virus to be transmitted from an infected cell to a healthy one?

A

Neuraminidase

45
Q

What is ‘in silico’ design?

A

Computer-aided rational design used to find inhibitor designs.

46
Q

Why is tamiflu orally active but relenza isn’t?

A

Because tamiflu is more hydrophobic than relenza so can cross intestine membranes.

47
Q

Define pharmacodynamics and pharmacokinetics

A

How well does it bind- thermodynamics (in vitro).

Kinetics of drug distribution and metabolism- pharmaceuticals (in vivo).

48
Q

List 7 ways of drug administration, what are the main 3?

A

Main 3: intravenous (100% absorption/instantaneous bioavailability/bypasses stomach and 1st liver metabolism/difficult to inject), intramuscular (easier to inject/harder to control rate of absorption), ORAL (safest and easiest/can get problems in stomach and 1st liver metabolism before site of action)

Others: mucous membranes (bypasses stomach and 1st liver metabolism), inhalation (avoids GI tract and 1st liver metabolism/ can cause lung irritation), transdermal (slow drug release/nearly constant drug levels in the blood achieved), rectal (good if patient unconscious etc/membrane irritation/extent of drug absorption unpredictable).

49
Q

Describe the steps in oral delivery

A
  1. Disintegration and dissolution (in aq medium of GI tract)
  2. Absorption (passive diffusion through hydrophobic membrane of upper intestine)
  3. Liver passage (metabolised to try make excretable)
  4. Drug action (has to cross more membranes to reach SOA, drug needs balance of solubility and lipophilicity)
50
Q

Define the partition coefficient (P)

A

conc of drug in organic phase/ conc in aq phase

larger P= too hydrophobic, smaller P= too hydrophillic

51
Q

What is the difference between kidney and biliary excretion?

A

Kidney: remove water soluble chemicals and water from blood, polar compounds more easily excreted, can’t be readsorbed.
Biliary: drug excreted in bile, can be readsorbed or excreted in faeces.

52
Q

What is the difference between Phase 1 and Phase 2 metabolism?

A

Phase 1= functionalisation by redox and hydrolysis

Phase 2= conjugation reaction, extrasolubilising agent attached to drug by conjugation to a reactive group.

53
Q

What is the role of cytochrome p450 in drug metabolism?

A

Phase 1 oxidation, enzymes in liver, can be affected by certain foods and drugs so want to avoid p450 metabolised drugs.

54
Q

What is the oxidising agent which converts NAD+ to NADH?

A

Alcohol dehydrogenase

55
Q

What is an example of a reducing environment?

A

Tumours

56
Q

What enzyme catalyses phase 2 conjugation reactions?

A

Transferase

57
Q

List 5 examples of phase 2 conjugation reactions and briefly explain them

A

Glucoronidation (Nu groups conj with glucuronic acid- ox glucose)
Sulfate conj (alcohol groups, steroids, form sulfate)
Glutathione conj (uses drug E+ properties, glutathione tripepeptide reacts through a free thiol Nu, once formed, glutathione is usually metabolised further rather than excreted
Methylation (of OH and NH2 groups)
Acetylation (esterification of COOH groups)

58
Q

Define the half life of a drug

A

Time taken for the active drug to fall by 50% from the PEAK PLASMA LEVEL.

59
Q

List and briefly explain 5 ways of increasing drug stability

A 
Metabolic blocking (places metabolically stable atom at the reactive position to prevent metabolism there, ie blocked active site)
Steric shields (protects susceptible groups form hydrolysis by  adding a bulky substit close to the hydrolytically labile bond (esters and amides)
Electronic effects (esters prone to hydrolysis, amides more stable due to resonance)
Stereochemistry (altering the stereo chem can sometimes prevent metabolism by making drug unrecognizable, eg D-peptides vs L-peptides, but can also lead to side effects)
Synergistic drugs (can stop a drug from being metabolised by administering a 2nd drug to inhibit that enzyme)
60
Q

What is Lipinski’s rule of 5?

A

For a drug to be orally active: MW <500, less than or equal to 5 H-bond donors, less than or equal to 10 H-bond acceptors, logP <5

NB: there are exceptions

61
Q

What can be used as a rescue drug for liver toxicity from paracetamol overdose?

A

A thiol drug, steers down the excretion route.

62
Q

What are the advantages of using prodrugs?

A

Improved bioavailability/improved membrane passage/ site specific activity (decrease side effects)/ modified half life/ lower toxicity/ improved formulation.

63
Q

Name and describe the two types of prodrugs

A

Carrier and bioprecursor

Carrier: prodrug less active than drug, covalent link between drug and transporter (broken by phase 1 hydrolysis), improved membrane passage by lipophillic functionalisation, SITE DIRECTED AND SPECIFIC DRUG DELIVERY, modified duration of action (Hammett parameters)

Bioprecursor: activated by phase 1 redox

64
Q

What are the difficulties with using/developing prodrugs?

A

Pharamcological- difficulty with in vitro screening
Pharmacokinetic- need to test in vitro first but won’t fully know the side effects
Toxicological- ‘off target’ toxicity, formation of toxic metabolites (not from OG drug) upon conversion

Chemistry and Disease (7 decks)

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