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BRS Pharm > Principles of Pharmacology > Flashcards

Principles of Pharmacology Flashcards

1
Q

what is pharmacology?

A

the study of drug action and how this influences physiological function

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2
Q

what is therapeutics?

A

patient focused drug prescribing and treatment of disease

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3
Q

why is selectivity important?

A

to avoid side effects/adverse effects

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4
Q

what are the 4 types of drug target?

A

receptors
enzymes
ion channels
transport proteins

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5
Q

what are the 4 types of drug-receptor interactions?

A

electrostatic
hydrophobic
covalent
stereospecific

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6
Q

what classification of drugs bind to and block receptors, produce no response

A

antagonists

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7
Q

what classification of drugs has an affinity for receptors and activates them but sub maximal efficiacy

A

partial agonists

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8
Q

what classification of drugs has an affinity for a receptor and activates them, maximal efficacy

A

full agonists

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9
Q

what is affinity?

A

determines strength binding of drug to receptor

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10
Q

what is efficacy?

A

ability of individual drug molecules to produce effect once bound to a receptor

Drug A - has affinity for the receptor but no efficacy. It therefore acts as a receptor antagonist. When bound to the receptor, it is effectively 'blocking' that receptor and preventing an agonist from binding to the receptor and inducing activation. 
Drug B - has affinity for the receptor and sub-maximal efficacy. It therefore acts as a partial agonist. When bound to the receptor, it can produce a partial response, but cannot induce the maximal response from that receptor. 
Drug C - has affinity for the receptor and maximal efficacy. It therefore acts as a full agonist. When bound to the receptor, it can produce the maximal response expected from that receptor.
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11
Q

what is potency?

A

refers to concentration or dose of drug needed to produce defined effect

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12
Q

what is a high potency drug?

A

a drug which produces large response at low concentrations

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13
Q

What is the difference between potency and efficacy? And which is more important?

A

potency is related to dose, efficacy is not

A highly efficacious drug can produce maximal response and this effect is not particularly related to drug concentration

efficacy is more important, you want to know if the drug you are giving can induce maximal response- the potency simply determines the dose needed

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14
Q

What is EC50?

A

Imagine you are conducting an in vitro experiment to test drug effectiveness. You might be working with a piece of lung tissue to text smooth muscle relaxation. You would add specific ‘concentrations’ of the drug to your in vitro preparation to test effectiveness.

The concentration that produced a 50% response would be the EC50.

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15
Q

What is ED50?

A

Imagine you are conducting a clinical trial to test drug effectiveness. You might be looking at the ability of the drug to relieve breathlessness. In this case, you would give individuals a specific ‘dose’ of the drug to test effectiveness. It is very difficult to determine a 50% response in one individual (what is a 50% improvement in breathlessness?). Instead, you would look for the dose of

drug that produced the desired effect in 50% or the individuals tested. This dose would be the ED50.

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16
Q

what are electrostatic drug-receptor interactions?

A

most common mechanism, includes H bonds and Van der Waals forces

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17
Q

what are hydrophobic drug-receptor interactions?

A

important for lipid soluble drugs

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18
Q

what are covalent drug-receptor interactions?

A

tend to be irreversible

less common

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19
Q

what are stereospecific drug-receptor interactions?

A

drugs exist as stereoisomers and interact stereospecifically with receptors

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20
Q

what are the major pharmacokinetic factors? (4)

A

absorption
distribution
metabolism
excretion

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21
Q

What do pharmacokinetic factors effect?

A

the amount of a drug that will reach a tissue

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22
Q

what is the concept of absorption?

A

passage of a drug from the site of administration into the plasma

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23
Q

what is the concept of bioavaliability? And what is the difference between bioavailability and absorption?

A

fraction of initial dose that gains access to systemic circulation

Overall, absorption delas with the process for drug transfer into the systemic circulation, whereas bioavailability deals with the outcome of drug transfer into the systemic circulation (i.e., how much)

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24
Q

what is the major determinant of absorption and bioavaliability?

A

the site of administration

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25
Q

what are examples of drug administration?

A 
oral
inhalation
dermal/percutaneous
intra-nasal
intravenous
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26
Q

do drugs tend to be water soluble or lipid soluble?

A

water soluble

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27
Q

what are the ways drugs move around the body?

A

bulk flow transfer
and
diffusional transfer

28
Q

how does the IV route of administration differ from all other routes?

A

IV - bulk flow transfer delivers drug directly to intended site of action (bulk flow is in e.g., bloodstream)

all other routes - must diffuse over at least 1 lipid membrane

29
Q

what are the mechanisms by which chemicals diffuse over plasma membranes? diffusional transfer

A

simple diffusion (most common across lipid bilayer)
diffusion across aqueous pores (not very common)
carrier mediated transport (also v common)
electrochemical gradient

30
Q

What is pinocytosis?

A

Pinocytosis involves a small part of the cell membrane enveloping the chemical molecule and forming a vesicle containing the drug
- The vesicle can then release the chemical on the other side of the membrane
Whilst this is relevant for some molecules such as insulin to the brain, it is rarely used for transport of drugs

31
Q

Are most drugs acids or bases? And what does that mean?

A

usualyl either weak acids or weak bases, threfore the drug will exist in 2 forms (ionised or unionised)

32
Q

Doesn’t this mean that weak bases would be trapped in the stomach and weak acids would be trapped in the blood?

A

A weak base will indeed be poorly absorbed from the stomach due to the low pH leading to a high drug ionisation. However, once the drug eventually reaches the small intestine, it will be able to access a huge number of transport proteins that will enable absorption from the gastrointestinal tract.

A weak acid could potentially be absorbed from the stomach in its unionised state. However, it would then become more ionised at physiological pH and potentially become ‘trapped’ in the blood. Once again, however, most tissues possess transport proteins that could potentially move the ionised drug from the blood into the tissue.

33
Q

In terms of parmacokinetics, where are the most important carrier systems relating to drug action?

A

1) Renal tubule
2) Biliary tract
3) Blood brain barrier
4) Gastrointestinal tract

34
Q

what are the main factors affecting distribution?

A

regional blood flow
plasma protein binding
capillary permeability
tissue localisation

35
Q

how does regional blood flow affect distribution?

A

different tissues receive different amounts of cardiac output
more drug is distributed to tissues with most blood flow
this blood flow is also affected by exercise, meals etc

36
Q

What organs receive the most and least cardiac output?

A

liver= 27%, heart 4%

37
Q

how does plasma protein binding affect distribution?

A

only free drugs (not bound to plasma protein) can diffuse out of the blood and access tissues
e.g albumin, testosterone binding globulin etc

38
Q

What factors does the amount of drug that is bound to proteins depend on?

A

the free drug conc

affinity for the protein binding sites

plasma protein conc

39
Q

how does capillary permeability affect distribution?

A

very lipid soluble drugs can diffuse across endothelial cells
less lipid soluble drugs need transport via carrier proteins

40
Q

what organ is the hardest to access

A

Brain - BBB

41
Q

What are the types of capillaries?

A

continuous, BBB (tight junction), fenestrated, discontinuous

42
Q

what organ is easiest to target

A

liver due to discontinuous capillaries

43
Q

What organ has fenestrated cappilaries?

A

kidney, enhances excretion of drugs

44
Q

what is drug metabolism?

A

conversion of drugs to metabolites that are water soluble and easier to excrete and eliminate

45
Q

what are the two phases of drug metabolism?

A
  1. main aim to introduce reactive group to drug
  2. main aim to add conjugate to reactive group

tgt increase lipid solubility which then aids excretion and elimination

46
Q

where and how are drugs metabolised?

A

Liver, cytochrome P450 enzymes

47
Q

Describe phase 1 of drug metabolism?

A
  • Main aim is to introduce reactive polar groups into their substrates
    • Phase 1 reactions can occur by oxidation, reduction and hydrolysis
    • The most common form in phase 1 is oxidation
    • However all oxidation reactions start with a hydroxylation step utilizing the cytochrome P450 system
    • The aim is to incorporate oxygen into non-activated hydrocarbons
    • A general rule, the end result of phase 1 metabolism is to produce metabolites with functional groups that serve as a point of attack for the conjugating systems of phase 2.
    • phase 1 will often produce pharmacologically active drug metabolites.
48
Q

What is a pro-drug?

A

In some instances, the parent drug has no activity of its own, and will only produce an effect once it has been metabolized to the respective metabolite
* these drugs are known as pro-drugs
* In this case, metabolism is required for the pharmacological effect. Of course, it can also be true, that active metabolites can have negative unintended effects.
* Liver damage as a result of paracetamol overdose, is due to a certain metabolite and NOT paracetamol itself

49
Q

Describe phase 2 of drug metabolism?

A

Phase 1 adds the functional groups that are susceptible to conjugation in phase 2. The result of phase 2 metabolism is the attachment of a substituent group, and the resulting metabolite is nearly always inactive and far less lipid soluble than the phase 1 metabolite. This facilitates excretion in the urine or bile. The figure below adds the common phase 2 conjugates that complement the common phase 1 metabolites.

50
Q

what is an issue for orally administered drugs?

A

absorption through the small intestine into the hepatic portal blood supply may lead to ‘first pass hepatic metabolism’

51
Q

what is first pass (hepatic/ presystemic) metabolism

A

orally administered drugs pass into the hepatic portal system, passing through the liver before systemic circulation
the drug may be heavily metabolised before reaching systemic circulation

52
Q

how is first pass hepatic metabolism overcome?

A

larger doses are administered to ensure enough drug reaches systemic circulation
however, the extent of FPHM differs between people so drug effects and side effects are difficult to predict

53
Q

how are drugs excreted?

A

mainly via kidney and liver (urine/bile)

but also through lungs and breast milk

54
Q

what are the major routes for drug excretion in the kidney?

A

glomerular filtration
active tubular secretion
passive diffusion across tubular epithelium (this is reabsorption so needs to be avoided for excretion)

55
Q

what is active tubular secretion?

A

removal of water soluble drugs from tubule to urine
80% of renal plasma passes onto blood supply to proximal tubule
proximal tubule has two active transport carrier systems - one acidic and one basic

56
Q

what is passive diffusion across the tubular epithelium?

A

reabsorption from kidney tubule into blood
lipid soluble
extent of reabsorption dependent on urine pH and drug metabolism

57
Q

what is biliary excretion of drugs?

A

liver transports drugs from plasma to bile via transporters
bile is then excreted into intestines and eliminated in the faeces
enterohepatic recycling can occur and significantly prolong drug effect (not excreted)

58
Q

what is diffusional transfer

A

molecule by molecule cross a short diffusion distance

inhaled, intradermal, intramuscular, subcutaneous etc (as they all cross at least one lipid membrane)

59
Q

what can unionised drugs do?

A

cross membranes as they are lipid soluble

60
Q

what do ionised drugs require

A

carrier proteins as they are not lipid soluble
but are water soluble so easy transfer in blood
less reaches tissue

61
Q

what does the ionisation of a drug depend on

A

the pH of the site where it is absorbed relative to the pKa

if pKa = pH then drug equally dissociated

for acids(low pKa): if pH less than pKa drug is unionised (more acidic pH than the acid = less ionisation)
if pH greater than pKa drug is ionised (if pH is more alkalotic than the acid = highly ionised)
for bases(high pKa): if pH greater than pKa drug is unionised (more alkalotic pH than the base = less ionisation)
if pH less than pKa drug is ionised (pH more acidic than the base = highly ionised)
62
Q

how does tissue localisation affect drug distribution

A

lipid soluble drugs will be better distributed to areas with high fat content e.g brain
water soluble drugs will be better distributed to areas with high water content e.g lean muscle

63
Q

what is glomerular filtration dependent on

A

size of drug - smaller is faster

64
Q

what is active tubular secretion dependent on

A

available transporters

better for acidic or basic drugs (water soluble)

65
Q

what is passive reabsorption dependent on

A

urine pH
extent of drug metabolism
better for lipid soluble drugs

66
Q

what type of drugs are more likely to be excreted and why

A

water soluble drugs
reduced passive reabsorption in kidney DCT
therefore excretion of drug is increased

67
Q

what is enterohepatic circulation

A

bile created from drugs excreted by liver to hepatic duct
goes to gallbladder
is excreted to intestines
is then reabsorbed by intestines to the liver again and cycle continues

a process called enterohepatic recycling can take place which can significantly prolong drug effect. An example of enterohepatic recycling;
1. A glucuronide metabolite is transported into the bile.
2. The metabolite is excreted into the small intestine, where it is hydrolysed by gut bacteria releasing the glucuronide conjugate.
3. Loss of the glucuronide conjugate increases the lipid solubility of the molecule.
4. Increased lipid solubility allows for greater reabsorption from small intestine back into the hepatic portal blood system for return to the liver.
5. The molecule returns to the liver where a proportion will be re-metabolised, but a proportion may escape into the systemic circulation to continue to have effects on the body.

BRS Pharm (9 decks)

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