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PHYL2064 > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

Define pharmacology

A

the science of drugs, their MOA, how their effects can be measured, their discovery, design and development, their actions on the organism and the actions of the organism on them.

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2
Q

What are the three types of names a drug has?

A

chemical, generic, trademarked

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3
Q

What kinds of drugs are able to be purchased over the counter?

A

those with high therapeutic indexes which means that a dose of the drug that may cause toxicitiy is hugely different from a therapeutic dose.

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4
Q

What are the 4 drug targets?

A

receptors, ion channels, enzymes & transporters

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5
Q

Why do drugs interact with some receptors, transporters, or enzymes but not others?

A

binding of the drug is very specific and if the receptor is activated change can occur within the cell. These interactions may be based on charge, hydophilicity/phobicity or shape.

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6
Q

Where are target receptors found?

A

can be on the cell membrane or intracellular

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7
Q

Name the 4 types of receptors from fastest acting to slowest.

A

ligand-gated ion channels, g-protein coupled receptors, kinase-linked receptors & nuclear receptors

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8
Q

What is the most common drug target?

A

G-protein coupled receptors (~40%)

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9
Q

Ligand-gated ion channels (onset, location, MOA, i.e.)

A

located on the cell surface
rapid-acting (milliseconds)
opens ion channels to allow direct movement of ions
i.e. nicotinic acetylcholine receptors.

AKA ionotropic repectors.

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10
Q

G-protein coupled receptors (onset, location, MOA, i.e.)

A

located on the cell surface
acts in seconds to minutes
activates a second messenger within the cell
i.e. beta-adrenoreceptor.

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11
Q

Why do g-protein coupled receptors often vary in response?

A

due to differing alpha subunits and intracellular second messengers

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12
Q

Describe the 4 step process of a g-protein coupled receptor being activated by a drug

A
  1. starts in a resting state
  2. agonist drug binds with receptor and alpha unit bound GDP (inactive) interacts with intracellular GTP (active)
  3. GTP dissociates from receptor and activates the target protein, while the other subunits (b & y) may also activate a 2nd target protein
  4. GTP hydrolysis occurs and the alpha subunit returns to the receptor
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13
Q

Kinase-linked receptors (onset, location, MOA, i.e.)

A

located on the cell surface
acts in minutes to hours
activates an enzyme cascade effect via a change in receptor shape within the cell
i.e. insulin receptors

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14
Q

What process is of particular relevance for kinase-linked receptors?

A

amplification (because they use a cascade effect)

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15
Q

What two changes occur during the kinase pathway after being activated by a drug?

A

kinase (adding a phosphate)
phosphatase (removing a phosphate)

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16
Q

Nuclear receptors (onset, location, MOA, i.e.)

A

intracellular
slowest acting (hours)
ligands cross the cell membrane directly and bind with receptors within the cell
i.e. estrogen receptor

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17
Q

Describe the process of a nuclear receptor being activated by a drug

A

ligands/hormones move across cell membrane and interact with the receptor within the cell

the hormone & receptor both migrate to the DNA within the nucleus, binding to key sequences in the DNA to cause transcription of desired proteins

biological action is then caused by mRNA synthesising new proteins within the cytoplasm

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18
Q

What affect do drugs have by targetting transporters?

A

blocking the transporters actions and not allowing the uptake of molecules

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19
Q

Give an example of a drug that targets transporters

A

anti-depressive drugs target a serotonin transporter located on the presynaptic side of a synapse

by doing this serotonin levels stay increased for a longer period increasing the chance that they will bind to receptors and thus improve signalling

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20
Q

Describe the MOA of drugs that target enzymes

A

these types of drugs (whether agonistic or antagonistic) closely resemble a substrate that an enzyme would normally bind with

often called a ‘lock & key’ mechanism these drugs can bind with the enzyme and either elicit a response (agonist) or block the natural agonist from eliciting a response (antagonist)

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21
Q

Enzyme inhibition can be described as what?

A

competitive, non-competitive, uncompetitive or functional

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22
Q

What is the difference between competitive and non-competitive inhibition?

A

competitive involves a drug binding with the active site on an enzyme and blocking the action of another substrate

non-competitive involves a drug binding to a secondary site (aka allosteric site) and changing the shape of the enzyme’s active site, disallowing a substrate to bind as it will no longer ‘fit’

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23
Q

What is the difference between an agonist drug and antagonist drug?

A

agonist produces a physiological change by binding to it’s receptor

antagonist clocks a normal physiological response by blocking its receptor from binding to other substrates

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24
Q

Are all agonists as effective as each other?

A

no- agonists can be high or low affinity agonists

high affinity means they will bind more readily, low affinity means there might need to be a higher concentration present to create the same effect

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25
Q

The response to a drug increases as the concentration does but it will plateau at some stage. Why is this?

A

because the receptors have a maximum carrying capacity so once all the available sites have been binded, there is no way to elicit more of a response. This is referred to as a ‘saturable’ manner.

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26
Q

Log scales are used to compare drugs, what measurement is often used?

A

the EC50 or the effective concentration for 50% effect

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27
Q

What are the y and x-axis of a concentration-response curve graph?

A

y-axis= response
x-axis= concentration

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28
Q

While looking at a concentration-response curve, which way will the curve shift to indicate that a drug is more potent?

A

to the left

a lower concentration is needed to elicit a response

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29
Q

While looking at a concentration-response curve, which way will the curve shift to indicate that a drug is more effective?

A

upwards

the same concentration has a larger response

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30
Q

Antagonists can be competitive, non-competitive, uncompetitive, or functional. What is uncompetitive antagonism?

A

where the antagonist binds permanently to the active site of its receptor

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31
Q

What type of antagonism can be reversed with an increase in agonist concentration?

A

competitive

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32
Q

What is functional antagonism? Give an example.

A

the sum of activity from two different drugs acting on two different receptors in an antagonistic way

acetylcholine causes gut motility while adrenaline slows it down, the tissue response will be a sum of both actions

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33
Q

How does drug tolerance occur?

A

through desensitisation or loss of receptors over time

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34
Q

What does ADME stand for?

A

Administration/Absorption
Distribution
Metabolism
Excretion

it refers to the pharmacokinetics of a drug

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35
Q

What is the quickest way to administer a drug and see effects and why?

A

intravenous because it does not undergo first pass in the liver

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36
Q

Name some things that can affect the absorption of a drug.

A

concentration gradient, gut motility, blood flow at the site of administration, formulation (rate of drug release by design), GI tract contents & lipophilicity of the drug

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37
Q

What is the first-pass effect?

A

if a drug is taken orally it must travel from the gut and through the liver before entering the bloodstream

at the liver ‘first-pass’ metabolism occurs as it tries to detoxify the body of the drug by metabolising it

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38
Q

What term describes how much of a drug is available for the blood stream after its first-pass through the liver?

A

bioavailabilty

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39
Q

What is the bioavailability of morphine?

A

20% (80% is metabolised during first-pass)

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40
Q

Distribution of a drug depends on what?

A

whether it is ‘free’ or ‘bound’ in the blood

drugs bound to proteins are inactive and cannot have an effect whereas free drugs are active and can

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41
Q

Why is it important to consider the concentration of bound drugs within the bloodstream even though they are inactive?

A

because if a binding protein is currently fully saturated with one drug, adding a second drug may displace some of the original drug resulting in higher concentrations of it free in the blood and possibly may have toxic effects

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42
Q

What is the purpose of the metabolism of drugs?

A

to increase the rate of elimination and decrease the likelihood of toxicity

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43
Q

How does our liver make drugs more easily metabolised?

A

by increasing the water solubility of the drug so that it can more easily be excreted in the urine

44
Q

There are two types of enzymatic reactions that occur during metabolism, what are they?

A

phase 1 reactions & phase 2 reactions

45
Q

What occurs during phase 1 enzymatic reactions?

A

oxidation, reduction & hydrolysis

46
Q

What occurs during phase 2 enzymatic reactions?

A

adding of a water-soluble molecule to the drug i.e., glucuronide, glutathione, sulphate, acetate

47
Q

Which enzyme family is associated with oxidative phase 1 reactions?

A

cytochrome P450 (CYP) family

most lipophilic drugs and environmental chemicals are substrates for one or more forms of P450

48
Q

What is the clinical significance of two drugs being metabolised by the same enzyme i.e. CYP?

A

this results in an interaction where the CYP enzyme is inhibited by drug A, resulting in decreased metabolism of drug B and therefore higher concentrations of drug B possibly resulting in toxicity

49
Q

In general, phase 2 metabolites are more … charged, more … soluble and more likely to be … by the liver and kidneys. This means they are … toxic.

A

highly charged
water soluble
excreted by kidneys and liver
less toxic

50
Q

Name some factors that affect drug metabolism

A

genetics, age, gender, other drugs being taken, food

51
Q

What are pro-drugs? Give an example.

A

a drug that requires metabolism to become active

i.e., codeine is metabolised to its active form morphine

52
Q

What is the role of the kidney in metabolism?

A

excretion primarily occurs here which is why young people, elderly people and people with renal disease must be monitored as they may have slower/impaired excretion of drugs and might be at risk of toxicity

only free drug can be filtered at the glomerulus, actively secreted in the proximal tubules (with the involvement of transporters), and reabsorbed in the distal tubules via passive diffusion

53
Q

What is the purpose of SAIDs & NSAIDs

A

decrease inflammation and pain

54
Q

Describe the 4 major events in a local inflammatory response

A
  1. chemical signals released by activated macrophages and mast cells at the injury site cause nearby capillaries to widen and become more permeable
  2. fluid, antimicrobial proteins and clotting elements move from the blood to the site, clotting begins
  3. chemokines released by various kinds of cells attract more phagocytic cells from the blood to the site
  4. neutrophils and macrophages clean up pathogens and cell debris, tissue heals
55
Q

How does inflammation clinically present?

A

redness, heat, pain, swelling and possible loss of function

56
Q

What are inflammatory mediators/cytokines? Give some examples.

A

chemical messengers secreted by numerous inflammatory cells and control inflammation

eicosanoids (derived from arachidonic acid i.e., prostaglandins & leukotrienes) and histamine

57
Q

How does the response time differ between eicosanoids and histamine and why? What is the clinical significance of this time delay?

A

histamine release can occur immediately because it is stored within mast cells whereas eicosanoids take time to be produced

there may be a delayed onset of swelling

58
Q

How are cytokines produced?

A
  1. inflammatory stimulus brings arachidonic acid from the phospholipid bilayer
  2. enzyme PLA1 turns this into free cytosolic arachidonic acid
  3. COX-1 & COX-2 turn this into prostaglandins and thromboxane
59
Q

What is the significance of COX-1 and COX-2 in the inflammatory process?

A

they are involved in making prostaglandins which are some of the big player chemical messengers in inflammation

60
Q

Glucocorticoids are a type of SAID, what are some common drugs under this banner?

A

hydrocortisone, prednisolone & dexamethasone

61
Q

Describe the MOA of SAIDs

A

two mechanisms, 1 reduces the synthesis of COX-2 which is an enzyme important for the synthesis of prostaglandins while 2 increases the transcription of lipocortin-1 which inhibits PLA2 (a type of prostaglandin)

62
Q

What indicates the use of SAIDs?

A

transplant rejection, rheumatoid arthritis, inflammatory bowel disease, psoriasis, lupus, asthma/allergies & septic shock

63
Q

What are some adverse effects of SAIDs?

A

immunosuppressive activity, worsen diabetes, sodium & water retention, increased risk of peptic ulcers and may increase osteoporosis

64
Q

True or false, NSAIDs are the most prescribed drug in the world?

A

true

65
Q

Name some relevant NSAIDs

A

ibuprofen, aspirin, COX-2 selective antagonists

66
Q

What are the 3 effects of all NSAIDs?

A

anti-inflammatory, anti-pyretic & analgesic

67
Q

What is the MOA of the anti-pyretic effects of NSAIDs?

A

act by interrupting the synthesis of PGE (produced by hypothalamic interleukin-1 or IL-1) whose role it is to elevate the body’s normal temperature set point from ~37 as set by the hypothalamus

68
Q

What is the MOA of the analgesic effects of NSAIDs?

A

indirectly reduces pain by reducing inflammation and therefore stimulating effects on nociceptors

69
Q

What is the MOA of the anti-inflammatory effects of NSAIDs?

A

inhibition of prostaglandin synthesis through inhibition of COX-1 & COX-2

70
Q

What indicates the use of NSAIDs?

A

swelling in arthritis, bone fractures, soft tissue injury, post-operative & dental pain, menstrual pain & headaches/migraines

71
Q

Compare COX-1 & COX-2 enzymes.

A

COX-1 ‘housekeeping’: coats stomach with mucus, aid in platelet aggregation, regulate renal blood flow, induce childbirth

COX-2 ‘inflammatory response’: sensitises skin receptors, increases body temperature by acting on hypothalamus, recruits inflammatory cells towards injured site, some role in renal homeostasis (only protective factor)

72
Q

True or false… the severity of the side effects of NSAIDs is indirectly proportional to the effectiveness of the anti-inflammatory

A

false, they are directly proportional

73
Q

What are the major side effects of NSAIDs?

A

GI upset:
-inhibition of gastric mucosal production by PGs
-blockage of the acid-secreting inhibitory effects of PGs due to systemic exposure to NSAIDs, not gastric exposure
-although direct irritation of the gastric mucosa may contribute

Renal effects:
-reduce renal blood flow/increased toxic effect of drugs
-due to inhibition of PG/prostacyclin production that maintains high renal blood flow

Cardiovascular effects:
-anticoagulant effects of some NSAIDs can prolong bleeding time leading to excessive bleeding/bruising

Uncommon effects:
-skin reactions of idiosyncratic rashes, erythematosus, and photosensitivity

74
Q

What is the MOA, affinity of COX-1 vs COX-2 and potential side effects of Aspirin?

A

irreversibly inhibits COX-1 & 2 through COX acetylation

> 10:1

reduced blood clotting, nephrotoxicity, gastric irritation, delay labour, CNS effects + Reye’s syndrome in children

75
Q

What is the MOA, affinity of COX-1 vs COX-2 and potential side effects of ibuprofen?

A

competitive reversible inhibitor of COX-1 & 2

1:2

increased risk of thrombosis, GI upset, better tolerated than other NSAIDs + safe for children

76
Q

What is the MOA, affinity of COX-1 vs COX-2, and potential side effects of COX-2 specific inhibitors such as celecoxib?

A

selective inhibition of COX-2

1:30

increased risk of heart attack + stroke, increased risk of GI bleeding

77
Q

What causes the negative side effects of COX-2 selective drugs?

A

reduction of PGI2 (prostacyclin) in blood vessels which is antithrombotic (reduces clotting) and antiatherogenic (plaque formation in arteries)

reduction of PGI2 & PGE2 in the kidneys which can result in hypertension and oedema as arterial pressure homeostasis is disrupted

78
Q

Given the side effects, how can COX-2 selective drugs be used safely?

A

they should be administered for a maximum of 3 weeks and are not recommended for patients before or after heart bypass surgery

79
Q

Which COX is paracetamol selective for and what are some potential side effects?

A

COX-3 selective (within the brain)

highly hepatoxic when overdosed due to metabolism in the liver

toxic doses:
10g= hepatoxicity
20-30g= fatal dose

80
Q

Which has a better anti-inflammatory effect, paracetamol or NSAIDs?

A

NSAIDs

81
Q

Which has a better anti-pyretic effect, paracetamol or NSAIDs?

A

paracetamol

82
Q

Which is better tolerated, paracetamol or NSAIDs?

A

paracetamol

83
Q

Describe how paracetamol overdose can occur

A

after a normal dose most of the drug is converted to non-toxic metabolites while 5% is oxidized via the cytochrome P450 enzyme system

this creates a highly reactive intermediary metabolite N-acetyl-p-benzoquinoneimine (NAPQI) and is normally detoxified by conjugation with GSH

during overdose, the normal metabolism pathways become saturated, and more NAPQI is produced while GSH supplies become exhausted

84
Q

Describe the 4 phases of paracetamol overdose

A

Phase 1 (0-24 hours) nausea and vomiting

Phase 2 (24-72 hours) right upper quadrant pain, elevated liver enzymes

Phase 3 (72-96 hours) vomiting, symptoms of renal failure, pancreatitis

Phase 4 (>4 days) resolution of symptoms or progression to fatality

85
Q

So how do we treat paracetamol overdose?

A

by administering acetylcysteine which replenishes GSH to better metabolise NAPQI

86
Q

How does alcohol consumption increase the likelihood of paracetamol toxicity?

A

it depletes GSH

87
Q

Define an adverse drug reaction (ADR)

A

any response to a drug which is noxious, unintended, and which occurs at doses normally used for therapy or disease

88
Q

Are ADRs more common in men or women?

A

women

89
Q

What are the 5 types of ADRs?

A

Type A, B, C, D & E

90
Q

Describe Type A ADRs, how are they addressed?

A

acute, predictable and related to MOA or ADME (specific groups may be more at risk of this type of ADR with metabolism playing a large role)

addressed by reducing dose of drug

91
Q

Give an example of a Type A ADR

A

phenytoin is an anticonvulsant used for epilepsy with a very narrow therapeutic index whereby 5ug can be the difference between therapeutic effects and toxic effects

92
Q

What are the 3 mechanisms of drug metabolism that impact type A ADRs?

A

competitive inhibition of P450s, potent inhibition of P450s & potent induction of P450s

93
Q

How does competitive inhibition of P450s occur?

A

when two drugs are competing for the same P450 enzyme resulting in inhibition of the metabolism of one or both drugs leading to an increase in circulating drug levels of both drugs

94
Q

How does potent inhibition of P450s occur?

A

happens when taking a drug that inhibits CYP at the same time as a drug that uses CYP for metabolism resulting less metabolism of the second drug

95
Q

How does potent induction of P450s occur?

A

happens when drug B induces an enzyme needed to metabolise drug B and now drug A’s effect is sub-therapeutic

96
Q

Describe type B ADRs

A

unpredictable, not necessarily related to MOA but may involve patient qualities (often is as a result of an allergic reaction)

97
Q

Give an exmaple of a type B ADR

A

anaphylaxis

98
Q

What percentage of ADRs reported are type B?

A

~20%

99
Q

Describe type C ADRs

A

chronic (continuous) effects which occur with long-term use of a drug as a result of drug tolerance

100
Q

Give an example of a type C ADR

A

medications that are used for schizophrenia over a long period of time may reduce the levels of dopamine in the substantia nigra and give rise to movement issues like dyskinesia

101
Q

Describe type D ADRs

A

delayed effects such as carcinogenicity (causes cancer) or teratogenicity (cause malformation of embryo)

102
Q

Give an example of a type D ADR

A

thalidomide used for anxiety was discovered to have caused 1000s of children to be born with limb formation abnormalities

103
Q

Describe type E ADRs

A

end of treatment effect/withdrawal symptoms

104
Q

Give an example of a type E ADR

A

withdrawal of opioids can cause anxiety, irritability, restlessness, and sleep disturbances as well as muscle aches, hypertension, and fever/vomiting/diarrhea

105
Q

What is a prescribing cascade?

A

when a new drug is given to counteract the side effects caused by a previous drug prescription

106
Q

What are some examples of possible prescribing cascades?

A

cholinesterase inhibitors > incontinence > anticholinergics

NSAIDS > hypertension > antihypertensives

107
Q

How do we avoid prescribing cascades?

A

by beginning new drugs at lower doses and adjusting accordingly, considering potential symptoms to be caused by ADR’s, asking patient’s if they have experienced new symptoms since changing medications, providing patient’s with information about possible side effects and what to do if these occur

PHYL2064 (7 decks)

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