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YEAR 1 - Physiology and Pharmacology (Anton) > 4. Principles Of Drug (& Hormone) Action > Flashcards

4. Principles Of Drug (& Hormone) Action Flashcards

1
Q

What is pharmacology?

A

The study of how drugs affect biological systems.

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2
Q

Describe the branches of pharmacology.

A
  • Pure pharmacology -> Identification and study of chemically sensitive sites and their mechanisms
  • Applied pharmacology
    • Chemical physiology -> How do these sites play a role in normal function?
    • Therapeutics -> Can these sites be exploited in treatment?
    • Toxicology -> Do these sites mediate toxic effects of chemicals?
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3
Q

Define a drug.

A
  • Any chemical agent which affects any biological process.
  • Generally organic chemicals of small molecular weight (<500g/mol)
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4
Q

Do drugs have to be synthetic?

A

No, the term also encompasses bodily chemicals.

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5
Q

What are some examples of biopharmaceuticals?

A
  • Therapeutic proteins from genetic engineering (e.g. hormones, blood clotting factors, enzymes)
  • Nucleic acids
  • Vaccines
  • Monoclonal antibodies
  • Cell-based therapies
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6
Q

What are the different methods of drug classification?

A

Based on:

  • Chemical structure
  • Main effect (e.g. analgesics)
  • Therapeutic use (e.g. antidepressants)
  • Mechanism of action
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7
Q

What are pharmacodynamics and pharmacokinetics?

A
  • Pharmacodynamics -> What the drug does to the body (e.g. drug receptors, efficacy, responses, toxicity, etc.)
  • Pharmacokinetics -> What the body does to the drug
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8
Q

What mnemonic is used to remember the branches of pharmacokinetics?

A

ADME:

  • Absorption
  • Distribution
  • Metabolism
  • Excretion
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9
Q

How can drugs cause a toxic effect on a molecular and cellular level?

A

On a molecular level, chemicals can:

  • Interact with proteins, lipids and DNA

On a cellular level, chemicals can:

  • Interfere with receptor-ligan binding
  • Interfere with membrane function
  • Interfere with cellular energy production
  • Bind to biomolecules
  • Perturb homeostasis (e.g. calcium levels)
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10
Q

Define a receptor.

A

A protein or macromolecule in or on a cell that is a recognition site for endogenous ligands or drugs. When a drug binds it initiates or blocks a response to an endogenous chemical.

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11
Q

Define endogenous.

A

Originating from within an organism.

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12
Q

What are main subtypes of drugs that bind to a receptor and what do they do?

A
  • Agonists -> May ctivate more than one type of receptor (e.g. ACh activates nicotinic and muscarinic receptors)
  • Antagonists -> Selectively block one type of receptor subtype (e.g. curare)
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13
Q

What are some criteria for a receptor?

A
  • Recognition -> Receptor protein must exist in a conformational state that allows for recognition
  • Saturability
  • Reversibility
  • Stereoselectivity -> Receptor must recognise only one of the optical isomers
  • Agonist specificity -> Structurally related drugs should bind well
  • Tissue specificity -> Binding should occur in the correct tissues
  • Transduction -> The binding of the agonist must be transduced into some sort of functional response
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14
Q

Give some examples of endogenous agents that act on receptors.

A
  • Hormones
  • Neurotransmitters
  • Growth factors
  • Vaso-active factors
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15
Q

Why are drugs so potent?

A

Their action is amplified by, for example, second messenger systems.

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16
Q

Define affinity.

A

The tenacity by which a drug binds to its receptor.

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17
Q

State the primary assumption of receptor theory.

A

A single ligand is binding to a homogenous population of receptors.

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18
Q

Describe the concept of receptor kinetics.

A

[L] + [R] -> [LR]

  • kon is the rate of the forwards reaction
  • koff is the rate of the backwards reaction
  • At equilibrium, the rate of formation equals the rate of dissociation, so: [L][R]kon = [LR]koff
  • KD is the equilibrium dissociation constant: KD = koff / kon = [L][R]/[LR]
  • KD is the [L] which produces 50% receptor occupancy
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19
Q

What is KD in receptor kinetics? What are the units?

A
  • It is an inverse measure of receptor affinity for a particular ligand
  • It is the concentration of the ligand that produces 50% receptor occupancy
  • Units: M/L
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20
Q

What does a high KD value indicate?

A

A low receptor affinity for a certain drug.

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21
Q

Describe the idea behind drug binding studies.

A
  • Measure the affinity not efficacy
  • No need for intact cells or tissues
  • Need a radio-ligand
  • Saturation binding curve may be plotted, where the drug concentration producing 50% binding is the KD value
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22
Q

How do agonists work?

A

Bind to receptor causing a change of conformation, leading to a cellular response.

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23
Q

Do agonists and antagonists have both an affinity and efficacy?

A
  • Agonist -> Affinity and efficacy
  • Antagonist -> Affinity but no efficacy
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24
Q

How do antagonists work?

A
  • Prevent agonist-mediated response by preventing a drug from binding and eliciting its normal response.
  • They may be competitive or non-competitive.
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25
Q

What factors can be meaured in antagonist action?

A
  • Affinity
  • Potency
  • Selectivity
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26
Q

What is efficacy?

A

The ‘strength’ of an agonist-receptor interaction along with the transduction mechanism’s in eliciting a response.

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27
Q

Is the effect of a drug proportional to the fraction of receptors occupied?

A

Yes, that is the classic theory. Note, however, that in some cases not all receptors need to be bound in order to produce the maximal effect.

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28
Q

How can the effect of a drug depending on dose be represented graphically?

A

A dose-response curve can be plotted, with either the drug concentration or log of the drug concentration on the x-axis. The logarithmic graph may be more suitable due to the wide range in drug concentrations used.

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29
Q

Describe the shape of a non-logarithmic and semi-logarithmic dose-response curve.

A
  • Non-logarithmic -> Usually a rectangular hyperbola
  • Semi-logarithmic -> Usually sigmoidal
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30
Q

What is EC50?

A
  • Effective concentration 50
  • The drug concentration that produces response halfway between the baseline and the maximal response
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31
Q

What is the difference between KD and EC50?

A
  • KD is a measure of the affinity of the receptor for the drug
  • EC50 is a measure of the potency of the drug

The two values are not necessarily the same (LOOK UP WHY!)

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32
Q

What are the different degrees of agonist?

A

In order of efficacy: Full antagonist > Partial antagonist > Antagonist

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33
Q

What is a partial agonist?

A

An agonist that only has partial efficacy relative to a full agonist, so that they are unable to cause a maximal response (even when all receptors are bound).

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34
Q

Give some clinical uses of partial agonists.

A

Partial agonists can be used to “wean off” abused drugs, by replacing them with the partial agonist which produces a lesser response.

e.g. Methadone for heroine abuse treatment

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35
Q

Are agonists and antagonists structurally similar?

A

Yes, they may be similar structurally, so an antagonist could be synthesised by modifying an agonist so that affinity remains high while efficacy is reduced.

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36
Q

Define a drug target.

A

Any biological binding/recognition element (usually a protein) for a drug.

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37
Q

Give some examples of drug targets.

A
  • Receptors
  • Ion channels
  • Carriers or transporters
  • Enzymes
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38
Q

What are the different types of receptors?

A

Cell-surface receptors:

  • Ligand-gated ion channels (ionotropic)
  • G-protein coupled receptors (metabotropic)
  • Enzyme-linked receptors

There are also nuclear receptors for hormones.

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39
Q

What is another name for ligand-gated ion channels?

A

Ionotropic

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40
Q

What is another name for GPCRs?

A

Metabotropic receptors

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41
Q

Why are there sometimes said to be 3 types of receptors and sometimes 4 types?

A

Because there are 3 types of cell-surface receptors, but there are also nuclear receptors which are sometimes also included as a 4th type.

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42
Q

Give some examples of ligand-gated ion channels (ionotropic receptors).

A
  • nAChR
  • GABA receptor
  • Glutamate receptor
43
Q

Give some examples of GPCRs.

A
  • mAChR
  • Alpha and beta adrenoreceptors
44
Q

Give some examples of enzyme-linked receptors.

A
  • Cytokine receptors
  • Insulin receptors
  • Atrial natriuretic factor (ANF) receptor
45
Q

Give some examples of nuclear receptors.

A
  • Receptors for steroid hormones
  • Receptors for thyroid hormone
46
Q

Describe the principles of how each of the receptor types works and how long the effects last.

A
47
Q

What are receptor subtypes?

A
  • Various different receptor kinds within each type of receptor.
  • They have slightly different amino acid sequences, which may affect their sensitivity to different drugs
  • e.g. Different nAChR types in brain and in muscle
48
Q

Describe how different receptor subtypes may arise.

A
  • Alternative splicing
  • Post-transcriptional modifications, including mRNA splicing and mRNA editing
49
Q

Describe the structure of ligand-gated ion channels (ionotropic receptors).

A
50
Q

Describe the structure of nAChR.

A
51
Q

What is the significance of the charge on ligand-gated ion channels?

A

They attract either anions or cations to the channel.

52
Q

Are neurotransmitters acting on ion channels always excitatory?

A

No, inhibitory neurotransmitters (such as GABA) can cause membrane hyperpolarisation due to an inwards Cl- current.

53
Q

Describe the structure of GPCRs (metabotropic receptors).

A
54
Q

Describe simply the general functioning of GPCRs.

A
55
Q

Why do GPCRs have a wide range of effects?

A

The G protein can interact with many different things.

56
Q

What are the main types of G-protein types?

A
  • Gs
  • Gi
  • Gq
  • Other types -> Gt
57
Q

Are GPCRs always activated by a neurotransmitter?

A

No, they may also be activated by protease cleavage of the extracellular N-terminal tail.

58
Q

What is the clinical relevance of GPCRs?

A

About 50% of modern therapeutic drugs act on GPCRs.

59
Q

Describe the mechanism of G-protein activation.

A
  • αβγ is a trimer formed from the covalently bound β/γ, but not α
  • When the ligand is not bound, the αβγ trimer is not connected to the receptor and GDP is bound to the α unit
  • When the ligand binds, it triggers a conformational change in the receptor, which increases the affinity for the αβγ trimer -> αβγ trimer binds to the receptor
  • α’s affinity for GTP increases -> So the GDP bound to α is replaced by GTP
  • The α (bound to the GTP) and β/γ units travel to their targets
  • Hydrolysis of GTP terminates signalling

Note: An individual agonist-receptor complex can activate more than one G-protein, so this process can happen with one G-protein binding after another.

60
Q

Does an individual agonist-GPCR complex activate just one G-protein?

A

No, one G-protein can bind, then another, then another…

61
Q

Describe the amplification mechanism in GPCRs.

A
  1. Individual agonist-GPCR complex can activate more than one G-protein
  2. An active G-protein can interact with the effector enzyme for a duration that is sufficient to generate multiple molecules of product
  3. If the product is a second messenger, further amplification occurs
62
Q

Define a second messenger.

A

A substance whose release within a cell is promoted by an agonist and which brings about a response by the cell.

63
Q

Name some of the targets for G-proteins.

A
  • Adenylate cyclase -> Leading to cAMP production
  • Phospholipase C -> Initiating IP3 and DAG signalling pathways
  • Ion channels -> Modulated especially via interaction with β/γ subunits
  • Rho kinase
  • MAP kinase
64
Q

What do Gi, Gs and Gq proteins stand for?

A
  • Gi -> Inhibitory
  • Gs -> Stimulatory
  • Gq -> No name really
65
Q

What mechanisms do Gi/Go, Gs and Gq proteins modulate?

A
  • Gi/Go -> Inhibiting adenylate cyclase activity (increasing cAMP production)
  • Gs -> Stimulating adenylate cyclase activity (decreasing cAMP production)
  • Gq -> Inositol phosphate pathway
66
Q

Which G-proteins function by an equivalent mechanism?

A

Gi and Gs proteins both modulate adenylate cyclase (an enzyme in the plasma membrane) activity, but Gi inhibits it, while Gs stimulates it.

67
Q

Describe the Gi and Gs protein mechanism of action.

A
  • After the G protein is activated (see flashcard on this!), the α subunit bound to GTP moves to adenylate cyclase
  • With αs subunits, this results in the stimulation of adenylate cyclase, so that cAMP production is increased
  • With αi subunits, this results in the inhibition of adenylate cyclase, so that cAMP production is reduced
  • cAMP acts as a second messenger to activate various processes, including activation of cAMP-dependent protein kinases
68
Q

What are Go-proteins?

A

Gi proteins are often called Gi/o proteins. (Check this!)

69
Q

Give an example of when adenylate cyclase may be inhibited due to receptor binding.

A

M2 and M4 inhibitory muscarinic receptors are GPCRs that are coupled to Gi proteins, so that adenylate cyclase activity is inhibited.

70
Q

What is the full name for cAMP?

A

Cyclic 3’,5’-AMP

71
Q

Describe the synthesis and breakdown of cAMP.

A

Synthesis:

  • Synthesised from ATP
  • Involves removal of PPi
  • Catalysed by adenylate cyclase

Breakdown:

  • Hydrolysed by cAMP phosphodiesterase
  • Produces 5’-AMP
72
Q

What terminates the effects of cAMP?

A

cAMP phosphodiesterase hydrolyses the cAMP to 5’-AMP.

73
Q

What does cAMP do?

A

It activates cAMP-dependent protein kinase A (PKA). This protein kinase can then phosphorylate specific enzymes.

74
Q

Describe the entire cAMP pathway when it is activated by a GPCR.

A
  • Ligand binding to GPCR causes activation of G-protein
  • G-protein activates (if Gs) or inhibits (if Gi) adenylate cyclase
  • Adenylate cyclase catalyses the formation of cAMP from ATP
  • cAMP activates protein kinase A (PKA)
  • PKA phosphorylates specific enzymes, modifying their activity
75
Q

How is cAMP degraded and how can this be inhibited?

A
  • By cAMP phosphodiesterase
  • This is inhibited by methylxanthines
76
Q

Describe the Gq protein mechanism of action.

A
  • After the G protein is activated (see flashcard on this!), the αq subunit bound to GTP moves to the PLC enzyme (phospholipase C)
  • PLC in turn hydrolyses PIP2 to DAG (diacyl glycerol) and IP3 (inositol triphosphate)
  • IP3 acts as a second messenger -> Binds to to IP3 receptors, triggering Ca2+ release from the ER
  • DAG also acts as a second messenger -> Activates protein kinase C
77
Q

Compare the protein kinases activated by Gi and Gs proteins with those activated by Gq proteins.

A
  • Gi and Gs -> Protein kinase A (PKA)
  • Gq -> Protein kinase C (PKC)
78
Q

What is GTP?

A

Guanosine triphosphate -> A nucleoside triphosphate.

79
Q

What does PIP2 stand for?

A

Phosphatidylinositol 4,5-bisphosphate (probably don’t need to know this though)

80
Q

What does DAG stand for?

A

Diacylglycerol

81
Q

What does IP3 stand for?

A

Inositol triphosphate

82
Q

Where are IP3 receptors found?

A

On the endoplasmic reticulum

83
Q

How is PIP2 resynthesised?

A
84
Q

Name two important GPCR you need to know about, apart from muscarinic receptors.

A
  • α1 adrenoreceptor -> Gq protein coupled
  • β1 adrenoreceptor -> Gs protein coupled
85
Q

Where are β1 adrenoreceptors found, how are they activated and what is the effect of this?

A
  • Found on cardiac myocytes
  • Activated by the binding of noradrenaline or adrenaline
  • Gs protein triggers adenylate cyclase, which increases cAMP, which results in increased PKA activity
  • PKA activates calcium channels in the cell membrane, so that intracellular Ca2+ concentration is increased -> This results in contraction
86
Q

Where are α1 adrenoreceptors found, how are they activated and what is the effect of this?

A
  • Found on vascular smooth muscle cells
  • Activated by noradrenaline
  • Gq protein activates PLC, which increases intracellular IP3
  • IP3 leads to increased release of Ca2+ from the sarcoplasmic reticulum, which causes contraction
87
Q

How do beta-blockers work?

A
  • Block β1 receptors so that adrenaline can’t bind
  • Therefore the cAMP pathway is not activated and contraction of the cardiac myocyte does not occur
  • This reduces cardiac contraction
88
Q

What are some other names for adrenaline and noradrenaline?

A
  • Adrenaline = Epinephrine
  • Noradrenaline = Norepinephrine
89
Q

Describe the structure of enzyme-linked receptors.

A
90
Q

Describe the principle on which enzyme-linked receptors work.

A
  • Extracellular domain of receptor has receptor functions, while intracellular domain has enzymatic functions
  • Binding of a ligand causes a conformational change in the enzymatic domain
  • Frequently, this leads to control of gene transcription and therefore various cellular effects
91
Q

What ligands bind to enzyme-linked receptors?

A
  • Growth factors
  • Cytokines
  • Hormones
92
Q

What cellular effects do enzyme-linked receptors lead to?

A

They affect gene transcription, so can alter:

  • Cell division
  • Inflammation
  • Apoptosis
93
Q

What are the main types of enzyme-linked receptors?

[EXTRA]

A
  • Receptor tyrosine kinases
  • Receptor serine/threonine kinases
  • Cytokine receptors
94
Q

Give an example of an enzyme-linked receptor signalling pathway.

A
95
Q

Where are nuclear receptors found?

A

In the cytoplasm or the nucleus.

96
Q

Describe the structure of nuclear receptors.

A
97
Q

What types of molecules are nuclear receptors?

A

Transcription factors

98
Q

Describe the principle on which nuclear receptors work.

A
  • Have a DNA-binding domain and ligand-binding domain
  • When the ligand binds, the receptor can act as a transcription factor, modulating DNA transcription
99
Q

What ligands bind to nuclear receptors?

A
  • Steroid hormones
  • Lipids
100
Q

What are the different types of nuclear receptor and how does each work?

A

Class I:

  • Present in cytoplasm
  • Bind steroid hormones
  • Binding of ligand triggers homo-dimerisation and migration to nucleus

Class II:

  • Present in nucleus
  • Bind lipids
  • Binding of ligand triggers dimerisation with retinoid receptor
101
Q

What are the main types of drugs that act on ion channels?

A
  • Blockers -> Occlude pathway directly
  • Modulators or “gating modifiers” (can be inhibitors or activators)
102
Q

What are the main types of drugs that act on ion transporters?

A
  • Inhibitors
103
Q

What are the main types of drugs that act on enzymes?

A
  • Inhibitors -> Prevent normal reaction
  • False substrate -> Drug is processed by gives abnormal product that interferes with a cellular pathway
  • Prodrug -> Require processing to be turned into an active form

YEAR 1 - Physiology and Pharmacology (Anton) (13 decks)

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