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Pharmacology and therapeutics > Drug Receptor Interactions > Flashcards

Drug Receptor Interactions Flashcards

1
Q

What is meant by a drug

A

A chemical substance that interacts with a biological system to produce a physiological effect.

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2
Q

List the different drug target sites

A

Receptors
Ion channels
Transport systems
Enzymes

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3
Q

What do the drug target sites all have in common

A

They are all proteins

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4
Q

How do drugs essentially illicit their response

A

By interacting with the drug target site

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5
Q

Summarise tolerance

A

Tolerance is the measured effect of repeated administration.
Doesn’t occur with all drugs
Limits the use of the drug

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6
Q

Where can receptors be found

A

Extracellularly (non-steroid)

Intracellularly (steroid)

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7
Q

Summarise receptors

A

Proteins within cell membranes (usually)
Activated by NT or hormone
Defined by agonists & antagonists
4 types of receptors

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8
Q

What are the 4 types of receptor

A

Ionotropic
GPCR
Enzyme-linked
Intracellular

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9
Q

What is each drug receptor defined by

A

By selective agonists and selective antagonists

e.g a compound that selectively stimulates dopamine receptors and not 5-HT or NA receptors

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10
Q

What are families of receptors defined by

A

By their structures and transduction systems used

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11
Q

What is meant by agonists and antagonists

A

Agonist- compound that stimulates the receptor

Antagonist- compound that blocks or inhibits the receptor

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12
Q

Give some examples of drugs that act on receptors

A

Acetylcholine (agonist for acetylcholine receptors)

Atropine (selective antagonist for muscarinic acetylcholine receptors)

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13
Q

What is atropine used for

A

pre-med before surgery- dry up secretions- particualry bronchial secretions
used to treat cardiac arrest, sinus bradycardia after myocardial infarction
side effects include dry mouth, dilated pupil, bronchodilatation, urinary retention

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14
Q

What is meant by an ion channel

A

Selective pores - allow transfer of ions down electrochemical gradients

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15
Q

What are the two types of ion channel

A

2 types 1) voltage-sensitive e.g. VSCC

2) receptor-linked e.g. nAChR

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16
Q

How are ion channels defined

A

By the gated mechanisms that they use

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17
Q

Describe receptor-linked ion channels

A

When Ach stimulates the nicotinic receptor- it changes its conformation opening a linked cation channel- allowing a current of Na+ to move into the cell- depolarising the cell- increasing the firing rate of the cell

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18
Q

What is important to remember about nicotinic receptors

A

They are excitatory

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19
Q

Describe how local anaesthetics work

A

Lots of action potentials generated in the wound by nociceptive receptors- which sends APs down sensory neurone to the sensory cortex via the thalamus- triggering pain
LAs (e.g lidocaine) get inside the Na+ channel and stereochemically inhibit it (preventing the influx of Na+ ions)- fewer APs- ‘numbing’ the pain

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20
Q

How are local anaesthetics administered

A

sub-cutaneous

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21
Q

How can calcium channel blockers be used to treat arrhythmias

A

ClassIV drugs (verapamil) block L-type Ca2+ channels, thereby decreasing the gradient of the pacemaker potential, slowing the rate of depolarisation in the SA node and prolonging the conduction delay in the AV node. They also have negative ionotropic effects by limiting the influx of Ca2+ during the plateau phase

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22
Q

What else can CCBs be used to treat

A

Hypertension- all blood vessels have sympathetic tone- CCBs prevent influx of Ca2+- reduced contraction of SM-dilation of the vessels- lowering BP
Can also be used to treat angina

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23
Q

What is meant by transport systems

A

Transport against the conc gradient- need ATP to function

glucose, ions, NTs

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24
Q

Summarise transport systems

A

Transport against concentration gradients (glucose, ions, NTs)
Specificity for certain species
Examples :Na+/K+-ATPase
: NA ‘uptake 1’

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25
Q

Give some examples of drugs that target transport systems

A

Tricyclic Anti-depressants (TCAs).

Cardiac glycosides.

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26
Q

What does each NT have

A

its own specific transporter system

e.g NA uptake 1 only found in NA nerve terminals

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27
Q

Describe tricyclic anti-depressants

A

Interfere with the function of NA uptake 1 protein
In clinical depression, the NA transport system is not functioning optimally in the CNS
TCAs slow down the uptake system of NA- so more remains in the synaptic cleft for longer enhancing NA.
Also enhances the activity of 5-HT- aiding in reducing the effects of depression.

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28
Q

Describe cardiac glycosides

A

Glycosides e.g digoxin have a central effect, stimulating the vagus nerve and increasing parasympathetic stimulation, thus slowing heart rate. It simultaneously exerts its positive inotropic effect by inhibition of Na+/K+ ATPase.
Inhibiting Na+/K+ ATPase increases the intracellular Na+, which increases I.C Ca2+- improving contractility.

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29
Q

What are enzymes

A

catalytic proteins that increase rate of reaction.

30
Q

Summarise the drug interactions with enzymes

A

Drug interactions:-

i) enzyme inhibitors
		e. g. anticholinesterases 				(neostigmine)	
ii) false substrates
		e. g. methyldopa
iii) prodrugs
		e. g. chloral hydrate  				trichloroethanol
31
Q

Describe false substrates such as methyldopa

A

sympathetic nerve terminals make NA. one of the steps in the biosynthesis of NA is the conversion of dopa to dopamine using DOPA decarboxylase
when methyldopa is used- methyl noradrenaline is released instead which has less potent effects compared to noradrenaline
therefore you reduce the vasoconstrictive effects of NA and get more vasodilation- reducing BP

32
Q

Describe prodrugs

A

chloral hydrate- hypnotic- used to treat insomnia
converted to trichloroethanol by enzymes in the liver- trichloroethanol is the hypnotic drug (i.e the active ingredient).

33
Q

Describe how enzymes can mediate the toxic effects of drugs

A

If you take too much paracetamol, the enzyme system that metabolises paracetamol in the liver becomes saturate. this results in paracetamol being metabolised by a different set of enzymes which results in the production of toxic products- which can damage the liver and kidney.

34
Q

How can we treat paracetamol overdose

A

Intravenous acetylcysteine or methionine - boosts the glutathione system- which mops up these reactive intermediates.

35
Q

Summarise non-specific drug actions

A

The drug isn’t specific to a receptor etc.
Physiochemical properties :

antacids
osmotic purgatives

36
Q

Describe antacids and osmotic purgatives

A

o Antacids – simple addition of a base to the acidic environment which evens acid-base balance- makes salt increasing pH- reducing symptoms of dyspepsia (usually magnesium or aluminium salts)
o Osmotic purgatives (laxatives) – draws water into the gut to decrease viscosity- softens the stool

37
Q

What is dyspepsia

A

indigestion

38
Q

Describe plasma protein binding

A

Drugs bind to albumin- leading to a reservoir of inactive drugs
No physiological response- not a drug target- more to do with pharmacokinetics as no response is mediated

39
Q

Give an example of plasma protein binding

A

N.B. Some drugs bind very strongly to plasma proteins and so can provide a dangerous and untapped reservoir of the drug (e.g. warfarin).

40
Q

Essentially, what are agonists and antagonists

A

Ligands

41
Q

List some agonists

A

Agonist (ACh; nicotine)

42
Q

List some antagonists

A

Antagonist (atropine; hexamethonium)

Hexamethonium is a nicotinic antagonist

43
Q

Describe hexamethomium

A

It was formerly used to treat disorders, such as chronic hypertension, of the peripheral nervous system, which is innervated only by the sympathetic nervous system. The non-specificity of this treatment led to discontinuing its use.
Blocks autonomic ganglia

44
Q

What does the potency of a drug depend on

A

‘Potency’ of a drug depends on:
i) Affinity
ii) Efficacy (‘intrinsic activity’)
 conformational change of receptor

45
Q

What is meant by the affinity of the drug

A

o Affinity – Strength-of-binding/Avidity of the drug to the receptor.

46
Q

Describe partial agonists

A

o Drugs can also have FULL or PARTIAL agonistic effects.
o PARTIAL agonists can lead to some antagonist activity.
partial agonists never generate the full response- have antagonist activity when co-administered with full agonists.

47
Q

Why do we use the word selective over specific

A

Selectivity – we don’t use the word specific as a drug may not be specific to the same receptors at a higher concentration (may bind to other receptors).

48
Q

What can happen when we increase the conc of a drug

A

Can begin to have actions on other drug targets- leading to the onset of side effects

49
Q

Explain the structure-activity relationship

A

Structure-activity relationship
 ‘lock and key’
 agonists  antagonists
 pharmacokinetics

small changes in the structure of a drug can completely change its activity- potentially turning an agonist into an antagonist.
changes in structure can also slow down its metabolism- leading to pharmacokinetic changes.

50
Q

Describe electrostatic forces

A

long range forces- bring drug to its target

51
Q

What else does the efficacy of the drug involve

A

the transducer system- enzymes its linked to- opening an ion channel etc.

52
Q

Describe the dose-response curve for agonists

A

when tissue response against conc- rectangular hyperbola

when tissue response against log of the conc– sigmoid

53
Q

Why do we take the log of the conc of the agonist

A

Can see max response more easily- can be analysed mathematically due to long straight section of the graph.

54
Q

What is the key property of antagonists

A

Affinity but no efficacy

55
Q

Describe the two different types of antagonists

A

Competitive and irreversible

56
Q

Describe competitive antagonists

A
  1. Competitive
     same site as agonist
     surmountable
     shifts D-R curve to right
57
Q

List some examples of competitive antagonists

A

atropine

: propranolol

58
Q

Describe irreversible antagonists

A
  1. Irreversible
     binds tightly or at different site (may bind to cation channel- agonist won’t be able to compete)
     insurmountable
59
Q

What is atropine

A

A competitive Ach muscarinic receptor antagonist

60
Q

Describe how competitive antagonists work

A

In the presence of a competitive antagonist, the agonist occupancy (i.e proportion of receptors to which the agonist is bound) at a given agonist concentration is reduced, because the receptor can only accommodate one molecule at a time.

61
Q

What happens to the log dose-response curve in the presence of a competitive agonist

A

A simple theoretical analysis predicts that in the presence of a fixed concentration of the antagonist, the log concentration-effect curve for the agonist will shift parallel to the right, without any change in slope or maximum.

62
Q

What is this shift to the right expressed as

A

As a dose ratio (the ratio by which the agonist concentration has to be increased in the presence of the antagonist in order to restore a given level of response). Theory predicts that the dose ration linearly increases with the concentration of the antagonist.

63
Q

What are the salient features of competitive antagonists

A

Shift of the agonist log concentration-effect curve to the right, without change of slope or maximum (i.e antagonism can be overcome by increasing the concentration of the agonist)
linear relationship between agonist dose ratio and antagonist concentration
evidence of competition from binding studies.

64
Q

What do the characteristics of reversible competitive antagonists reflect

A

They reflect the fact that agonist and competitive antagonist molecules do not stay bound to the receptor but dissociate and rebind continuously.
The rate of dissociation of the antagonist molecules is sufficiently high that a new equilibrium is rapidly established on addition of the agonist.
In effect, agonist molecules are able to replace the antagonist molecules on the receptors when the antagonist unbinds, although they cannot of course, evict bound antagonist molecules.

65
Q

How does displacement occur

A

Displacement occurs because, by occupying a proportion of the vacant receptors, the agonist effectively reduces the rate of association of the antagonist molecules; consequently, the rate of dissociation temporarily exceeds that of association, and the overall antagonist occupancy falls.

66
Q

Describe how irreversible antagonists exert their effects

A

The antagonist binds to the same site on the receptor as the agonist but dissociates very slowly, or not at all, from the receptors, with the result that no change in the antagonist occupancy takes place when the agonist is applied.
Can also change the conformation of the active site.

67
Q

Why is the distinction between reversible and irreversible antagonism not always so clear

A

Due to the phenomenon of spare receptors; if the agonist occupancy required to produce a maximal response is very small (say 1% of the total receptor pool), then it is possible to block irreversibly 99% of the receptors without reducing the maximal response.
The effect of a lesser degree of antagonist occupancy will be to produce a parallel shift of the log concentration-effect curve that is indistinguishable from competitive antagonism
Only when the antagonist occupancy exceeds 99% will the maximum response be reduced.

68
Q

When does irreversible antagonism occur in drugs

A

In drugs that possess reactive groups that form covalent bonds with the receptor

69
Q

A drug acting as an inhibitor at a particular drug target site prevents the removal of neurotransmitter from the synapse. Which type of drug target is this drug acting on?

A

Transport protein

70
Q

How will the log concentration- effect curve change in the presence of an irreversible antagonist

A

The curve will shift to the right and fall.

Can’t achieve max response- response blocked.

Pharmacology and therapeutics (30 decks)

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