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PMCOL 200 > Pharmacology Intro > Flashcards

Pharmacology Intro Flashcards

1
Q

What is Pharmacology?

A

The study of how drugs interact with living systems

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2
Q

T or F. Drug receptors are usually proteins and drugs can influence their function

A

T

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3
Q

Pharmacokinetics

A
  • How drugs react with our body (before it reaches target receptor); absorption, distribution, metabolism, excretion (ADME)
  • How drugs are dosed, administered, how frequently, how much
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4
Q

Detailed interaction of drugs with specific receptors

A

Pharmacodynamics

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5
Q

T or F. Pharmacology is very applied life science

A

T

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6
Q

Antihistamine used in the 1980s and 1990s

A

Seldane (Terfenadine - generic)

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7
Q

Terfenadine

A
  • supposedly an H1 receptor antagonist (anti-histamine)
  • blockbuster drug b/c did not cause drowsiness
  • BUT actually, metabolized by liver into ACTIVE antihistamine form = fexofenadine
  • thus, terfenadine is a PRODRUG
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8
Q

Terfenadine to Fexofenadine

A

Alkylated group on drug is oxidized by metabolism in liver

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9
Q

Receptors

A
  • molecular target of drug

- actions of drugs is the result of their interaction with a target receptor

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10
Q

Prodrug

A
  • not intrinsically active

- activated by some metabolic step after administration

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11
Q

Terfenadine is metabolized quickly in liver by

A

first pass metabolism

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12
Q

A ‘good’ pharmacokinetic profile

A

long lifetime in body; especially that it’s not eliminated extremely quickly

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13
Q

Off-target effect of terfenadine

A
  • metabolism of terfenadine to fexofenadine is inhibited
  • inactive form can go to heart and cause cardiac arrhythmias
  • terfenadine is a very powerful blocker of certain proteins (hERG ion channels) that control electrical activity and beating of heart
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14
Q

‘Torsades de pointes’

A

off-target effect of terfenadine (runny nose medication)

  • potentially lethal cardiac arrhythmia
  • patients may be susceptible
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15
Q

Off-target effects

A
  • drugs not usually perfect for just one receptor type
  • sometimes they will influence closely related receptors (H1 vs H2)
  • sometimes they will influence completely unrelated receptors (H1 vs potassium channels in the heart)
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16
Q

Adverse events

A

undesirable drug effects

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17
Q

On-target effects

A

adverse events that arise

- related to the mechanism of action of the drug

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18
Q

NNT vs NNH

A

numbers needed to treat vs numbers needed to harm

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19
Q

Some reasons for adverse events of Terfenadine

A
  • substances that inhibit the activity of certain liver enzymes in drug metabolism (CYP3A4); diminished liver function, antibiotics (erythromycin) or antifungals + grapefruit juice (CYP3A4 inhibitor)
  • some patients will carry mutated versions of the genes encoding susceptible ion channel ‘off-targets’ in the heart
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20
Q

Simple solution to adverse effects of Terfenadine

A

administer metabolite of terfenadine which does not have cardiotoxic effects – Allegra

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21
Q

Pharmacogenomics

A

the genetic background of a patient can significantly affect how they respond to a drug

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22
Q

Drug interactions

A
  • very common for one drug/substance to adversely affect the response to another
  • ingesting multiple drugs at once can have unexpected consequences
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23
Q

Intracellular receptors

A
  1. receptors inside cell (drug has to be membrane permeable - hydrophobic)
  2. drugs must be lipid soluble (or transport mechanism)
  3. steroid hormones and their analogs
  4. mode of action: bind to LBD of a receptor, leading to displacement of HSP or other chaperone, this exposes DNA recognition domain and leads to activation of transcription of target genes
  5. effects have slow onset; long-lasting (not rapidly reversible)
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24
Q

A large fraction of therapeutic drubs target this family of transmembrane receptors

A

GPCRs

G proteins are distinct from receptors

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25
Q

GPCR - G proteins activity

A
  • at rest, G-alpha is bound to receptor and it is bound to GDP (nucleotide)
  • ligand binds to receptor, that triggers GDP/GTP exchange; G-alpha releases GDP and binds to GTP coupled to dissociation of G-alpha from complex;
    G beta gamma also dissociates and those can act as effectors in signalling pathways in the cell as they have downstream targets and vary depending on type of receptors activated
  • G-alpha while bound to GTP can also activate downstream signalling cascades
  • Eventually, G-alpha has intrinsic GTPase activity where it will hydrolyze GTP back to GDP form; “molecular timer mechanism” – return system back to basal resting state when it re-binds to receptor
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26
Q

G-beta/gamma vs G-alpha

A

G beta gamma (act as a unit) usually stays tethered with the membrane and they can directly activate various downstream effectors ; generates some signals

G alpha subunits have initial affects on initial components of a cascade that have much more downstream effects that allow for amplification of a signal = target adenylate cyclase (AC), and phospholipase C (PLC) - activated when G alpha q are activated

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27
Q

How are GPCRs usually categorized?

A

based on the subtype of G-alpha that it is associated with

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28
Q

Adenylate cyclase (AC)

A
  • an enzyme that will amplify signal by repeatedly causing ATP inside cell to move into a form called cAMP dependent protein kinases (biological signal) that will lead to activation of protein kinase A
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29
Q

Gs vs Gi

A

Gs trigger increased AC activity
Gi suppresses
** happens very quickly!

30
Q

Activation of Phospholipase C

A
  • Gq
  • leads to production of IP3 (from breakdown of PIP2)
  • IP3 triggers release of intracellular Ca 2+ stores (ER)
  • (from PIP2) DAG activates protein kinase C and target substrates
  • very quick!
31
Q

PLC

A
  • phospholipase C hydrolyzes phospholipids in the membrane
32
Q

TKRs

A
  • activation driven by dimerization of receptors in the presence of a ligand
  • receptors autophosphorylate and become activated
  • Receptor itself is a kinase (unlike GPCR where it relied on intermediates to phosphorylate)
33
Q

Fastest mechanism of signalling in the body

A

Ion channels; depends on electrical signals generated by these channels
binds AAs or neurotransmitters

34
Q

Ion channels

A
  • allow ions to cross plasma membrane very rapidly
  • changes in membrane voltage (underlies transmission of signals in the nervous system, beating of heart, etc.)
  • different ion channel types are controlled by distinct stimuli (ligand binding or membrane voltage changes); drugs that target these alter their response to these stimuli, or block the flow of ions
35
Q

Common drugs for psychiatric conditions target …

A

ligand-gated channels

36
Q

Other varieties of drug targets

A
  • structural proteins (microtubules)
  • DNA replication machinery (foreign or native)
  • membrane transport proteins
  • enzymes
  • foreign proteins (bacterial cell walls, bacterial DNA/RNA machinery)
37
Q

Agonism

A

a substance/drug binds to a receptor and influences its activity
-> usually depicted as a concentration-response curve

38
Q

EC50

A

effective concentration 50

- refers to the concentration of drug that yields a 50% maximal effect

39
Q

Emax

A

maximal biological effect observed with the drug

40
Q

Efficacy

A

term that refers to the maximal drug effect (Emax)

- biological response of some kind; effect size

41
Q

Potency

A

term that refers to the concentration dependence (EC50)
- drug with strong potency has a low EC50 (only small concentration needed to generate a large effect)
High EC50 = weak

42
Q

Drugs with different efficacy exhibit a difference in …

A

the maximal effect that can be achieved

43
Q

T or F. Receptors can have multiple agonists with distinct actions on the receptor

A

T!

44
Q

Drugs with different potency exhibit different…

A

concentrations required for a particular effect

45
Q

Agonists are usually categorized based on their

A

efficacy

46
Q

Different types of agonist and antagonist

A

full - can generate the maximal observed effect

partial - can generate a fractional effect

antagonist - cannot generate a biological effect on their own

inverse - cause suppression of basal activity

47
Q

Why is pharmacokinetics important?

A

they define how often or how much of a drug you should be taking in order for the conctn of the drug to be at its optimal level in your body for an optimal amount of time

48
Q

Important considerations for route of administration

A
  • convenience: it is easy to take a medication orally (vs. injection/IV, other routes)
  • bioavailability: different drugs may be absorbed with different efficiency from the gut
  • processing: hepatic portal circulation is a major consideration; drugs absorbed from the gut first encounter the liver BEFORE entering systemic circulation so there can be significant processing/breakdown
49
Q

Extraction ratio

A

clearance (liver)/blood flow
high extraction ratio = attractive property for prodrug but not for a drug delivered in active form, so cleared out and degraded quickly = low bioavailability

50
Q

Inverse of extraction ratio

A

related to bioavailability; thus, inversely proportional

51
Q

Routes of administration

A
  1. oral - most common; rate of absorption is slow and affected by intake of food; influenced by breakdown in the gut, processing in the liver (variable between indivs)
  2. intravenous - delivered directly into the systemic circulation; very rapid onset; inconvenient and requires expertise; high control over circulating level by controlling rate of infusion/amount injected
  3. intramuscular/subcutaneous - into muscle, or below skin; rate of absorption depends on blood flow to site; common use to “depot” preparations (slow dissolving for sustained releasE)
  4. inhalation - absorption is through epithelium in the lungs, and can be very rapid
  5. sublingual - rapid absorption route, also bypasses ‘first pass’ effects despite taking orally
  6. transdermal (ointment or patch) - convenient, slow absorption, and sustained exposure
52
Q

Bioavailability

A

fraction of unprocessed/unaltered drug that reaches the systemic circulation after administration by a particular route

53
Q

Distribution

A

in pharmacokinetics, refers to how a drug/substance is partitioned into different body ‘compartments’ after it is absorbed
-> can have a big influence on the effective concentration of a drug in the body, as well as the lifetime of the drug in the body

54
Q

2 Key Factors of Distribution

A
  1. binding to plasma proteins (eg. albumin)
    - drugs will circulate in an eq’m between ‘free’ and ‘bound’
    - usually only the ‘free’ fraction is considered to be pharmacologically active
    - some drugs are highly bound
  2. drug accumulation in tissues
    - accumulation is favoured for drugs that are lipophilic
    - more highly perfused tissues can accumulate more readily than tissues with poor perfusion
    - key parameter is VOD
55
Q

VOD

A

Volume of distribution
total amount of drug in body/[drug] (in blood, plasma, serum, unbound, etc.)
- not meant to represent a real volume; just a concept
- high VOD = longer lifetime

56
Q

T or F. The rate of elimination depends on the concentration of drug

A

T, reservoir of drug in the tissues can prolong the lifetime of the drug in the body

57
Q

Biotransformation

A

key mechanisms leading to elimination

  • metabolism in liver (phase 1 and 2)
  • excretion (kidney/gut)

**biotransformation refers to when the liver modifies a drug for excretion and it also describe the process when a liver modifies a prodrug into an active drug for example

58
Q

Metabolism in liver phases

A

1 - mixed function oxidase system (CYP family enzymes) generates oxidative modifications of drugs (hydroxylation, dehydrogenation, etc.)
2 - conjugation of parent compound, or phase 1 product with large polar adducts to make the product more prone to excretion

59
Q

How is a drug eventually excreted?

A
  1. bile/feces:
    - biotransformed drugs in the liver are incorporated into bile and secreted into the gut
    - modifications (large polar adducts) make these drugs more polar and less prone to be reabsorbed in the digestive tract
  2. urine:
    - drug passes through glomerular filtration, or is actively secreted in to the renal tubule, and excreted in urine
60
Q

Why is drug elimination typically described by a half-life?

A

enzymes and systems mediating drug elimination are not saturated; exponential decay equation can be used to describe elimination

61
Q

In a few notable cases, especially ethanol, elimination is capacity limited

A

bc ethanol concentrations are much higher than the affinity of a key enzyme involved in their elimination
-> capacity-limited elimination

62
Q

How is safety or efficacy studied/surveilled?

A
  • Controlled human studies = after considerable pre-clinical development, optimization, animal testing = to assess dosage, administration, safety, efficacy
  • Phase 1: small scale (Dozens of subjects), testing for tolerable dosing ranges, bioavailability, excretion
  • Phase 2: intermediate scale (hundreds), testing for efficacy (sometimes different dosages), monitoring for safety in greater numbers of patients
  • Phase 3: large scale, randomized, double-blinded trial, compared against a placebo or current accepted treatment
63
Q

Systematic reviews, meta-analysis

A

gold standard; approach to combine data from multiple trials, often after a drug has been approved; help guide future policy

64
Q

Forest plots provide data on:

A
  • # of trials
  • size of each trial (size of symbol)
  • outcomes of trials (not always consistent)
  • overall summary of all trials
  • OR (odds ratio): ratio of event rate in treatment vs control (which one is favoured in individual trials, vs overall)
65
Q

Therapeutic index

A

ratio of the median toxic dose and effective dose

  • TD50/ED50
  • the bigger the difference (ED50 and TD50) the better bc it gives you a much bigger window with patients who are not responding a slightly higher dose to see if they respond before they begin to have adverse outcomes
66
Q

In patient studies, effect or toxicity is often described using a…

A

quantal dose-response curve

67
Q

Relative risk reduction

A
  • 1 - (event rate on treatment group/control group)
  • event = defined in whatever study you are reading; ex: death by any means, etc.
  • reporting relative risk reduction while de-emphasizing other important info is misleading
68
Q

Absolute risk reduction

A
  • more descriptive way to report the benefit of taking a drug
  • described absolute number of cases that are prevented by taking a drug (rather than a percentage relative to baseline)
  • = event rate in control - event rate in treatment group
  • policymakers will use this to determine if rate of benefits are good enough for the public health to fund this
69
Q

Number needed to treat

A
  • another way to think about absolute risk, or population-level benefit of a drug
  • = 1/ARR
  • x ppl need to take drug in order for 1 to see beneficial effect
70
Q

Key points to consider about NNT

A
  • low NNT is good; NNT = 1 means just about everybody taking drug will receive desired benefit
  • high NNT not good
  • NNH ; low NNH is bad and high is good!
  • some drugs are given with a high NNT bc the potential outcome they are preventing are very very severe like death or so on.. Falls on judgement of regulators to decide whether the benefit to a population outweighs the potential risk to a population
71
Q

What does a negative absolute risk mean?

A

means that an event has a higher rate in the experimental group so 1/ARR = number needed to harm

PMCOL 200 (4 decks)

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