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immu3102 > meds2002 > Flashcards

meds2002 Flashcards

1
Q

What are some targets for drugs at the cell surface?

A

1) transporters
2) receptors
3) ion channels

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2
Q

What are some targets for drugs in the cytoplasm?

A

1) enzymes
2) nuclear receptors
3) protein synthesis

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3
Q

examples of drugs on receptors

A

agonists
antagonists
modulators

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4
Q

examples of drugs on ion channels

A

blockers

modulators

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5
Q

examples of drugs on enzymes

A

inhibitors

false substrates

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6
Q

examples of drugs on transporters

A

blockers

false substrates

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7
Q

where do we get compounds from?

A

natural prdoucts-herbs, animal products
combinatorial chemistry
random screening of compounds using high through put assays
structure based drug design

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8
Q

What are some things that makes a good drug?

A 
effective
non-toxic
minimal side effects
bioavailability
mechanisms of action
inexpensive to manufacture
acceptable route of administration
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9
Q

What are some factors affecting bioavailability

A 
different pH environments of the body
diffusion through cell membranes
blood brain barrier
metabolism
off target binding
effects can be modulated by administration route
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10
Q

why is pKa important to looked at

A

we need to predict what form a drug is in

Ionic forms of drugs penetrate membranes slowly

ionic bonds can lead to strong interactions with target

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11
Q

Nicotinic acetylcholine receptor

A

ligand gated ion channel
5 subunits come together to form an ion channel
multiple subtypes of alpha and beta subunits

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12
Q

mAChR

A

g protein
7 transmembrane domain
5 subtypes

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13
Q

example of ion dipole or dipole-dipole bonds

A

quaternary amine of acetylcholine found close to the lone pair of electrons on an oxygen atom of the hydroxyl group of a serine residue

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14
Q

sidechain of leucine as an example of hydrophobic interactions

A

The side chain of a leucine residue prefers to be in close proximity to an aromatic group of nicotine, and avoid polar groups such as the tertiary amine of nicotine

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15
Q

properties of protein backbone

A

some protein backbones can form hydrogen bonds

lots of Os and Ns

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16
Q

Why is oral blood not always recommended

A

Oral drugs usually means that the drug in the intestine is absorbed into the portal circulation. The portal blood is first delivered to the liver. The liver is the major organ of biotransformation

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17
Q

What are some things that help with drug absorption

A

Solute carrier transporters.
They help increase intestinal uptake of numerous drugs

They have a physiological role in anion and cation transporters

i think this includes both passive and active transport pathways

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18
Q

Drug absorption: role of ABC efflux transporters

A

the example given was P glycoprotein.

They basically are located in enterocytes, and they decrease drug uptake into the portal circulation

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19
Q

How does drug ionization affect drug disposition in tissues

A

ionization influences drug movement between aqueous and lipid environments

Strong acids/bases-ionised at any pH

weak acids/bases-extent of ionization depends on the pH of the aqueous environment

For a weakly acidic drug, an increase in H+ suppresses ionisation and favours diffusion through a membrane

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20
Q

What is the significance of the intestine in drug metabolism

A

Some drugs are extensively metabolised in enterocytes, whereas some are minimally metabolised

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21
Q

What is the second most important contributor to a decreased portal circulation

A

A newly absorbed drug enters the portal circulation
The plasma proteins may limit the free drug concentration

and only unbound drug in plasma can enter tissues

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22
Q

What kind of compounds do plasma protein bind to

A

See supplementary online file 2
serum albumin binds many acidic drugs

whereas a acidglycoprotein binds many basic drugs

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23
Q

If a drug is extensively metabolised and has a high first pass effect, hepatic extraction is:

A

high

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24
Q

bioavailability definition

A

It is an important pharmacokinetic quantity describing how much of a dose is available after administration

The bioavailability of an intravenous dose is 100%

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25
Q

Why do we have intraocular and intranasal injections

A

Eye drops and nose drops are intended to act locally.
This generally minimises systemic effects

However, it can get disproportionately high plasma concentrations of drugs because some drug can enter the systemic circulation

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26
Q

How do biotransformation enzymes help with the elimination of different enzymes

A

they convert lipid soluble chemicals into more polar products
These are more readily eliminated
Usually metabolites are also less active
However, some important drugs are prodrugs that themselves have low activity
pro drugs are activated by metabolism

27
Q

Where does biotransformation occur in the body?

A 
Liver (1)
Lung(0.1 to 0.2)
intestine (0.06)
placentra (0.05)
adrenals (0.02)
skin(0.01)
28
Q

What is the major class of phase I biotransformation enzymes?

A

CYPs, cytochrome P450s

29
Q

How are CYPs different from other drugs

A

CYPs act on diverse substrates (low substrate specificity

30
Q

What are some CYP structure and function notes

A

All CYPs have a haem group involved in oxygen activation

The polypeptide chain differs between CYPs and controls substrate specificity

Each CYP is encoded by a different gene
Variations in amino acid sequence often influence enzyme function

31
Q

What are some important properties of CYPs that can influence therapy

A

They are readily inhibited-giving rise to pharmacokinetic drug-drug interactions

Some are inducible-where exposure to drugs and chemicals can increase the amount of the CYP in liver

Often subject to extensive pharmacogenetic variation

32
Q

What is the major CYP in the human liver?

What does it do

A

CYP3A4
readily inhibited,
highly inducible
many drugs 60% metabolised by this enzyme

33
Q

What is the implication of grapejuice inhibition on CYP3A4

A

grapefruit juice contains a chemical that inhibits intestinal metabolism and allows more of a dose to be absorbed into the systemic circulation

34
Q

How might CYP genes be activated

A

PXR is a transcriptional regulator of CYP. It helps upregulate CYP

RXR works with PXR to activate CYP genes

CAR was also mentioned

35
Q

CYP2D6

A

is debrisoquine hydroxylase
can add or remove functional groups-specifically hydroxylation, demethylation and dealkylation

It could also activate some prodrugs

36
Q

What is the difference between having a single nucleotide polymorphism in coding regions and regulatory regions

A

If it is seen in coding regions, it could affect protein function

if it is seen on regulatory regions, it can affect the amount of protein synthesised

37
Q

The CYP2D6 gene is highly polymorphic

A

extensive metabolisers carry 2 active alleles
poor metabolisers carry 2 nonfunctional alleles
intermediate metabolisers carry 2 low activity alleles or 1 active and 1 inactive allele

ultrarapid metabolisers carry multiple copies of CYP2D6

38
Q

What are 2 forms of gene polymorphism?

A

SNP
and
VNTR

39
Q

What is phase 2 metabolism

A

The phase 1 metabolites are conjugated with very polar endogenous molecules such as glucuronic acid and sulfate

after phase ii conjugates, they are easily excreted in urine and faeces

40
Q

Why are polar molecules more easily secreted

A

Because they are more hydrophilic, and therefore more water soluble. They prevent reabsorption

41
Q

How do polar molecules move out of cells

A

ABC transporters
They are open dimers,
binding of ATP produces a conformational shift
The substrate is effluxed and ATP is dephosphorylated to produce ADP
The starting conformation is restored to accept further substrate present in the cell

42
Q

Where are drug metabolites eliminated in the systemic and faeces?

A

Transporters can direct the drug metabolite back into the systemic circulation for elimination in urine or bile for elimination in faeces

43
Q

Renal elimination(urine)

A

glomerular filtration
active tubular secretion
tubular reabsorption

44
Q

What kind of drug is removed at glomerular filtration

A

removal of free drug-drug which is not bound to plasma proteins

45
Q

What kind of drug is removed at active tubular secretion

A

Drug which had been transported from blood into urine

46
Q

What kind of drug is favoured at tubular reabsorption

A

passive process in which drug in urine diffuses back into blood
favours unionised drug
urinary pH important

47
Q

What is the point of urinary alkalinisers

A

They transiently increase pH which facilitates excretion of weak acids as they remain more ionised and remain in urine

non-ionised acidic drug in blood can move across tubular membrane

so ionised acidic drug decreases reabsorption

48
Q

What is the physiological role of bile

A

excretion of cholesterol
absorption of lipids
stimulation of intestinal motility

Drug conjugates formed in liver can be excreted in bile and then deposited in intestine

49
Q

what are the 2 major mechanisms for drugs to appear in faeces

A

By not being absorbed into the systemic circulation so drug passes along the intestine

by being absorbed, excreted in bile and then being deposited back into the intestine

50
Q

What happens after biliary excretion of drugs

A

After biliary excretion, gut bacteria can cleave phase ii drug conjugates, for example glucuronide is removed
This restore drug or phase 1 metabolite,

51
Q

Enterohepatic recycling

A

It could happen sometimes apparently. This may produce a secondary phase

52
Q

Pulmonary elimination

A

The major organ of excretion for gases and volatile substances that do not require metabolism

The breathalyzer test quantifies the pulmonary excretion of ethanol

53
Q

Elimination in breast milk

A

unknown

54
Q

Affinity

A

refers to the drug’s ability to bind to the target

quantified as the concentration of drug required to occupy 50% of target proteins

55
Q

intrinsic efficacy

A

the maximal effect a drug can produce on an tissue as a proportion of the maximal effect of a full agonist on that tissue

full agonist->intrinsic efficacy=1
antagonist->intrinsic efficacy =0
partial agonist=intrinsic efficacy between 0 and 1

56
Q

What factors may intrinsic efficacy account for

A

more than 1 activated state of a receptor

binding to a small propotion of the total receptors can give a maximum response

57
Q

potency

A

the concentration of a drug that causes a specified effect

a drug that causes a specified effect at a smaller concentration is more potent

58
Q

Why do we get side-effects from drugs sometimes

A

Because no drug is totally specific to a target, so we get side effects

59
Q

What is selectivity

A

ability of a given drug concentration to produce one effect over another

60
Q

What are 3 stages of drug action in ligand receptor interactions

A

1) binding
2) conformational change and transduction
3) response

61
Q

ligand

A

a molecule that binds to an active site on a macromolecule

62
Q

agonist

A

a ligand that binds to and activates a receptor to produce a response in the cell

63
Q

antagonist

A

a ligand that binds to a receptor but does not activate it. Agonists reduce the probability of an agonist binding to the receptor thus reduce or block its action

64
Q

Allosteric modulators

A

A molecule that binds to an active site on a macromolecule to enhance or reduce a response from an agonist

it has no effect on its own and may alter affinity or intrinsic efficacy of the agonist

immu3102 (12 decks)

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