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Pharmacology MBCHB2 > Lecture 2; Mechanisms of action > Flashcards

Lecture 2; Mechanisms of action Flashcards

1
Q

Whats the difference between drug and medicine?

A

Drug: chemical/substance that USUALLY used to treat a disease/condition

Medicine: is USED to treat a disease/condition

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2
Q

Describe the dose to effect and the main parameters involved:

A

Dose -> Concentration:

  • Determined by pharmacokinetics
  • CL (Clearance), Vd (Volume of distribution)

Concentration -> Effect

  • Determined by Pharmacodynamics
  • Emax, EC50
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3
Q

How are concentrations of medicines measured in a patient?

A

Plasma concentrations are measured

It would be more ideal to measure concentration at site of action as this would be a more realistic measure

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4
Q

What are the four primary targets of medicines?

A
  • Ion channels
  • Enzymes
  • Carrier molecules
  • Receptors

(Most medicines produce effect by binding to proteins and causing a conformational change)

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5
Q

What are the exceptions to the four primary targets of medicines?

A
  • Cytokines and DNA
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6
Q

What are receptors?

A

Proteins which specifically recognise a particular neurotransmitter/hormone and upon binding undergo a conformation change leading to activation/inhibition of cell signalling

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7
Q

What are the four main families of receptor?

A
  • Ligand gated ion channels
  • G-protein coupled receptors
  • tyrosine kinase/cytokine receptors
  • Nuclear/steroid hormone receptors

(Increasing time to effect as you move down the list)

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8
Q

Define: Affinity, Efficacy, Agonist, Antagonist

A

Affinity: Attraction of a ligand (drug) for a receptor
Efficacy: (Intrinsic activity)
Agonists: Have affinity and efficacy (mimics endogenous compounds)
Antagonists: Have affinity but NO efficacy (prevents)

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9
Q

Describe 3 important properties of ligand gated ion channels, its timecourse and tertiary structure

A
  • Fast signal transmission (ms)
  • All multi-subunit complexes

3 imp properties:

  • Activated in response to specific ligands
  • Conduct ions through otherwise impermeable cell membranes
  • Select among different ions
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10
Q

Describe the function structure of the nicotinic ACh ion channel:

A
  • Five TM2 helices are sharply kinked inwards halfway through the membrane forming a constriction
  • TM2 helices are believed to snap to attention when ACh binds, opneing the channel
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11
Q

Give some medicine examples of GABA(a) ion channels as targets:

A

Benzodiazapines i.e valium (agonist) and barbituates i.e flumazenil (antagonist)

GABA (a) binds to the ion channel, confirmation change and Cl flows in and hyperpolarises the neuron

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12
Q

How do g protein coupled receptors work?

A

Ligand binds g-Protein, activating it and causing it to rise intracellular messangers i.e cAMP, IP3 etc and these impact the nucelus

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13
Q

How do g-protein couples receptors work? what are some drugs that target these?

A

inc. cAMP and PKA etc etc

B-adrenoreceptors i.e propranolol
Adenosine receptors i.e caffeine, theophylline

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14
Q

How do tyrosine kinase receptors work?

A

Receptor functions as an enzyme that transfers phosphate groups from ATP to tyrosine residues on intracellular target proteins

Mediates the actions of growth factors, cytokines and certain hormones i.e insulin

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15
Q

Whats an example of a tyrosine kinase receptor?

A

VEGFR2

  • Ligand stimulated receptor dimerisation and autophosphorylation, triggers pathway
  • Activaiton serves to promote endothelial health
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16
Q

What are some protein kinase inhibitors and what do they do? (tyrosine kinase receptors)

A
  • Trastuzumab is used in those with HER-2 genes (Which upregulate EGF), to prevent enhanced VEGFR activation

More specific than traditional cancer drugs

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17
Q

Where are nuclear/steroid hormone receptors?

A

Receptor in cytoplasm of cell, thus ligand must be able to cross membrane i.e lipid soluble

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18
Q

How do drugs bind to receptors? and whats the implications of binding strength?

A
  • Van der waals forces (Weak forces)
  • H bonding (stronger)
  • Ionic interactions (stronger than H bonds)
  • Covalent (essentially irreversible)

(These stronger binding means the receptors are generally recycled every 7 days, may or may not be recycled)

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19
Q

How does affinity and drug concentration relate?

A

The higher the affinity of the drug for the receptor, the lower the concentration at which it procuces a given effect.

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20
Q

What is Emax and EC50?

A

Emax = Concentration to produce maximum effect

EC50 = Concentration to produce 50% effect

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21
Q

What is dose vs concentration?

A

Dose is the actual amount of medicine administered

Concentration is what that dose produces in the body

22
Q

What is potency?

A

How left shifted the EC50 is, i.e how little concentration to produce the 50% effect. (more potent = lower EC50)

EC50 is used to measure the potency of an agonist.

23
Q

What demonstrates potency, EC50 and EMax?

A

Dose response curves

24
Q

Are concentration response curves good for describing affinity?

A

No, receptor response and response is not strictly proportional

  • Considerable amplification could occur i.e low recept. occupancy for max response
  • Many factors downstream might interact to produce maximal response
25
Q

What is efficacy?

A

The ability of a drug to bind to a receptor and cause a change in the receptors action is termed efficacy and measured by Emax.

  • drug with positive efficacy = will activate a receptor to promote a cellular response = Agonist
  • drug with negative efficacy = will bind a receptor to decrease basal receptor activity = Inverse agonist
  • A drug with no efficacy will bind to the receptors but have no effect on activity = Antagonist
26
Q

Describe agonism:

A

Drugs that ellicit max tissue response are full agonists, drugs that produce less are partial agonists

  • Full agonists can produce a graded response then!

NB: partial agonists cannot produce maximal response even at 100% receptor occupancy and therefore are less likely to trigger receptor plasticity.

27
Q

What are the types of agonisms?

A

Full agonist
Partial agonist
Antagonist

NB: Inverse agonist (Bidirectional response)

28
Q

What are antagonists?

A
  • Compound that does not activate or inactivate the receptor
  • Antagonists have affinity but NO efficacy
  • Defined by how they bind to the receptor i.e reversible and irreversible competitive antagonism
29
Q

What is a a reversible competitive antagonism? List 3 examples

A
  • Bind in a reversible manner to the receptor to compete directly with the agonist binding

I.e Metoprolol, Naloxone, Losartan

30
Q

What is irreversible competitive antagonism? List an example:

A

Drug covalently binds to the receptor. Not reversible. Reduces the number of receptors available to the agonist.

I.e Clopidogrel. (antiplatelet)

31
Q

With an example, describe receptor terminology:

A 
Adrenergic receptors (Family)
Alpha or beta (Sub-family)
A1 A2 B1 B2 (Subtype)
32
Q

Why is selectivity for sub types important? give an example

A
  • Preferential binding to a certain subtype leads to a greater effect at that subtype than others
    i. e salbutamol at b2 (lungs) rather than b1 (heart)

Lack of selectivity can lead to unwanted drug effects i.e fenoterol

33
Q

What are typical vs atypical anti-psychotics?

A

Typical: Dopamine antagonists i.e haloperidol (like zombies)

Atypical: Dopamine and 5HT antagonists i.e quetiapine (non-selective)

34
Q

Discuss receptor plasticity:

A
  • Receptor states and populations do not remain constant over time
  • This plasticity is largely responsible for the changes that occur in effectiveness of chronic drug (or endogenous compound) over time
    i. e tolerance, insulin resistance

I.e population dependent on drug exposure

35
Q

Describe the regulation of receptors:

A
  • Changes in receptor states i.e Desensitisation / exhaustion of mediators
  • Change in receptor populations i.e Up or down regulation
36
Q

Describe how desensitisation and internalisation of receptors occurs?

A

In some instances receptors are sensitised and then internalised / broken down and not replaced.

Depends on the external environment

37
Q

What can happen with chronic salbumatol use?

A

Chronic agonist administration can lead to down regulation i.e
- Chronic salbutamol can cause internalisation of receptors -> less receptors available for stimulation -> Decreased broncodilation

Thus recommended daily limit b/c toxicity and receptor plasticity

38
Q

What can chronic antagonist use lead to?

A

Chronic antagonist administration can lead to up regulation
- I.e chronic propranalol can increase synthesis of B1 receptors in the heart -> less antagonism -> Decreased drug effect (therapeutic failure) increasing HR and BP

39
Q

Describe the time course rapid desensitisation:

A

Receptors that rapidly desensitise can rapidly resensitise

But this cant be distinguished from the response because it is too rapid

40
Q

What are 3 clinically significant concerns of receptor desensitisation and examples:

A

Tolerence i.e morphine, salbutamol

Adverse effects i.e antipsychotics (D2 antagonists)

Therapeutics effects i.e tricyclic antidepressants

41
Q

What are some non-protein receptor targets?

A

Non-protein receptor targets

  • Enzymes (COX inhibitors)
  • Carrier proteins (TCAs and SSRIs)
  • Ion Channels (local anaesthetic)

Non-protein targets

  • Soluble ligands i.e inflam mediators
  • DNA
42
Q

What are some examples of enzymes that are targeted by drugs and how?

A
  • Cyclooxygenase and NSAIDS - used to treat pain and inflammation
  • HMG CoA reductase and statins, used for lowering cholesterol
  • Cholinesterase inhibitors i.e donepezil use for dementia b/c loss of ACh activity
43
Q

Describe how NSAIDS work

A

NSAIDS inhibit cyclo-oxygenase that converts arachidonate to cylic endoperoxides this would eventuall lead to prostaglandin production that generates pain etc

44
Q

What are the effects of cyclooxygenase inhibition?

A

NSADI inhibition of COX1 and COX2

  • > Dec inflam
  • > Dec pain
  • > Dec fever

BUT ALSO

  • Reduction of homeostatic pathways involved in:
  • Kidney function (possible AKI) and maintenance of gastric mucosa (ulcers)
45
Q

Whats the solution to avoiding the potential adverse effects of cyclooxygenase inhibitors?

A

COX2 selective inhibitors (Coxibs)

  • Greater safety against GI side effects
  • Increased risk of CV event though = strict regulation
46
Q

Whats an example of a drug thats the enzyme HMG-CoA?

A

Statins i.e simvastatin

Decreases synthesis of cholesterol

47
Q

Describe some drugs that interact with carrier proteins:

A

Drugs that interact wtih monoamine neurotransmitter uptake proteins:

  • Fluoxtine (SSRI) (takes weeks, not conclusive as to why)
  • SNRI i.e venlaflaxine
48
Q

What are some drugs that act on ion channels?

A

Voltage gated ion channels

  • Lignocaine (local anaesthetic)
  • Ca channel blockers i.e verpamil and nifedipine
49
Q

What are biopharmaceuticals?

A

Medicines of biological origin

50
Q

What are some examples of biopharmaceuticals?

A

Peptides
Gene therapy
Cell therapy
Monoclonal ABs (bind targets and signal to immune system for destruction)

51
Q

What are some examples of monocloncal antibodies:

A

Infliximab

Trastuzumab

52
Q

Why are biologics used in asthma?

A

5% dont respond to traditional therapies

Target specific chemokines using AB based therapy

Can reduce need for corticosteroids

Pharmacology MBCHB2 (18 decks)

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