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Phase 2a - Introductory Clinical Sciences > Basic Pharmacology > Flashcards

Basic Pharmacology Flashcards

1
Q

define pharmacodynamics

A

the effect of the drug on the body

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2
Q

define pharmacokinetics

A

the effect of the body on the drug

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3
Q

what are some types of drug targets?

A

receptors, enzymes, transporters, ion channels.

most drug targets are proteins

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4
Q

name some different types of receptor

A

ligand-gated ion channels,

G protein coupled receptors,

tyrosine kinase-linked receptors,

cytosolic/nuclear receptors

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5
Q

give an example of a ligand-gated ion channel

A

nicotinic ACh receptor

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6
Q

give some examples of G protein coupled receptors

A

muscarinic ACh, adrenergic, dopamine, serotonin and opiate receptors

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7
Q

what are some examples of tyrosine kinase linked receptors?

A

insulin, platelet-derived growth factor, epidermal growth factor

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8
Q

what type of receptors are steroid receptors?

A

cytosolic/nuclear receptors

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9
Q

what does the ADME acronym of pharmacokinetics stand for?

A

Absorption Distribution Metabolism Excretion

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10
Q

how does the nicACh receptor work?

A

ligand-gated ion channel. ACh binds to N-terminal of both alpha subunits - activates receptor. pore opens, and there’s an influx of cations.

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11
Q

describe the structure of a G protein coupled receptor

A

single polypeptide chain, with 7 transmembrane-spanning alpha helices. ligand-binding domain is within membrane on 1+ of the alpha helices. 3rd intracellular loop is larger - interacts with G protein.

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12
Q

how do G protein coupled receptors work?

A
  1. if an agonist binds to receptor, there’s a conformational change - increased affinity for G protein.
  2. G protein is activated by losing a GDP and gaining a GTP.
  3. active G protein is then able to interact with other effectors like enzymes/ion channels.
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13
Q

what are the two main types of target for G proteins?

A

ion channels. secondary messengers.

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14
Q

how do DNA-linked (aka nuclear receptors) work?

A

located intracellularly. agonist binds to receptor. agonist-receptor complex transported to nucleus, by chaperone proteins. complex can bind to specific DNA sequences (through “zinc fingers”), altering expression of certain genes.

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15
Q

why is it useful to know what type of receptor is involved in a pathophysiological response?

A

can develop drugs that act at that receptor. can quantify drug action at the receptor.

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16
Q

define an agonist

A

a compound that binds to a receptor and activates it

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17
Q

define an antagonist

A

a compound that reduces the effect of an agonist - bind to receptors but don’t activate them, do not induce a conformational change.

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18
Q

what is a drug’s “EC50”?

A

the concentration of the drug to achieve half the maximal response - found at 50% on a dose-response curve. used to indicate POTENCY.

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19
Q

what are “full agonists”?

A

have high efficacy and are able to produce a maximal response while occupying only a small % of available receptors. will hit 100% on a dose-response curve.

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20
Q

what are “partial agonists”?

A

low efficacy. unable to elicit maximal response even if occupying all available receptors.

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21
Q

how would you identify a more potent (higher affinity) drug by comparing dose response curves?

A

will be more to the left - lower concentration of drug required to achieve the same response as the curve to the right

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22
Q

how would you identify a partial agonist on a dose response curve?

A

Emax is below 100% - the maximal response reached is less than 100%

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23
Q

describe the effects of a competitive antagonist

A

binds to receptors, preventing agonist from binding. parallel shift of dose-response curve to right. maximum response not reduced, just higher concentrations needed to reach it. amount the dose-response curve is shifted reflects affinity of antagonist.

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24
Q

what is affinity?

A

describes how well a ligand binds to the receptor - property shown by agonists and antagonists

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25
Q

what is efficacy?

A

describes how well a ligand activates the receptor - shown only by agonists

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26
Q

describe the concept of “receptor reserve”

A

there is an excess of receptors (spare receptors) - 50% response rarely corresponds to a 50% occupancy of receptors

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27
Q

describe “signal transduction”

A

agonist binds to receptor. there’s a signalling cascade - several steps. this elicits a response.

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28
Q

describe “signal amplification”

A

at each stage in the signalling cascade induced by agonist binding to receptor, the signal is amplified - e.g. one enzyme is activated, and catalyses the next reaction more than once etc etc

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29
Q

what is drug tolerance?

A

reduction in drug effect (agonist) over time. occurs in response to continuous, repeated, high concentrations.

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30
Q

how does desensitisation of receptors occur?

A

they become uncoupled, or internalised, or degraded

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31
Q

what are the actions of NSAIDs?

A

analgesis. anti-pyretic. anti-inflammatory.

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32
Q

how do NSAIDs work?

A

inhibit cycloxygenase (COX) which catalyses conversion of arachidonic acid to prostaglandin H2 (PGH2). PGH2 is acted on to generate prostanoids, including prostaglandin E2, believed to cause pain.

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33
Q

how do NSAIDs inhibit COX?

A

bind to active site, where arachidonic acid usually binds - competitive inhibition

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34
Q

what is the effect of aspirin on COX?

A

irreversible inhibition

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35
Q

how do ACE inhibitors work to reduce blood pressure?

A

lower BP by inhibiting ACE, preventing conversion of angiotensin I to angiotensin II, which would act on AT1 receptors to induce vasoconstriction

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36
Q

describe the mechanism of ACE inhibitors

A

they mimic the di/tri-peptide at the end of angiotensin I, enabling them to bind to the active site of ACE

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37
Q

how do proton pump inhibitors work?

A

irreversibly inactivate the proton pump (H+/K+-ATPase) in parietal cells, inhibiting acid secretion

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38
Q

describe the basic mechanism of diuretics

A

inhibit ‘symporters’: furosemide inhibits Na+, K+, 2Cl- cotransporter (ascending loop) thiazides inhibit Na+, Cl- cotransporter (distal tubule)

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39
Q

how do diuretics work to reduce hypertension and help with heart failure?

A

reduce reabsorption of salt from filtrate = increased excretion of ion. water reabsorption is inhibited - increased excretion of water.

40
Q

how do neuronal uptake inhibitors work?

A

increase neurotransmitter concentration at cleft by inhibiting the uptake transporters

41
Q

describe the mechanism of calcium channel blockers

A

most literally block the channel - sit in the opening, preventing Ca2+ from passing through. this reduces vasoconstriction.

42
Q

give some examples of recombinant proteins in clinical use

A

insulin, Epo, growth hormone, IL-2, gamma-IFN, IL-1 receptor antagonist

43
Q

list some examples of “biopharmaceuticals”

A

recombinant proteins, engineered proteins, therapeutic monoclonal antibodies, gene therapy

44
Q

describe the basic principles of gene therapy

A

delivery of nucleic acid polymer to cell.

DNA is delivered using a viral vector.

therapeutic gene for mutated gene.

suppress gene expression.

45
Q

give 3 examples of new components to drug discovery and development

A

combinatorial chemistry

high-throughput screening (HTS)

structure-based drug design

46
Q

what is combinatorial chemistry?

A

generation of leads. biochemical modification of natural products. synthesis of smaller molecules

47
Q

what are two important sources of natural products for drug development?

A
  1. tropical rainforest 2. the sea
48
Q

what is the idea behind combinatorial biosynthesis?

A

large enzyme complexes generate natural products - manipulate biosynthetic material to generate structural analogues

49
Q

what is high-throughput screening (HTS)?

A

used to screen leads generated by combinatorial chemistry/biosynthesis. automated robotics screening 50,000 compounds a day

50
Q

what 3 things can’t high-throughput screening establish?

A

bioavailability. pharmacokinetics. toxicology.

51
Q

what is the idea behind structure-based drug design?

A

use X ray crystallography, NMR, and 3D structures of purified target enzyme/receptor to learn about active/binding site - design a drug to fit it

52
Q

what are the 3 phases determining the plasma level of a drug?

A
  1. uptake into the plasma 2. distribution from the plasma 3. elimination from the plasma
53
Q

what does the rate of diffusion relate to?

A

inversely proportional to distance to diffuse.

proportional to temperature.

proportional to concentration gradient

54
Q

what are the compartments of the body? what divides them?

A

plasma (5l), interstitial fluid (15l), intracellular fluid (45l) - divided by tissue lipid rich barriers

55
Q

name the 5 different mechanisms by which a substance can move between body compartment

A
  1. simple diffusion 2. facilitated diffusion 3. active transport 4. through extracellular spaces 5. non-ionic diffusion (ions pass through membrane in an un-ionised form)
56
Q

define bioavailability

A

amount of drug taken up into the systemic circulation as a proportion of the amount administered

57
Q

list some different routes of administration

A

oral - intramuscular - intravenous - transcutaneous - intrathecal - sublingual - inhalation - topical - PR - PV

58
Q

how do drugs move across the gut membrane (following oral administration)?

A

simple diffusion of the lipid soluble freely diffusible non ionised fraction. most tablets are weak acids/bases

59
Q

describe what types of drugs tend to be distributed to which compartments

A

plasma - protein/large macro-molecules - can’t cross out of vessels. interstitial fluid - water soluble intracellular - lipid soluble (can cross cell membranes)

60
Q

what is “volume of distribution”?

A

the volume (in litres) that the drug would occupy if it was distributed through all the compartments as if they were plasma

61
Q

what are the main routes of elimination for the majority of drugs?

A

renal and/or hepatic

62
Q

what is “clearance”?

A

removal of drug from plasma by either liver or kidneys. 1. volume of plasma that can be completely cleared of drug per unit time 2. rate at which plasma drug is eliminated per unit plasma concentration both definitions are measures of efficiency mls min-1

63
Q

describe how renal clearance works

A

all factors affecting renal blood flow will affect clearance. water soluble molecules pass through glomerular endothelial gaps - eliminated by glomerular filtration. larger water soluble molecules can be eliminated by active tubular secretion

64
Q

how do we measure renal clearance? what do we assume?

A

clearance = rate of appearance in urine / plasma concentration. assume that the rate of elimination = rate of appearance in urine.

65
Q

what are the maximum rate of renal clearance by glomerular filtration and by active secretion in adults?

A

130 mls min-1 = GF

600 mls min-1 = AS

66
Q

what will the effects of renal impairment be on drugs in the body?

A

reduced clearance and prolonged elimintation (in renally excreted drugs anyway). danger of accumulation - toxicity

67
Q

what adjustments should be made for renal impairment when prescribing?

A

choose alternative drugs that aren’t renally eliminated - avoid nephrotoxic drugs. reduce dose. monitor plasma concentrations if there’s a toxicity risk. if on haemodialysis, give normal doses.

68
Q

describe how hepatic clearance works

A

all involves active transport. active transport systems vary in efficiency for different compounds. active secretion (if water soluble) from liver into bile duct.

69
Q

what is the hepatic extraction ration?

A

proportion of drug removed by one passage through liver.

70
Q

describe what is seen in high HER (hepatic extraction ratio) and low HER

A

high HER - can be so high that clearance is only limited by hepatic blood flow - perfusion limited. low HER - process is slow and inefficient. low amount removed - diffusion limited.

71
Q

what are the effects of enzyme induction on hepatic clearance?

A

large increase in clearance for low HER drugs. minimal effect on clearance of high HER drugs.

72
Q

what is “first pass metabolism”?

A

used to describe drugs with high HER - are removed from bloodstream almost entirely on the first pass through the liver. limited uptake from oral administration.

73
Q

what is the general purpose of hepatic drug metabolism?

A

to increase water solubility, so the drug may be secreted into bile, or renally excreted. some ‘pro’ drugs are activated in the liver.

74
Q

where do 95% of phase I hepatic metabolism reactions occur?

A

liver smooth ER

75
Q

describe phase I hepatic metabolism

A

non-specific reactions, recognise and attack specific side chains. oxidative reactions by adding OH or O groups to side chains. removal of CH3, NH2, SH. hydroxylated molecule is more soluble.

76
Q

what is cytochrome p450?

A

massive enzyme complex with a haem centre, which catalyses oxidative hydroxylation. major cytochrome in phase I reactions. needs energy and oxygen.

77
Q

describe phase II hepatic metabolism

A

conjugation reactions. addition of glucuronic acid to an -OH side chain of the drug to form glucuronide

78
Q

what is the impact of liver failure on drug metabolism/excretion?

A

minimal effect until 70% of functioning liver is lost. prolonged duration of action of many drugs, risk of accumulation and toxicity.

79
Q

list some different types of IV infusions

A

IV drugs, IV fluids, blood products, Ig, total parenteral nutrition

80
Q

why give IV infusions?

A

steady state plasma level can be maintained for as long as necessary. accurate drug delivery. some drugs are ineffective by other routes. closer to physiological processes than intermittent dosage.

81
Q

what considerations must be made for infusing drugs with a high volume of distribution?

A

small fraction will stay in plasma, long time to reach a steady state. adjusting infusion rate takes ages to change plasma concentration. ‘loading’ bolus dose often recommended.

82
Q

what is meant by a “steady state” in infusion therapy?

A

infusion dosage = rate of elimination from plasma

83
Q

what groups of patients are more prone to adverse effects of drugs?

A

pregnant women - avoid teratogenics.

breastfeeding women - can pass to infant.

patients with comorbidities - esp. liver/kidney diseases.

elderly people - polypharmacy, drug interactions, reduced renal clearance, nervous system sensitive to side-effects.

children - immature clearance systems

84
Q

what are some potential sources of error in drug prescribing?

A

the number of different times the same info is translated/transposed. inadequate info on admission. duplication - paper, different teams. clerical/legibility/administration errors. emergency situations.

85
Q

what are some patient risk factors for drug interactions?

A

age, polypharmacy.

lifestyle - OTC medications, “natural” remedies.

genetics, hepatic disease, renal disease

86
Q

what are the main types of drug interactions?

A

synergy - drugs interacting together, eg paracetamol and codeine for increased analgesic effect.

anatagonism.

other.

87
Q

what are some drug risk factors for drug interactions?

A

narrow therapeutic index, steep dose/response curve, saturable metabolism

88
Q

what is involved in pharmacodynamic interactions?

A

direct conflict between the effects of drugs

89
Q

what elements of drug absorption can lead to an interaction?

A

motility, acidity, solubility, complex formation, direct action on enterocytes

90
Q

what elements of drug metabolism can lead to an interaction?

A

cytochrome p450 inhibition - drug A blocks metabolism of drug B in plasma leading to increased effects.

induction - drug C induces CYP450 enzymes, increase drug B metabolism, decreased therapeutic effects

91
Q

how does grapefruit juice impact drug metabolism?

A

affects cytochrome P3A4

increases bioavailability

92
Q

how do receptor based drug interactions occur?

A

drugs that impact the same receptor types in different ways.

agonists, partial agonists, antagonists e.g. propranolol will reduce effect of salbutamol

93
Q

what do patients take that could influence response to prescription drugs?

A

food, alcohol, smoking, complementary medicines, homeopathy, medical herbalism, OTC meds

94
Q

what is the concept behind homeopathy?

A

BS, mostly.

“like to treat like” more dilute = more therapeutically potent (actually so dilute the solutions are unlikely to even contain a single molecule of original - “water memory”) basically relies on placebo effect

95
Q

what are the principles behind medical herbalism?

A

cleaning the body - removal of toxins.

mobilising the circulation - heating agents.

stimulating digestion - cooling agents.

nourishment and repair - tonic.

Phase 2a - Introductory Clinical Sciences (6 decks)

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