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pharmacology unimelb > pharmacological principles (week 1-4) > Flashcards

pharmacological principles (week 1-4) Flashcards

1
Q

List the 3 drug origins

A
  1. Synthetic chemicals
  2. Biotech product
  3. Phytochemical
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2
Q

Define and give an example of a drug with a synthetic chemical origin

A

Synthetic chemicals = produced in factories/chemists synthetically.
EXAMPLE: aspirin produced by chemical reactions from starting molecules

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3
Q

Define and give an example of a drug with a biotechnology product origin

A

Biotech product
EXAMPLE: recombinant antibodies or recombinant proteins (insulin)

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4
Q

Define and give an example of a drug with phytochemical origin

A

Photochemical = from plants
EXAMPLE: morphone and codeine from poppy seeds

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5
Q

What is pharmodynamics?

A

Pharmodynamics = what drugs do to your body

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6
Q

What is pharmacokinetics?

A

Pharmacokinetics = what the body does to drugs

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7
Q

What is a drug target?

A

Drug target = a drug binding site that upon association with a drug leads to a change in a physiological response

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8
Q

List and describe 3 examples of drug targets that are NOT proteins

A
  1. anti-cancer drugs and anti-microbial drugs that bind directly to DNA
  2. anti-sense oligonucleotides or small interfering RNAs target RNA not protein
  3. bisphosphonates that bind to calcium salts in the banes
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9
Q

In what scenario does a drug NOT have a drug target?

A

Antacid correcting pH balance - technically doesn’t bind anywhere

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10
Q

What are the 4 protein targets of drugs?

A
  1. Receptors
  2. Ion channels
  3. Carriers (transporters)
  4. Enzymes
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11
Q

Define a receptor as a drug target, including how it functions and different ways it acts functionally

A

Receptors = biological macromolecules that recognise and respond to endogenous chemical signals or exogenous drugs

It binds to a ligand (molecule that binds to a receptor) at a binding site (where ligand binds to receptor)

Agonist = a ligand that activates a receptor - turns on that receptor and activates some form of signaling pathway

Antagonist = a ligand that binds to a receptor without activity - binds and sits there, blocking whatever normally binds there

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12
Q

What are the 4 receptor types?

A
  1. ligand-gated ion channels (ionotropic receptors)
  2. g-protein-coupled receptors (metabotropic)
  3. kinase-linked receptors
  4. nuclear receptors

All four receptor types are extremely common targets used in pharmaceuticals

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13
Q

Describe the process in which ligand-gated ion channels functions

A
  1. Some sort of channel ions will travel through
  2. Causes hyperpolarisation or depolarisation of cell - like action potentials and nerves
  3. Result is cellular effect - very quick effect (milliseconds)
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14
Q

List and describe the characteristics of ligand-gated ion channels

A

> Millisecond timescale

> Most often binds extracellularly (gate is on cell surface), but can bind intracellularly

> Ligand binding alters conductance of selective ions through channel resulting in cellular effect

> Tube-like macromolecules w/ protein subunits that pass through plasma membrane

> 3-5 subunits arranged around central aqueous channel (pore)

Acronym: MELTS
M = Milliseconds
E = Extracellular
L = Ligand -> conductance
T = Tube
S = Subunits

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15
Q

Give and describe an example of a ligand-gated ion channel

A

Nicotinic Acetylcholine Receptor
> Receptor has 5 subunits: 2x alpha subunits, beta subunit, gamma subunit, delta subunit
> Won’t open without acetylcholine

PROCESS:
1. Alpha subunit is ligand binding domain - where acetylcholine will bind and open up the channel

  1. Sodium channels will flow into the cell causing an action potentia
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16
Q

Describe the process in which G-protein coupled receptors functions

A
  1. Have GPCR, a seven-trans membrane style receptor, on the outside of that receptor ligand will bind
  2. On inside of receptor G-protein will couple
  3. Ligand binds turning on the receptor
  4. Receptor will turn on a G-protein - an intracellular signalling complex made up of an alpha, and beta and gamma subunits - is normally bound to GDP but when activated is converted to a GTP
  5. G-protein couples the receptor through to other effector which will often turn on some other signalling, creating a domino effect of signalling - phosphorylation cascade
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17
Q

List the structural features of a G-protein coupled receptor

A

> 7 transmembrane regions

> extracellular region - ligand-binding domain

> G-protein alpha and beta-gamma subunits

> effector cell - enzymes, ion channels, transporters, gene transcription regulators

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18
Q

List and describe the characteristics of G-protein coupled receptors

A

> These receptors are more general and most abundant (most common) - 33% of targets in 2017 - although other types are starting to catch up

> G-proteins can be stimulatory or inhibitory

> Can couple a range of things (effector) - enzymes, ion channels, transporters, gene transcription regulators

> When effector activates secondary messenger can end up with protein phosphorylation cascade, but ALSO sometimes have changes in calcium depending on what’s happening

> Seconds timescale

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19
Q

Give and describe an example of a G-protein coupled receptor

A

Muscarinic Acetylcholine Receptor

PROCESS:
1. Starts with standard GPCR and G-protein with GDP bound = is inactive

  1. Agonist binding then GTP swaps in for GDP causing the activation of the G-protein
  2. Alpha unit if g-protein will diffuse away and bind to effector
  3. Once effector is turned on GTP hydrolyses and get inactive form of G-protein again
  4. Agonist will come off and process will repeat
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20
Q

List and describe the characteristics of kinase-linked receptors

A

> Unlike G-protein coupled (linked to g-proteins) is linked to kinase -
1. Enzymatic Cytosolic Domain = receptor itself has intrinsic kinase action to turn on phosphorylation, OR
2. Link to Adapter Enzymes = is an adapter kinase that will do that

> General result is phosphorylation then gene transcription and protein synthesis

> Takes hours to take effect

> Are single-membrane-spanning proteins - unlike G-protein coupled receptors that have 7 membrane spamming domains = transduce signals by forming dimers, work through modulating phosphorylation

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21
Q

List the 3 types of kinase-linked receptors

A

THREE KINASE-LINKED RECEPTOR TYPES:
1. Receptor tyrosine kinases (RTKs)
2. Receptor serine/threonine kinases
3. Cytokine receptors

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22
Q

Describe the process in which receptor tyrosine kinase (RTK) would functions

A

Single protein with extracellular ligand binding domain =

  1. Helix to go through membrane with intrinsic tyrosine kinase domain in the middle
  2. Once ion binds get dimerisation of two subunits of receptors = tyrosine autophosphorylation
  3. End up with twho knase domains that come into proximity and phosphorylate each other and turn on the receptor
  4. Receptor/phosphorylation intracellularly is what’s turning on signaling cascade - get cascaded phosphorylation
  5. Results in activation of transcription factors and change in gene expression - happening over hours
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23
Q

Describe the process in which receptor serine/threonine kinases would functions

A

Same process as receptor tyrosine kinase (RTK) - EXCEPT, instead of tyrosine have a serine or threonine getting phosphorylated

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24
Q

Describe the process in which cytokine receptors would functions

A

Operates differently to tyrosine/serine/threonine kinases =

  1. Cytokine binding to receptor on extracellular domain
  2. Alpha helix through membrane but doesn’t have enzymatic activity on the inside
  3. Instead recruit Jak (in this case) - a cytosolic kinase that does the same thing as enzymatic activity in other kinase-linked receptors
  4. Turns on phosphorylation
  5. Phosphorylation can be recognised by trascription factor Stat (in this case)

This is referred to as “JACKSTAT” signaling pathway - commonly presented, generic mechanism that’s activated by cytokines

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25
Q

List and describe the characteristics of nuclear receptors

A

> Are intracellular receptors (as compared to surface style or extracellular receptors)

> Don’t have to be IN nucleus - but action happens within nucleus

> Generally monomeric proteins = 1 subunit - often this will dimerise once activated

> Since are intracellular drug must get inside the cell - drugs commonly lipophilic

> Nuclear receptor class can:
- be transcription regulatory factors
- have enzymatic activity
- sit within cytoplasm or nucleus

> going to affect gene transcription - resulting in changes in protein synthesis and cellular effects

> Similarly to kinase-linked receptors will take hours (as is at gene transcription level)

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26
Q

Give and describe an example of a nuclear receptor

A

Estrogen Receptors (ER) - Steroid Hormone Receptors =

  1. Is initially in cytoplasm of the cell
  2. Steroid is lipophilic molecule that can easily pass through lipid bilayer of cell
  3. Once gets intracellular will bind to receptors - which is typically kept in a complex and inactive state
  4. Once activated (often dimerising) - translocates into the nucleus binding to DNA and changing transcription
    NOTE: Doesn’t always have to change transcription through binding directly to DNA, can bind to other transcription factos
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27
Q

Define an ion channel as a drug target, including how it functions and different ways it acts functionally

A

> This type of drug target is not mutually exclusive from ligand-gated ion channels - can overlap in terms of definition, is also a type of ion channel

> All ion channels are gateways for through cell membranes for ions

> Very selective of ions allowed through channel - important for membrane excitability = stimulation of action potentions, hyperpolarisation and depolarisation

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28
Q

List the two main types of ion channels

A
  1. Ligand-gated channels = type of receptor, open in response to ligand binding - block ion channel itself
  2. Voltage-gated channels = open in response to changes in transmembrane voltage - moldulate conductivity of ion channel
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29
Q

Define a carrier/transporter as a drug target, including how it functions and different ways it acts functionally

A

> Gateways for passage of polar and small molecules and ions - not ion channels, are active transporters to get things across liipophilic cell membrane = pumps

> As are pumps, need an energy source = can use ions and electrochemical grandients to exploit their energy to transport something else as well - OR use classic energy, ATP, hydrolising it for energy

> Because are pumps can pump drugs into and out of the cell

> Explain how different people react differently to drugs that are ‘pharmacokinetics’ - if one individual has lots of a pump may pump drug all the way out of all cells, someone else might have different expression levels and not pump it all out of the cell = different responses

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30
Q

Name an example of a carrier/transporter receptor

A

Selective serotonin reuptake inhibitors (SSRIs)

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31
Q

Define an enzyme as a drug target, including how it functions and different ways it acts functionally

A

> Enzymes are targeted by mimicking endogenous substrate - normally enzyme will chop up something to do something = if give a substrate that looks a lot like endogenous substrate it will bind in same area but won’t be able to do what it typically does

> Typically will act as competitive inhibitor

> Sometimes binding can be non-competitive or can be irreversible - but most of drugs will bind to receptors and come off

> Typically won’t be positive or a permanent change to enzyme/drug target

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32
Q

Name an example of an irreversible enzyme targeting drug

A

EXAMPLE: Aspirin - binds irreversibly, covalently attaching to target enzyme, cyclooxygenase (COX)

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33
Q

What is a pro-drug, and what’s an example of a drug that has an enzyme as it’s target as a pro-drug

A

Some drugs require enzymatic activation - pro-drugs
–> ie. given inactive drug that once gets to certain area of the body where you want it to work enzyme there will convert it to the right drug you want

EXAMPLE: Codeine - not particularly active itself but body will convert it into morphine as active compound within body that will have opiate effect

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34
Q

Describe an enzymes function surrounding drug metabolism

A

Enzymes are very important for metabolism and drugs will often be metabolised - can have negative effect though as many are metabolised into toxic compounds

EXAMPLE: paracetamol - high doses is toxic not because paracetamol is toxic but because its converted into something toxic

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35
Q

What is the importance of selectivity for drugs?

A

> Drugs are rarely entirely selective - selectivity for target depends on affinity (dosage, concentration etc.)

> More selective a drug is the less likely it is to bind to things we don’t want it to and have adverse effects

> Different tissues and cell types may express same drug type - important to consider how drugs move around the body (pharmacokinetics

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36
Q

What is an example demonstrating the importance of drug selectivity?

A

Antidepressant was initially nonselective - tricyclic antidepressant (TCA) could cause respiratory depression - SSRIs now more selective for certain receptors and less dangerous

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37
Q

Define ‘pharmacodynamics’

A

Effect of drugs on the body

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38
Q

What is the binding and cell activation process for an agonist?

A
  1. Binding to receptor (either on surface or within the cell)
  2. Stimulus occurs within the cell promoting a change in cellular biochemsitry
  3. Change in cellular biochemistry causes a response and change in cell behaviour
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39
Q

Define Affinity as a drug property

A

Likelihood or tendency of ligand to bind to receptor - measure of the attraction of a ligand for biological target

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40
Q

Define Efficacy as a drug property

A

Chance that a bound ligand will induce a signaling change within the cell - strength of a drug in evoking a response of tissue

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41
Q

What effects the likelihood of binding and then a response occuring?

A

Binding likelihood increases when there is an increased amount of the ligand or increased receptors

  • Affinity
  • Efficacy
  • Potency

NOTE: Just because a ligand binds doesn’t mean it will produce an effect - antagonists

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42
Q

How is affinity quantified?

A

Equilibrium dissociation constant - Ka for agonists, Kb for antagonists

Ka/Kb = off-rate / on-rate

Off-rate = amount of drug coming off receptor
On-rate = amount of drug bound to receptor

Higher affinity drugs have a lower Ka/Kb value - equilibrium is dynamic

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43
Q

What are the characteristics of a ligand with high affinity for a target?

A
  1. Quick on-rate - will bind quickly
  2. Slow off-rate - will bind for longer
  3. Low Ka/Kb - inversely proportional

Even at low concentration will have more ligands bound to target than a ligand with low affinity

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44
Q

Define receptor occupancy

A

= governed by law of mass action - rate of chemical reaction is proportional to concentration of reactants

Forward rate = [A] x [receptor] x constant (on-rate)

Backward rate = [drug-bound receptors] x constant (off-rate)

At equilibrium they are equivalent

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45
Q

Define fractional receptor occupancy

A

= for any concentration of drug there’s an amount of bound receptor and total number of receptors in the system

If [drug] = Ka then fractional receptor occupancy is half, BECAUSE Ka = value at a certain concentration that half of the receptors are occupied (at equilibrium)

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46
Q

What factors does efficacy depend on in an agonist?

A

Ability to:

  1. induce activation of receptor (intrinsic efficacy)
  2. stimulus-response coupling from receptor activation to tissue response
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47
Q

What is a drug with 0 efficacy?

A

A drug with no ability to activate a receptor - an antagonist

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48
Q

What are the x and y axes on a drug response curve?

A

x-axis = logarithmic drug concentration with linear numbers [log M]
y-axis = % of maximal effect

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49
Q

What are the two main parameters for a concentration response curve?

A
  1. Maximum response (Emax) = maximal response or effect drug can produce - sigmoid curve plateaus
  2. Potency = concentration of the drug required to give an effect of a certain size (often 50%)
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50
Q

Why can’t a response curve be used to measure affinity?

A

Response isn’t directly proportional to receptor occupancy

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51
Q

Define potency as a drug property

A

The drug concentration required to elicit a given effect

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52
Q

What is EC50 and why is it used?

A

Drug concentration that can elicit a 50% response - 50% mark on concentration response curve

Use EC50 to compare potency between different drugs - lower EC50 = higher potency

EXAMPLE: On a curve if [log M] at 50% effect is logEC50 = -7.6, EC50 is 10^-7.6 = 25 nanomolar (nM)

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53
Q

How does potency effect a concentration response curve?

A

Higher potency shifts to the left, lower potency shifts to the right

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54
Q

How does efficacy of a partial agonist differ to a fill agonist?

A

Partial agonists typically have lower Emax

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55
Q

Why isn’t response directly proportional to receptor occupancy?

A

Receptor reserve = mechanisms that links receptor binding and response has a reserve capacity - system maintains spare receptors

For a full agonist receptor pool is larger than needed for full response

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56
Q

Define desensitisation/tachyphylaxis

A

Short acting: When the effect of a drug diminishes upon continuous administration over minutes or less - the tissue or cell can adapt to the drug

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57
Q

Define tolerance

A

Long acting: When effect of a drug slowly diminishes upon repeated administration and exposure over hours, days, weeks etc.

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58
Q

What 4 factors causes desensitisation and tolerance?

A
  1. Receptor loss: receptor being internalised within the cell, degraded, or recycled
  2. Change in expression level of receptors: get more or less receptors over time
  3. Exhaustion of mediators within the cell that do signaling
  4. Physiological adaptation

Drug can rebound and recover from desensitisation and tolerance if the drug is removed

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59
Q

What are characteristics of a good therapeutic agonist?

A
  • Aren’t always drugs with high affinity, high potency, high efficacy
  • High selectivity is desired - affinity at target receptor vs non-target receptor
  • Balance of benefits and adverse effects

Partial agonists may be preferred

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60
Q

What is an example of a partial agonist ‘good’ therapeutic drug?

A

EXAMPLE: Salbutamol targeting beta-2 adrenosceptors to treat asthma - is a partial agonist = causes less desensitisation so disappearance of receptors known to happen with long period of stimulation doesn’t happen

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61
Q

What is a receptor antagonists and what are the the types of more specific antagonists branching off it?

A

receptor antagonists = bind to same receptor as agonist

orthosteric site and allosteric site branch off from receptor antagonists

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62
Q

What is a orthosteric site and what are the the types of more specific antagonists branching off it?

A

orthosteric site = binding side is exactly the same receptor as the agonist

reversible and irreversible competitive antagonists branch off from orthosteric site

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63
Q

What is a allosteric site and what are the the types of more specific antagonists branching off it?

A

allosteric site = binding to a different site on the same receptor

reversible and irreversible non-competitive antagonists branch off from allosteric site

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64
Q

What is a non-receptor antagonist and what are the the types of more specific antagonists branching off it?

A

non-receptor antagonist = binds elsewhere from the agonist

chemical and functional antagonists branch off from non-receptor antagonist

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65
Q

What are the characteristics of a reversible competitive antagonist?

A

Most common and important type of antagonism in lab and clinic - high potency and selectivity achievable

Competitive Antagonist (reversible) = binds to agonist binding side (orthosteric site) and doesn’t activate the receptor - is competing with agonist - doesn’t stay bound, will dissociate and rebind continuously

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66
Q

What is an example of a reversible competitive antagonist?

A

EXAMPLE: Naloxone = opioid receptor antagonist that can reverse effect of morphine and other opioids - will compete with morphine/opioid, reversing effect of morphine when treating overdose

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67
Q

What are the effects of a partial agonist when it is combined with a full agonist?

A

The partial agonist will act as an antagonist to the full agonist, decreasing the potency of the agonist resulting in a higher EC50. It will eventually be surmountable, producing the same Emax

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68
Q

Which way does a concentraiton curve shift when an antagonist is added and how does this effect the potency?

A

Shifts curve (parallel when antangonist is competitive and reversible) to the right and apparent potency of the agonist is reduced

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69
Q

What is an example of an irreversible competitive antagonist?

A

EXAMPLE: Phenoxybenzamine = covalently binds to alpha adrenoceptors (non-selectively) blocking the effects of catecholamines - used in treatment of tumours in adrenal medulla

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70
Q

What is an example of a partial agonist acting as an antagonist?

A

EXAMPLE: Buprenorphine = partial opioid receptor agonist - can be used as an analgesic to reduce opioid withdrawal symptoms - if someone took morphine at the same time (full agoinst) buprenorphine wound act as an antagonist to the morphine

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71
Q

How does an allosteric modulator function and what are the effects it has?

A

Allosteric modulation bind to an AG protein coupled receptor whereas an agonist binds in one pocket and allosteric modulator binds in another - both bind to and effect the same receptor but at different sites.

When allosteric modulator (antagonist) binds it causes conformational change in receptor causing effects that are:

  • NEGATIVE - can act as inhibitor of agonist
  • POSITIVE - can act as potentiator increasing agonist action

THEREFORE, can increase/decrease affinity or efficacy of agonist to site

72
Q

What is an example of an allosteric modulator?

A

EXAMPLE: Benzodiazepines = positive allosteric modulators of GABA-A receptors - potentiates effects of GABA which is an inhibitory neurotransmitter causing anxiolutic sedative and anti-convulsant effects

73
Q

What are the clinical applications of allosteric modulators?

A

Can change coupling receptors to different pathways = biased algorithm - can direct receptor towards different intracellular signaling pathways

74
Q

What is a chemical antagonist?

A

A molecule that binds to or destroys the ligand itself - agonist can no longer bind to target because it is destroyed

Uncommon for small molecule drugs - common for therapeutic antibodies though

75
Q

What is an example of a chemical antagonist?

A

EXAMPLE: Mepolizumab = anti-IL-5 antibody - binds to ligand IL-5 and stops it from binding to the receptor, having an anti-asthma effect

76
Q

What is a functional (physiological) antagonist?

A

Opposes the biological effect of an agonist by acting on a different site on a different receptor - may be an antagonist to the cell effect being targeted can be an agonist at the receptor it’s binding to

77
Q

What is an example of a functional/physiological antagonist?

A

EXAMPLE: Salbutamol = used to treat asthma - acts as an agonist at beta-2-adrenoseptor causing relaxation in smooth muscle relaxing airways - antagonises the contradictory pathway of contractile agonists acting on other receptors = ie. acetylcholine at muscarinic receptors

78
Q

Aside from being used for therapeutics how can antagonists be used? (as tools?)

A

Antagonists are used to understand: physiology of systems, biochemistry of systems, immunology, neuroscience, any biomedical discipline

Used to discover new signaling pathways and new receptors - if agonist works on a cell type we know of, then antagonist is added and it can only interfere with someone of response and some is unchanged can potentially discover new receptors and different receptors an agonist may be acting on

79
Q

What is the action of somatic neurons?

A

Innovate skeletal muscle and regulate skeletal muscle contraction

80
Q

Where does the sympathetic divison of the ANS originate?

A

Fight or flight: cell bodies originate in thracic and lumbar portion of the spinal cord - ganglion is closer to the cell body

81
Q

Where does the parasympathetic division of the ANS originate?

A

Rest & digest: nerves originating from cranial and sacral portion of spinal cord and brain - ganglion closer to effector cell

82
Q

What are the tissues of the sympathetic nervous system that are of sympathetic innovation?

A
  1. Adrenal medula = on top of kidney, secretes noradrenaline and adrenaline (neurotransmitter and hormone)
  2. Most peripheral blood vessels and sweat glands
83
Q

What are the tissues of the parasympathetic nervous system that are of parasympathetic innovation?

A

The lungs = predominantly parasympathetic innovation - sympathetic more regulares airway dilation through adrenaline not lungs themselves

84
Q

What is a complimentary effect of the sympathetic and parasympathetic divisions of the ANS?

A

Saliva = sympathetic secretes mucus and ensymes, parasympathetic = responsible for watery secretion

85
Q

What is the junction at the end of skeletal muscle cells called?

A

Neuromuscular junction

86
Q

What is the junction at the end of the ANS cells called?

A

Neuroeffector junctions

87
Q

What are the steps in chemical transmission? (neurotransmitter transmission)

A
  1. Action potential propagation and depolarisation of pre-synaptic nerve terminal - change in the membrane voltage allows…
  2. Opening of voltage-gated calcium channels = channels permeable to calcium - since extracellular calcium concentration is higher than inside the nerve terminal will have an influx of calcium as goes down electrochemical gradient into nerve terminal
  3. Increase of Calcium concentration leading to fusion of vesicle with plasma membrane = increase in intracellular calcium needed for exocytosis/calcium dependent vesicular exocytosis - when have fusion of synaptic vesicle containing neurotransmitters to plasma membrane of the terminal, allowing…
  4. Neurotransmitter release into synapse or junction - binding and activating post-synaptic/post-junctional receptors creating a cellular response
88
Q

In what cell(s) is acetylcholine the neurotransmitter released?

A

skeletal muscles, parasympathetic nerves, sweat glands, adrenal cells, preganglionic neurons

89
Q

In what cell(s) is noradrenaline the neurotransmitter released?

A

sympathetic nerves

Has a feedback loop from noradrenaline (NA) of when there is enough or too much NA released

90
Q

What is an acetylcholine receptor called?

A

Cholinoceptor -

  1. Nicotinic (ligand-gated ion channels) (nAChR) = ganglionic transmission, skeletal muscles - fast response
  2. Muscarinic (G-protein) (mAChR) = parasympathetic nerves - intermediate response
91
Q

What is a noradrenaline receptor called?

A

Adrenoceptor

α- and β-adrenoceptors (G-protein) = sympathetic nerves - intermediate response

92
Q

What is co-transmission?

A

The release of more than one neurotransmitter at the same time (usually a dominant one) all go bind to their own receptors to produce a combined certain effect

Can have pre and post junctional neuromodulators to increase or decrease the amount of neurotransmitters released from the nerve terminal

93
Q

What steps of chemical transmission can be targeted by drugs, and how?

A

All steps in chemical transmission can be pharmacologically targeted:

  1. Can inhibit voltage-gated calcium channel so there’s no influx of calcium into nerve terminal
  2. Can inhibit or increase synthesis of neurotransmitter - if increase have greater capacity to release more and visa versa
  3. Can affect storage of neurotransmitters - if neurotransmitters aren’t stored in vesicles can undergo metabolism making less available for release from synapse
  4. Can modulate release of calcium dependent vesicular exocytosis
  5. Can inhibit or activate post-junctional receptors
  6. Affect reuptake of neurotransmitters - recycling of neurotransmitters back into nerve terminal for re-releasing - can inhibit or increase this
  7. Can inhibit degradation of neurotransmitters in nerve terminal and junctional space
94
Q

What are the characteristics of noradrenaline?

A
  • most often neurotransmitter, can be hormone if gets into blood
  • produced in sympathetic nerve terminal, little bit in adrenal glands
95
Q

What are the characteristics of adrenaline?

A
  • circulating hormone
  • produced in adrenal gland primarily
  • similar structure to noradrenaly with methyl group on nitrogen - therefore have similar pharmacological properties
96
Q

What is a catacolamine?

A

Adrenergic mediators (noradrenaline and adrenaline) are catacolamines

  • they come with a catacol group (benzene right with hydroxyl groups and amide side chain)
97
Q

What is the SYNTHESIS process for a catecholamine in the sympathetic nerve terminal?

A

In the nerve terminal = noradrenaline

  1. L-tyrosine, an amino acid is transported into nerve cell via transporter
  2. L-DOPA is produced when L-tyrosine undergoes hydroxylation by enzyme tyrosine hydroxylase
  3. Dopamine (DA) is the product of L-DOPA being converted by the enzyme DPA decarboxylase
  4. Dopamine is transported into synaptic vesicle by V-MAT
  5. Noradrenaline is synthesised by dopamine-beta-hydroxylase in synaptic vesicle
98
Q

Once synthesised how is a catecholamine in the sympathetic nerve terminal RELEASED?

A

When an AP is triggered nuclear fusion releases NA into synapse or neuro-effector junction

99
Q

How is a catecholamine in the synmpathetic nerve terminal STORED?

A

Stored in vesicle - this controls neurotransmitter release and protects them from metabolistic enzymes in nerve terminal

100
Q

What is the SYNTHESIS process for a catecholamine in the chromaffin cells?

A

In chromaffin cell = adrenaline

SAME FIRST 5 STEPS AS NORADRENALINE:

transported into nerve cell via transporter

  1. L-DOPA is produced when L-tyrosine undergoes hydroxylation by enzyme tyrosine hydroxylase
  2. Dopamine (DA) is the product of L-DOPA being converted by the enzyme DPA decarboxylase
  3. Dopamine is transported into synaptic vesicle by V-MAT
  4. Noradrenaline is synthesised by dopamine-beta-hydroxylase in synaptic vesicle

FURTHER STEPS:

  1. Adrenaline formed when noradrenaline is converted by PNMT
101
Q

How is a catecholamine in the chromaffin cells STORED?

A

Once synthesised adrenaline is transported into neurosecretory granules for storage

102
Q

Once synthesised how is a catecholamine in the chromaffin cells RELEASED?

A

Adrenaline is released into circulation following the activation of nicotinic receptors on plasma membrane (acetylcholine (ACh) binding to nicotinic receptors)

103
Q

What does the drugs L-DOPA & Carbipoda modulate and how?

A

TARGETING NEUROTRANSMITTER SYNTHESIS

L-DOPA increases dopamine synthesis by providing more substrate.

Carbipoda is a DOPA decarboxylase inhibitor (what turns L-DOPA into Dopamine)

This is used to treat diseases like Parkinsons that lack dopaminergic neurons in the CNS and therefore need increased dopamine output to counteract it.

L-DOPA can cross the blood-brain barrier into the CNS where needed. Carbipoda can’t. Therefore Carbipoda prevents increase in dopamine in peripheral nerves where it is not needed to prevent adverse effects. It can’t prevent dopamine increase in the CNS though as it can’t cross that blood-brain barrier - only get effect where it’s wanted (CNS) not in peripheral NS

104
Q

What does the drug Reserpine modulate and how?

A

TARGETING NEUROTRANSMITTER SYNTHESIS

Inhibits the release fo catecholamines (VMAT) = VMAT inhibitor

Binds to inhibit vesicular monoamine transporters, preventing dopamine from synthesising into noradrenaline

Often used as tool to deplete neurotransmitter storage

105
Q

How is inactivation primarily caused in the sympathetic nervous system?

A

Inactivation primarily through reuptake of noradrenaline via:

  1. (PRIMARY) high affinity norepinephrine transporter (NET)
  2. (SECONDARY) extraneuronal uptake via low-affinity organic cation transporter (OCT3)

Noradrenaline can then be re-released

106
Q

How is inactivation primarily caused in cholinergic systems (that release acetylcholine)?

A

Inactivation primarily through degrading acetylcholine (ACh) - enzyme degrades

107
Q

What do the drugs Tricyclic Antidepressants (TCAs) modulate and how?

A

Inhibits noradrenaline (norepinephrine) transporters (NET) in CNS

Allows more noradrenaline to stay in junction for longer and bind to receptors causing a greater and more prolinged response

108
Q

What does a MAO inhibitor modulate and how?

A

Inhibits the metabolistic action of monoamine oxidase (MAO) - preventing the breakdown of noradrenaline in the cytoplasm

More can then be take up by the vescle, or can leak out into the juction having a greater effect

109
Q

What is an indirectly acting sympathomimetic drug?

A

Mimic the effect of sympathetic nervous system indirectly - without acting as an agonist at the receptor, instead increasing noradrenaline available

110
Q

What are examples of indirectly acting sympathomimetics (IAS)?

A

Tricyclic antidepressants, MAO inhibitors, ephedrine, tyramine

111
Q

What is tyramine and how does it function as a drug?

A

Drug-food interaction - is found in many foods and is the substrate for monoamine oxidase = competes with noradrenaline for metabolism therefore inhibiting monoamine ocidase (MAO)

112
Q

What is a directly acting sympathomimetic drug? What is an example?

A

Binds and stimulates adrenoceptor

EXAMPLE: exogenous (grown and created outside of an organism) adrenaline

113
Q

What are the 4 subtypes of adrenoceptors?

A

alpha 1, alpha 2, beta 1, beta 2

114
Q

How does a beta subtype adrenoceptor act?

A

Noradrenaline binds to beta 1 or beta 2 which are linked to a G-protein alpha subunit (Gas) (s=stimulatory)

G-protein subunit after being activated can stimulate adenylate cyclase (AC) - membrane bound enzyme that converts ATP to cyclic AMP (cAMP)

cAMP is a secondary messenger that activates futher enzymes that create a response

115
Q

How does an alpha subtype adrenoceptor act?

A

ALPHA 1:
Linked to G-alpha-Q protein - stimulates a membrane-bound enzyme - phospholipase C (PLC)

PLC is responsible for conversion of POP2 into 2 important sickling molecules - IP3 and DAG causing an increase in calcium concentration

Increased calcium in smooth muscle causes contraction

ALPHA 2:
Linked to G-alpha-i proteins - inhibitory protein that inhibits membrane bound enzyme adenylate cyclase (AC)

Decreases cAMP

Often located pre-junctionally and act as a negative feedback system restricting NA release

116
Q

What tissue/organs does alpha 1 effect and what does it do?

A

= most blood vessels (smooth muscle) - constriction

Also: pupil dilation and relaxation of gastrointestial system

117
Q

What tissue/organs does alpha 2 effect and what does it do?

A

= pre-junctional synapse - NA negative feedback system

Also: sometimes post-junctionally

118
Q

What tissue/organs does beta 1 effect and what does it do?

A

= heart muscle - increases HR and contraction

Also: renin secretion in kidney

119
Q

What tissue/organs does beta 2 effect and what does it do?

A

= bronchi - bronchodilation, relaxation

Also: blood vessels and gastrointestinal dilation, glycogenolysis in liver

120
Q

What is an example of an alpha 1 agonist drug?

A

Phenylephrine = nasal decongestant - constriction of blood vessels in nose

121
Q

What is an example of an alpha 1 antagonist drug?

A

Prazosin = anti-hypertensive, lowers blood pressure

122
Q

What is an example of an alpha 2 agonist drug?

A

Clonidine = anti-hypertensive through CNS action

123
Q

What is an exampe of an alpha 1 and 2 combined antagonist drug?

A

Phentolamine = manage hypertension

124
Q

What is an example of a beta 2 agonist drug?

A

Salbutamol = asthma bronchodilator

125
Q

What is an example of a beta 1 agonist drug?

A

Dobutamine = acute heart failure preventative - increases heart strength

126
Q

How is acetylcholine (ACh) synthesised?

A
  1. Choline enters the cell via choline transporters
  2. Choline acetyltransferase (cHAT) takes the acetyl from acetyl coenzyme A and adds it to the choline to make acetylcholine
127
Q

How is acetylcholine (ACh) stored?

A

Once synthesised acetylcholine (ACh) is stored in vesicles, which it is transported into bi vesicular acetylcholine (against concentration gradient)

128
Q

How is acetylcholine (ACh) released?

A
  1. Vesicle with membrane protein synaptobrevin docks at presynaptic membrane
  2. Synaptobrevin forms SNARE complex with SNAP 25 and syntaxin
  3. Calcium enters nerve terminal and binds to synaptotagmin on vesicle
  4. Synaptotagmin triggers membrane fusion between vesicle and terminal membrane - causing ACh release
129
Q

How is acetylcholine (ACh) metabolised?

A

Metabolised through acetylcholinesterase (AChE) - outside the cell and breaks down ACh metabolising it

130
Q

How do drugs modulate cholinergic activity?

A
  1. Prevent the formation of acetylcholine in the cell through breaking down the SNARE complex
    EXAMPLE: botulin toxin
  2. Inhibiting aceytcholinesterase (AChE) and causing more ACh in the junction eliciting a greater effect
    EXAMPLE: anticholinesterases
131
Q

What are the acetylcholine (ACh) receptors and receptor subtypes?

A
  1. Muscarinic receptors (M1-5) MAChR
    - G-proteins
    - M2 and M3 are only ones relevant
  2. Nicotinic receptors (N1-2) NAChR
    - ligand-gated ion channel
132
Q

What is an example of an antagonist with selective activity at the ACh receptors (one for each receptor)?

A

Muscarinic antagonist

EXAMPLE: atropine
- competitive reversible antagonist
- ‘anti-DUMBELS’ - CNS effects = restlessness
- doesn’t discriminate muscarinic subtypes
- reduced secretion during anaesthesia

Nicotinic antagonist

EXAMPLE: d-tubocurarine
- competitive reversible antagonist
- acts at neuromuscular junction but ganglia at higher concentrations - less selectivity
- neuromuscular blocking drug for surgical paralysis
- adverse effects = hypotension due to ganglion block

133
Q

What are examples and effects of reversible anticholinesterases?

A

Medium-duration anticholinesterases:

EXAMPLE: Physostigmine - selective for parasympathetic junctions
- causes increased parasympathtic effects
- used for glaucoma (eye disease from blockage of draining system)

EXAMPLE: Neostigmine - selective for neuromuscular junction
- causes increased muscular response
- reverse competitive neuromuscular block - myasthenia gravis (muscle weakness fron antibodies degrading nicotinic receptors)

134
Q

What are examples and effects of irreversible anticholinesterases?

A

EXAMPLE: Organophosphates
- binds and covalently modifies AChE so enzyme can no longer be activated
- causes muscarinic effects
- can treat organophosphates poisoning with muscarinic receptor antagonist

135
Q

What are the characteristics of a muscarinic receptor and it’s subtypes? (signal transfuction mechanism)

A

Muscarinic receptors (M1-5) MAChR
- G-proteins
- M2 and M3 are only ones relevant

  • M2 = coupled to Gai (inhibitory G-protein) - decreases cAMP causing decreased contractile force - is located in the heart = activation causes decrease in HR, bradycardia
  • M3 = coupled with Gaq - activating PLC enzymes that convert PIP2 into IP3 and DAG - increases intracellular calcium and leads to smooth muscle contraction, or on sweat glands increases secretion - on smooth muscle and sweat gland
136
Q

What are the characteristics of a nicotinic receptor and it’s subtypes? (signal transfuction mechanism)

A

Nicotinic receptors (N1-2) NAChR
- ligand-gated ion channel (iontropic)
- composition of subunits varies which forms subtypes with differing properties (specificity, oermeability of ion, physiological response)

  • N1 = neruomuscular junction
  • N2 = autonomic ganglia
137
Q

What is the difference between dose and concentration?

A

Dose is how much of a drug is given whilst concentration is the amount that actually ends up being present in the body at the target

138
Q

What factors determine concentration of a drug in the body?

A

A.D.M.E

A - Absorption
D - Distribution
M - Metabolism
E - Excretion

139
Q

What is the difference between local and systemic drug actions?

A

Local = drug exerts effect on target at or near site of administration - has access to limited tissue etc.
= less adverse effects

Systemic = drug enters the bloodstream to access the target and in doing so will access many tissues (musct cross membranes to access target)
= more potential for adverse effects

140
Q

How can drugs, small and large molecule be absorbed and cross membranes?

A

Small molecules:
1. Diffusion through lipid
2. Diffusion through aqueous channels
3. Carrier

Large molecules:
4. pinocytosis - attracted to part of the membrane they can invaginate

141
Q

What properties effect absorption?

A
  1. pH (most drugs are weak acids or bases)
  2. aqueous solubility (must be in solution)
  3. lipid solubility (to cross cell membrane)
142
Q

How does pH effect absorption?

A
  • uncharged small molecules are more likely to be lipid soluble and well absorbed - passive lipid diffusion
  • If charged can’t be lipid soluble and will likely need a carrier - more energy and time demanding
  • If it is charged like charges will absorb better - EXAMPLE: inflammatory environments are very acidic so an acidic drug would best be absorbed over a basic drug
  • There are varying pH levels throughout the gastrointestinal track (although most absorption is done through the small intestine)
143
Q

How does lipid solubility effect absorption?

A
  • If being distributed systemically and taken orally as a drug need to cross 2 membranes - in gastrointestinal lining and blood vessel lining
  • easier to get through these linings which are lipid membranes if is lipid soluble
144
Q

What are some important considerations with orally administered drugs?

A

PROS
- most convenient route (therefore most common)

  • variety of forms dose can be put in

CONS
Drugs will go through first pass metabolism after oral absorption:

  • exposed to enzymes in saliva and gastrointestinal fluid that could break down drugs
  • first pass hepatic metabolism - will pass through liver, the major organ for drug metabilism before reaching circulation

NOTE: metabolism can also be used in the favour of drugs - prodrugs (need to be metabolised to then be in active form)

145
Q

What are some important considerations with injectable routes of drug administration?

A

4 injectable routes:
1. subcutaneous (sc)
2. intramuscular (im)
3. intradermal (id)
4. intravenous (iv)

  • drug instantaneously enters blood stream
  • more precise amount of drug enters blood stream, no absorption required
  • BUT even once in blood stream still need to get to target - dose still won’t be same as concentration
  • concentration determined by bioavailability
146
Q

What is bioavailability (F) and what is it affected by?

A

= proportion of active drug that enters systemic circulation

  • is 100% following iv administration - less than 100% for other routes, some lost along the way
  • impacted by how much drug is absorbed - pH, lipid solubility etc.
  • impacted by how much undergoes first pass metabolism by enzymes both in the liver and in other locations throughout the body
147
Q

What is distribution in relation to drug administration?

A

= drug reaching the target - how it is spread through the body

  • driven by circulation of blood
  • can be affected by molecular size, lipid solubility, plasma protein binding (free drug has tissue access, more difficult if binds to plasma protein in blood)
  • distribution is rarely uniform - concentrated or excluded from areas (especially due to pH - changes influence lipid solubility) - affinity
  • being distributed and eliminated at the same time but distribution is faster
  • drugs reach a “distribution equilibrium”
148
Q

What dictates absorption rate?

A

Slowest rate of reaction - lots of processes going on but slowest one will limit it

149
Q

What is volume distribution?

A

Volume of body water in which the drug appears to be dissolved in after it has distributed through the body quickly

  • constant that relates amount of the drug in the body to plasma concentration (determined during development phase)

EQUATION = amount in body (dose) / plasma concentration (initial concentration)

  • important as relates dose to what could be initial concentration in the plasma
  • is an apparent value - smaller for drugs that bind to plastma protein, larger for drugs that distribute to tissues or taken up into cells
  • need to be careful with what you use value for - the subset of people results were gathered don’t represent everyone especially when they’re all often men

-

150
Q

What is precision medicine?

A

A move away for “one size fits all” medical approach - fitting drugs to the patients = personalised medicine

  • need to ensure drugs aren’t too effective and toxic, but also not too ineffective and a waste of time - balance is needed
151
Q

What is pharmacogenomics, why is it important?

A

How variation in genes influences the effect of drugs

Important:
- economic issues - huge cost to patients, pharma industry and healthcare system (which subsidizes medicine use)

152
Q

What causes variabilities within the population in drug response?

A

DNA polymorphisms:
- germ line mutation (inherited)
- somatic mutation (cancer)

Often single nucleotide polymorphism (SNPs)

153
Q

What changes to SNPs cause in drug responsitivity?

A
  1. Direct effect
    - change in protein structure/function: change binding of drug, alternative splice (different drug protein synth), more or less modulated by drug
  2. Gene transcription effect
    - change in gene transcription and hence quantity of protein produced - polymorphism in promoter regions
154
Q

What are potential single nucleotide polymorphisms (SNPs)?

A
  1. silent mutation - base change with no effect (same amino acid)
  2. conservative missense mutation - makes a different amino acid but no change in effect
  3. nonconservative missense mutation - different amino acid that changes function
  4. frame-shift mutation - insertion of nucleotide throwing everything off and greatly impacting function and expression

All above factors can change how drug interacts - potentially causing advers reactions

155
Q

What are other motential mutations that can have consequences that aren’t single nucleotide polymorphisms (SNPs) with an example?

A

Exchange different chromosomal regions

  • often associated with cancer

EXAMPLE: Philadelphia chromosome - exhcnage on chromosomal level leads to increased cancer formation

156
Q

What is a consequence of single nucleotide polymorphisms (SNPs) for proteins?

A

Ubiquitin pathway = ubiquitin picks up on polymorphisms and degrades prteins - then just don’t have functional proteins

157
Q

How can polymorphisms be detected?

A
  • DNA sequencing (genome/exome)
  • microarray - for known SNPs
158
Q

How does the body effect drugs when polymorphism has occured? (pharmacokinetics)

A
  1. Can reduce formation of active compounds if drug is a pro-drug
  2. Can influence half life of drug
  3. With reduced enzyme activity drug may reach higher plasma concentration for longer periods - toxicity
  4. If enzyme is TOO active may not achieve therapeutic concentration at target
159
Q

What is an example of drugs having varying effects for different people?

A

EXAMPLE: Suxamethonium = supposed to be a short duration skeletal muscle relaxant used in surgery

Cholinesterase is the enzyme that metabolises suxamethonium - is found in plasma

Polymorphic fors found to have varying effects
1. increased activity of plasma cholinesterase = wears of faster and doesn’t have significant effect even in high dosages
2. decreased activity/inactivity of plasma cholinesterase = wears of slowly and even in small doses has a significant and prolonged effect

Dosage to be titrated for individuals to ensure consistent effect

160
Q

What are the impacts of polymorphisms in anti-cancer drugs?

A
  • germline and tumour genomes can broadly effect the efficacy/safety of anti-cancer drugs
  • chemotherapy drugs consider epidermal growth factor receptor (EGFR) polymorphism to predict success with kinase inhibitors in certain lung cancers
161
Q

What are the feasible factors surrounding pharmacogenomics in the future?

A
  • has become a lot cheaper
  • has been successful for some drugs
162
Q

What are some infeasible factors surrounding pharmacogenomics in the future?

A
  • interpretation of sequence is problematic
  • healthcare workers not trained in understanding genome sequences and how to best help patients
  • old pharm companies “one size fits all” model doesn’t fit for profits - drug would get more expensive?
  • ethics of how OTHER stuff they find will be managed? other issues in sequence
163
Q

What are the main factors involved in how drugs get out of the body? (elimination)

A
  • Metabolism (liver)
  • Excretion (kidney)
164
Q

What is the characteristics and purpose of metabolism?

A

Set up the drug to be able to disappear in urine in two phases (through salicyclic acid or glucuronide)

  • mainly occurs in liver but also in most tissues
  • increases water solubility to facisitate excretion
  • enzyme-catalysed reactions
165
Q

Describe the mechanisms behind phase 1 of drug metabolism

A
  1. BREAK DOWN DRUGS TO MAKE SOLUBLE

Cytochrome P450 = enzymes responsible for many phase 1 drug metabolism reactions - metabolise anything we injest to maximuse nutrient benefits and minimise harm

  • depending on drug-drug and drug-food reactions alongside other variables can have idiosyncratic effects = unexpected response
166
Q

Describe the mechanisms behind phase 2 of drug metabolism

A
  1. MAKE WATER SOLUBLE

Big molecules get added that are water soluble and relatively stable

EXAMPLE: glutathione conjugation - protects against many things including reactive oxygen species

167
Q

What is the different processes of drug elimination for hydrophobic vs hydrophilic drugs?

A

Hydrophilic: don’t go through phase 1 or 2 metabolite - straight to excretion

Hydrophobic: can go through phase 1 metabolite and then phase 2 or just straight to phase 2

Excreted mainly by kidney

168
Q

What are the 3 processes of renal excretion?

A
  1. Glomerular filtration
  2. Tubular secretion
  3. Tubular reabsorption
169
Q

What are the mechanisms of glomerular filtration?

A

Fenestrated capillaries has gaps - size filter where most things (small enough) will go through to get drug OUT of the blood

However, drugs can’t leave the blood in this way if they’re protein bound in blood, free form drugs can get through tissues more easily

170
Q

What are the mechanisms of tubular secretion?

A

If can’t get through glomerular filtration because too big active carriers can move OUT of the blood stream for excretion through active transport

171
Q

What are the mechanisms of tubular reabsorption?

A

Drugs will get BACK INTO the blood due to lipid solubility just as they can get into tissue and out of blood to bind to targets - can also get out of the kidney

Consequently why it is important to ensure they’re water soluble - so they’re in a form that keeps them in the urine

affected by:
- passove movement across membrane
- pH

Can be manipulated - ie. can make urine more basic in aspirin overdose to decrease absorption and increase excretion

172
Q

Define clearance in relation to elimination

A

= how efficiently we remove the drug from the blood stream (volume of blood cleared by drug/unit time) - CONCEPTUAL

Helps to determine dose rate to achieve a steady state [plasma] - not too much but also not too much being lost

173
Q

What is drug half-life?

A

= how long a drug exists

In first order processes decay is proportional to amount you have - concentration in plasma

Irrespective of starting point of concentration time to get to half of initial level is the same

174
Q

How many half-lifes is it to remove 95% of a drug after a single dose?

A

4 half lives

175
Q

How many half-lifes is it until a steady state is reached with chronic dosing

A

6 half lives

176
Q

Why is half- life important?

A

Helps determin the frequency at which a dose should be given

177
Q

What is the exception to half-life principles?

A

Zero-order - half-life is difficult to predict as concentration changes are not consistent = require regular monitoring

Is zero-order because process is saturated

EXAMPLE: Alcohol - enzymes saturated quickly and effectively

pharmacology unimelb (2 decks)

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