Mechanisms of drug action Flashcards

1
Q

List the 4 types of drug antagonism

A

1) Receptor blockade
2) Physiological antagonism
3) Chemical antagonism
4) Pharmacokinetic antagonism

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2
Q

Why do we need to be careful when co-administering drugs

A

Co-administering drugs can diminish the response of another drug- so we may need to change doses or look for different classes- to select ones that don’t interact.

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3
Q

Summarise receptor blockade

A

§ Two forms of this (explained above) – competitive and irreversible.
§ Receptor blockade can also display “Use-dependency” of ion channel blockers, i.e. Local anaesthetic.
i. Use-Dependency = The more the cell is active/used, the faster the block is absorbed and blocks the ion channels.

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4
Q

Explain how receptor blockade works

A

Non-competitive antagonism describes the situation where the antagonist blocks at some point downstream from the agonist binding site on the receptor, and interrupts the chain of events that leads to the production of a response by the agonist.

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5
Q

Describe the effects of receptor blockade

A

The effect will be to reduce the slope and maximum of the agonist log concentration-response curve, although it is quite possible for some degree of rightward shift to occur too.

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6
Q

Give some examples of drugs that use the receptor blockade

A

Ketamine enters the ion channel pore of the NMDA receptor blocking it, thus preventing ion flux through the channels.
Drugs such as verapamil and nifedipine prevent the influx of Ca2+ through the cell membrane and thus non-selectively block the contraction of smooth muscle produced drugs acting at any receptor that couples to these calcium channels.

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7
Q

Explain use dependency

A

If the tissue is more active, a certain drug ( such as an ion channel blocker) will act more completely and faster because if the tissue is more active- more of the ion channels will be open- allowing the drug to get into the ion channel and block it.

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8
Q

Relate use dependency to local anaesthetics

A

The alpha, delta and C nociceptive neurones are firing rapidly (lots of action potentials generated when soft tissue is damaged to relay pain). Therefore local anaesthetics act preferentially on these neurones compared to other types of neurones (showing selectivity to the pain neurones).

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9
Q

Summarise physiological antagonism

A

§ Drugs that counters the effect of another substance by acting on different receptors.
i. I.E. If the body has too much NA and thus too much vasoconstriction, histamine can be delivered to counter the vasoconstriction (by acting on H1 receptors instead of adrenergic receptors)

Different receptors  opposite effects in same tissue
e.g. NA + histamine on B.P
NA acts on alpha reeptors to constrict blood vessels and raise BP
Histamine acts on H1 receptor to cause vasodilation and decrease BP

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10
Q

Explain physiological antagonism- giving examples

A

Physiological antagonism is a term used loosely to describe the interaction of two drugs where opposing actions in the body tend to cancel each other. For example, histamine acts on receptors of the parietal cells of the gastric mucosa to stimulate acid secretion.
While omeprazole blocks this effect by inhibiting the proton pump; the two drugs can be said to act as physiological antagonists.

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11
Q

Summarise chemical antagonism

A

§ Drugs that interacts in solution to antagonise a reaction (as opposed to binding to specific receptors).
i. I.E. If people have heavy metal poisoning, you give dimercaprol (chelating agent) to bind the heavy metal and form non-toxic clumps which can be excreted (before they get absorbed).

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12
Q

Explain chemical antagonism

A

It refers to the uncommon situation where the two substances combine in solution; as a result the effect of the active drug is lost.
Examples include the use of chelating agents (dimercaprol) that bind to heavy metals (Pb2+) and reduce their toxicity, and the use of the neutralising antibody infliximab, which has an anti-inflammatory action due to its ability to sequester the inflammatory cytokine TNF.

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13
Q

Summarise pharmacokinetic antagonism

A

§ Drugs (agonists) that are administered, are antagonised by the body itself that reduces the concentration of the active drug at the site of action.
i. I.E. reduced absorption, blocked distribution, increased metabolism, increased excretion.

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14
Q

Explain pharmacokinetic antagonism

A

Pharmacokinetic antagonism describes the situation in which the ‘antagonist’ effectively reduces the concentration of the active drug at its site of action. This can happen in various ways:
The rate of metabolic degradation of the active drug may be increased (e.g the reduction of the anticoagulant effect of warfarin when an agent that accelerates its hepatic metabolism, such as phenytoin is given)
Alternatively, the rate of absorption from the G.I tract ma be reduced, or the rate of renal excretion may be increased.

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15
Q

Describe the use of barbiturates

A

Use to treat epilepsy, and are used in surgery and in general anaesthesia

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16
Q

Explain the clinical importance of barbiturates

A

When used over a long period of time, they are enzyme inducers. This means that they increase the expression of enzymes that metabolise barbiturates in the liver. Warfarin (and also TCAs) are metabolised by the same system of enzymes. This results in warfarin being metabolised more quickly and thus a higher dose is needed to produce the intended effect ( blood clotting time can be measures by analysing a drop of blood from the thumb- this is called the prothrombin time test

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17
Q

What is meant by drug tolerance

A

This is the gradual decrease in responsiveness to a drug with repeated administration (occurs over days or weeks)

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18
Q

Describe the issue of tolerance with benzodiazepines

A

Anti-convulsant and anti-anxiolytic drugs- but lose their effectiveness over time

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19
Q

List the 4 methods of drug tolerance

A
Pharmacokinetic factors
Loss of receptors 
Change in receptors
Exhaustion of mediator stores
Physiological adaptation
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20
Q

How do pharmacokinetic factors lead to tolerance

A

§ Due to an increased rate of metabolism.

i. E.G. Barbiturates, alcohol.

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21
Q

Explain how pharmacokinetic factors lead to tolerance

A

Tolerance to some drugs, for example barbiturates and ethanol, occurs partly because repeated administration of the same dose produces a progressively lower plasma concentration, as a result of increased plasma concentration (increased expression of the enzymes that metabolise them i.e the cytochrome P450 enzymes for barbiturates)
The degree of tolerance that results is generally modest, and in both of these examples other mechanisms contribute to the substantial tolerance that occurs.
However, the pronounced tolerance to nitrovasodilators results mainly from decreased metabolism, which reduces the release of the active mediator, nitric oxide.

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22
Q

Summarise loss of receptors as a cause of tolerance

A
  1. Loss of receptors; (N.B. There can also be receptor “up-regulation” – Denervation supersensitivity)
    § Due to membrane endocytosis of receptors (through receptor “down-regulation”).
    i. E.G. beta-adrenoceptors.
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23
Q

Explain why we see a loss of receptors

A

Prolonged exposure to agonists often results in a gradual decrease in the number of receptors expressed on the cell surface, as a result of internalisation of receptors. This is seen for beta adrenorecdeptors and is slower than the uncoupling process seen in the change of receptors. Similar changes have been described for other types of receptor, including those for various peptides. The internalised receptors are taken into the cell by endocytosis of patches of the membrane, a process that normally depends on receptor phosphorylation and the subsequent binding or arrestin proteins to the phosphorylated receptor.
This type of adaptation is common for hormone receptors and has obvious relevance to the effects produced when drugs are used for extended periods. It is generally an unwanted complication when agonist drugs are used clinically.

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24
Q

Describe receptor upregulation in denervation super sensitivity

A

Soft tissue damage can damage the afferent alpha motor neurones to the skeletal muscle- resulting in a loss of input. The skeletal muscle responds to this by increasing the expression of receptors on the pain fibres to amplify the incoming signal to maintain its normal output- receptor expression is fluid.

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25
Q

Summarise a change in receptors

A

Receptor desensitization
 conformational change (may result in a change in affinity

nAChR at NMJ

continuously stimulating receptors- reduce efficacy of agonist and reducing the responsiveness of the system.

26
Q

With relation to the NMJ explain how a change in receptors can lead to tolerance

A

Among receptors coupled to ion channels, desensitisation is often rapid and pronounced. At the NMJ, the desensitised state is caused by a conformational change in the receptor, resulting in tight binding of the agonist molecule without the opening of the ion channel. Phosphorylation of intracellular regions of the receptor protein is a second, slower mechanism by which ion channels become desensitised.

27
Q

Describe how GPCRs show desensitisation by a change in receptors

A

Most GPCRs also show desensitisation. Phosphorylation of the receptor interferes with its ability to activate second messenger cascades, although it can still bind the agonist molecule. This type of desensitization usually takes seconds to minutes to develop, and recovers when the agonist is removed.

28
Q

Summarise what is meant by an exhaustion of mediator stores

A

§ Physiological mediators become exhausted.

i. E.G. Amphetamine – the stores of NA that are usually released become exhausted.

29
Q

Explain how an exhaustion of mediator stores can lead to tolerance

A

In some cases, desensitisation is associated with depletion of an essential intermediate substance. Drugs such as amphetamine, which acts by releasing amines from nerve terminals, show marked tachyphylaxis because the amine stores become depleted.

30
Q

Describe how amphetamine works

A

Amphetamine is a drug of abuse- leads to euphoria and excitability
Very lipid soluble- can be snorted and cross the mucosa barrier
Taken into mono-amine nerve terminals by uptake proteins- then binds to the vesicles- leading to the release of NA
Eventually, NA runs out- diminished response if taken again whilst stores have not recovered.

31
Q

Summarise physiological adaptation

A

Homeostatic responses
Tol§ The body physiologically adapts to administration of the drug over time.
i. E.G. A drug causing a drop in BP could cause the RAS to activate in response to raise the BP.erance to drug side effects

32
Q

Describe how physiological adaptation can lead to tolerance

A

Diminution of a drug’s effect may occur because it is nullified by a homeostatic response. For example, the blood-pressure lowering effect of thiazide diuretics is limited because of gradual activation of RAAS.
Such homeostatic mechanisms are very common, and if they occur slowly the result will be a gradually developing tolerance. It is a common experience that many side effects of drugs, such as nausea or sleepiness, tend to subside even though drug administration is continued. We may assume that some kind of physiological adaptation is occurring, presumably associated with altered gene expression, resulting in changes in the levels of various regulatory molecules, but little is known about the mechanisms involved.

33
Q

What are the receptor families based on

A

4 types based on  Molecular structure

 Signal transduction systems

34
Q

Summarise the ion channel

A
Type 1:	Ion channel-linked receptors
	  Fast responses (m secs)
	  nAChR- skeletal NMJ, in autonomic ganglia and in the brain
 GABAA
5-HT
ionotropic glutamate receptors
purinergic P2X receptors
35
Q

What is the nAChR also known as

A

the cys-loop receptor (so called because they have in their structure a large intracellular domain between trans membrane domains 3 and 4 containing multiple cysteine residues).

36
Q

Describe the other types of ion channel-linked receptors

A

In addition to the ligand gated-ion channels found on cell membranes that mediate fast synaptic transmission, there are also intracellular ligand-gated ion channels- namely the inositol triphosphate (IP3) and ryanodine receptors that release Ca2+ from intracellular stores

37
Q

Describe the structure of the nAChR

A

The nAChR consists of a pentameric assembly of different subunits, of which there are 4 types (alpha, beta,gamma and delta), each of molecular weight 40-58kDa.
The subunits show marked sequence homology, and each contains four membrane-spanning alpha helices inserted into the membrane.
The pentameric structure possesses two acetylcholine binding sites, each lying at the interface between one of the two alpha subunits and its neighbour.
Both must bind acetylcholine molecules for the receptor to be activated.
Each subunit spans the membrane four times, so the channel comprises no fewer than 20 membrane-spanning helices surrounding a central pore.

38
Q

Summarise the structure of the ion channel

A

Oligomeric assembly of subunits surrounding central pore

39
Q

Describe receptor heterogeneity and subtypes

A

Receptors within a given family generally occur in several varieties, or subtypes, with similar architecture but significant differences in their sequences, and often in their pharmacological properties. Nicotinic acetylcholine receptors are typical in this respect; distinct subtypes occur in different brain regions, and these differ from the muscle receptor.
Some of the known pharmacological differences (e.g sensitivity to blocking agents) between muscle and brain acetylcholine receptors correlate with specific sequence differences; however as far as we know, all nicotinic acetylcholine receptors respond to the same pharmacological mediator and produce the same kind of synaptic response, so why so many variants have evolved is a puzzle.

40
Q

What does the sheer speed of transmission at ionotropic receptors imply

A

that the response is a direct one

In contrast to other receptor families, no intermediate biochemical steps are involved in the transduction process.

41
Q

Summarise GPCRs

A

Type 2: G-protein-coupled receptors
 Slower responses (secs)
 1-adrenoceptors (heart)

42
Q

Give some examples of GPCRs

A
GPCRs constitute the commonest single class of targets for therapeutic drugs.
mAChRs
adrenoreceptors
dopamine receptors
5-HT (serotonin receptors)
receptors for peptides
purine receptors
43
Q

What is key to remember about metabotropic receptors

A

They are not composed of subunits

44
Q

Describe the structure of GPCRs

A
7TM domain- alpha helices spanning the membrane
No subunits (BUT the G protein has 3 subunits alpha, beta and gamma, with the alpha possessing GTPase activity)
The G protein interacts with a binding pocket on the intracellular surface of the receptor.
Extracellular binding domain (agonist may bind here or could just sit in the membrane)
This activates the G protein domain and allows it to bind to the intracellular domain (C terminal end)- triggering the intracellular response
45
Q

Summarise kinase linked receptors

A

Type 3: Kinase-linked type
 insulin/growth factors (mins)
Only ONE subunit (alpha helix)

46
Q

Describe the structure of kinase linked receptors

A

The receptors all share a common architecture, with a large extracellular ligand-binding domain connected via a single membrane spanning helix to the intracellular domain- often the catalytic activity of tyrosine kinase.

47
Q

Summarise the signal transduction pathway in kinase- linked receptors

A

Signal transduction generally involves dimerization of receptors, followed by autophosphorylation of tyrosine residues. The phosphotyrosine residues act as acceptors for the SH2 domains of a variety of intracellular proteins, thereby allowing control of many cell functions.
They are mainly involved in events controlling cell growth and differentiation, and act indirectly by allowing gene regulation.

48
Q

Give two important pathways that kinase-linked receptors utilise

A

The Ras/Raf/mitogen-activated protein (MAP) kinase pathway, which is important in cell division, growth and differentiation.
The Jak/Stat pathway activated by many cytokines, which controls the synthesis and release of many inflammatory mediators.

49
Q

What does the fact that many different kinases exist allow for

A

There are many kinases, with differing substrate specificities, allowing specificity in the pathways activated by different hormones.
Desensitisation of GPCRs occurs as a result of phosphorylation by specific receptor kinases, causing the receptor to become non-functional and to be internalised.
There is a large family of phosphatases that act to dephosphorylate proteins and thus reverse the effects of kinases.

50
Q

Summarise intracellular receptors

A

Type 4: Intracellular steroid type receptors
 steroids/thyroid hormones (hrs)
 regulate DNA transcription

51
Q

What are some of the ligands for intracellular receptors

A

Their ligands are wide and varied, including steroid drugs and hormones, thyroid hormones, vitamins A and D, various lipids and xenobiotics.

52
Q

Describe the structures of intracellular receptors

A

Extracellular binding domain- where the agonist binds- this causes the receptor to unfold- exposing the DNA binding domain- which is made up of ‘zinc fingers’ (no alpha helix subunit)- the receptor can then interact with the genetic material to alter transcription- and thus produce more proteins and RNA from the genetic material.

53
Q

Describe the two different classes of intracellular receptors

A

Class 1- present in the cytoplasm, form hormones in the presence of the ligand, and migrate to the nucleus. Their ligands are mainly endocrine in nature (steroid hormones)
Class 2- NRs are constitutively present in the nucleus and form heterodimers with the retinoid X receptor. their ligands are usually lipids (e.g the fatty acids).

54
Q

Describe the second messenger cAMP

A

can be activated or inhibited by pharmacological ligands, depending on the nature of the receptor and G protein.
adenylyl cyclase catalyses formation of I.C messenger cAMP (from ATP)
cAMP activates protein kinases such as PKA that control the cell function in many different ways by causing phosphorylation of various enzymes and other proteins (i.e contractile proteins)

55
Q

Describe the second messenger Phospholipase C

A

Catalyses the formation of two intracellular messengers,IP3 and DAG from membrane phospholipid
IP3 acts to increase the cytosolic Ca2+ by releasing Ca2+ from intracellular compartments.
Increased free Ca2+ initiates many events, including contraction, secretion, enzyme activation and membrane hyperpolarisation.
DAG activates various protein kinase C isoforms, which control many cellular functions by phosphorylating a variety of proteins.

56
Q

Describe phospholipase A2 as a second messenger

A

leads to formation of arachidonic acid and thus eicosanoids (which are released as local hormones) and can act as a ligand for G proteins
can also stimulate ion channels

57
Q

Describe the effect GPCRs can have on ion channels

A

opening potassium channels, resulting in membrane hyperpolarisation
inhibiting calcium channels, thus reducing neurotransmitter release.

58
Q

Describe the role of the G protein

A

When the G protein binds to the agonist occupied receptor, the alpha subunit binds GTP, dissociates and is then free to activate an effector (membrane enzyme) in some cases the beta gamma subunit is the activator species
Activation of the effector is terminated when the bound GTP molecules is hydrolysed, which allows the alpha subunit to recombine with beta-gamma

59
Q

Summarise the characteristics of the inotropic receptors

A

Location- membrane
effector- channel
coupling- direct
examples- nAchR, GABAa receptor

60
Q

Summarise the characteristics of GPCRs

A
Location- Membrane
Effector- enzyme or channel
coupling- G protein
example- mAchR
adrenoreceptors
61
Q

Summarise the characteristics of kinase-linked receptors

A

location- membrane
effector- enzyme
coupling- direct
example- insulin receptor, growth factor and cytokine receptors

62
Q

Summarise the characteristics of I.C receptors

A

location- inside the cell
effector- gene transcription
coupling- via DNA
Example- steroid/thyroid receptors