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Primary Pharmacology > Mechanisms Of Drug Action > Flashcards

Mechanisms Of Drug Action Flashcards

1
Q

What are the characteristics of physiochemical mechanisms of drug action?
Examples

A

Non specific
Depend on properties of drug eg size, shape, pKa, acid/base status, water solubility

Examples include pH effects (charge neutralisation), eg. Sodium citrate, protamine
Osmotic effects
Adsorption
Chelation

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2
Q

How does sodium citrate work, why is it preferred to calcium bicarbonate

A

Binds h ions forming citric acid reducing h concentration so raising ph
Calcium bicarbonate also binds h+ but in doing so forms co2 resulting in gas production, bloating and flatulance

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3
Q

Why should sodium citrate not be used as a long term anti acid

A

High sodium load

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4
Q

How does protamine work

A

Fish protein with high arginine content which makes it highly basic
Forms a complex with acidic heparin with no anticoagulant effect

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5
Q

Example of an osmotic physiochemical drug
How does it work

A

Mannitol
Osmotic effect in plasma leading to expansion of extracellular volume and reduction in blood viscosity.
Freely filtered and minimally reabsorbed renal so causes increased urine production

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6
Q

Example of drug that works by physiochemical adsorption

A

Activated charcoal

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7
Q

How do chelating agents work?

A

High number of oxygen, sulphur and nitrogen atoms forming coordinate bonds with metal ions

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8
Q

Ideal chelating agent properties

A

Water soluble
Not undergone bio transformation
Low affinity for calcium
Forms non toxic compound that is readily excreted

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9
Q

What does penicillamine bind

A

Lead
Copper
Mercury

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10
Q

What does edta bind

A

Calcium
Lead

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11
Q

What is suggamadex
Structure

A

A gamma cyclodextrin
Oligosaccharide with eight sugar residues

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12
Q

Difference between alpha, beta and gamma cyclodextrins

A

Number of sugar residues
Alpha 6
Beta 7
Gamma 8

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13
Q

Types of ligand gated ion channels

A

Pentameric receptors
Ionotrophic glutamate receptors
Purinergic receptors

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14
Q

Structure of a pentameric ligand gated ion channel

A

4 full transmembrane domaines
Both terminals external
2 cystine bridges near the nh2 terminal

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15
Q

Examples of pentameric ligand gated ion channels

A

Nicotinic ach
GABAa
5-HT3

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16
Q

How does ach bind to the nicotinic receptor

A

Needs two molecules to bind to the alpha subunits cooperatively

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17
Q

What ions pass through nicotinic ach receptors when activated

A

Mainly na
Some k
Some ca (selectivity for divalent cations 5x less than monovalent)

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18
Q

How does suxamethonium work
What creates a similar picture to this pathologically

A

Binds to nicotinic acetylcholine receptor causing to to open. Because it is not broken down in the synaptic cleft by acetylcholinesterase (broken down by plasma cholinesterases) opening lasts much longer than activation by ach. The receptors become desensitised and no longer respond to ach.
Organophosphate poisoning causing irreversible inhibition of acetylcholinesterases.

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19
Q

Other than nmj where are nicotinic ach receptors found
Why are these effected differently to nmj receptors by cholinergic drugs

A

Autonomic ganglia in the CNS
Different subunit composition

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20
Q

What are the major inhibitory CNS neurotransmitters
Where are they located mainly

A

GABA - supraspinally
Glycine - spinal cord and hindbrain

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21
Q

Configuration of a GABAa receptor
Where does GABA bind?

A

2alpha, 2 beta, 1 gamma ( though can be different)
GABA binds in two locations between the alpha and beta subunits

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22
Q

Which drugs interact with the GABAa receptor
Where

A

Benzodiazepines - between the alpha and gamma subunits (as does flumazenil as an antagonist)
Voletiles, etomidate, barbiturates and propofol are all allosteric modulators of the other sites.

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23
Q

What drug inhibits 5HT3 receptors

A

Ondansetron

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24
Q

What sort of receptor is a 5HT3 receptor?
What are the other seratonergic receptors?

A

Pentameric ligand gated ion channel
3 others are ionotrophic, rest are all gpcrs

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25
Q

Where are 5HT3 receptors found - action on blocking?

A

Centrally in vomiting centre - antiemetic
Vagus nerve - blockage of vagal afferents stimulating vomiting reflex

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26
Q

What are the ionotrophic glutamate receptors
What is their structure

A

NMDA, AMPA, kainite
4 subunits, 2 transmembrane forming a pore, 2 regulatory (one transmembrane, 1 cshaped on cytoplasmic side)

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27
Q

What is the ligand binding in physiology to the NMDA glutamate receptor

A

Glutamate binds to pore forming subunits
Glycine binds to the regulatory subunits as a coactivator

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28
Q

What ions are ionotropic glutamate receptors permiable too

A

Mainly calcium but also na and k

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29
Q

What drugs effect NMDA receptors
Where are NMDA receptors mainly found

A

Non-competitive inhibition from
Ketamine, N2O, and xenon
Hippocampus

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30
Q

What drug effects purinergic ionotropic receptors
Where are they located and native activation
Effect
Structure

A

Pentobarbital providing analgesia
Widespread cns and PNS, activated by atp and its metabolites
Permeability to all na k and ca
2 transmembrane domaines with large loop externally, end terminals both internal

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31
Q

Structure and mechanism of a GPCR

A

Seven helical transmembrane domains clustered together with extracellular n terminus and intracellular c terminus.
When ligand binds to 2nd/3rd extracellular loops then helicies twist causing a confimational change in domain associated with G protein coupling - the 2nd/3rd intracellular loops
On activation more likely for g protein to bind to receptor. Once bound conformational change which causes dissociation of gdp from alpha subunit in exchange for gtp.
The GTPalpha subunit then dissociates from the beta gamma subunit.
The GTPalpha subunit has energy and can now interact with target (eg ion channel or enzyme)
Once GTP hydrolysed back to GDP can reassociate with beta gamma subunit
Sometimes beta gamma subunit also acts to open k channels

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32
Q

Subclassifications of GPCRs

A

Gs - activates adenylyl cyclase
Gi - inhibits adenylyl cyclase
Gq - activates phospholipase c causing PIP to DAG and IP3

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33
Q

What sort of receptor types are muscurinic ach receptors
Drugs effecting them

A

M1 M3 and M5 - Gq
M2 and M4 - Gi

All effected by atropine and glycopyrronium, only M2 and M4 by ipratropiu

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34
Q

Adrenoreceptor classification
Specific agonists and antagonists

A

Alpha 1 - Gq - phenylephrine, phentolamine
Alpha 2 - Gi - clonidine, yohimbine
Beta 1 and 2 - Gs - isoprenaline + salbutamol, beta blockers

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35
Q

Opiate Type of receptor
What subcategory is effected by remifentanyl and pentazocin

A

All Gi
Remi = m
Pentazocin = k

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36
Q

Type of GPCR at gaba b receptor and agonist

A

Gi
Baclofen

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37
Q

Function of tyrosine kinase receptors

A

Cytoplasmic portion forms a catlytic site that is activated by external ligand binding

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38
Q

Which drugs act on voltage gated ion channels

A

Local anaesthetics
Phenytoin, lamotrigine, carbamazepine
Nifedipine, verapamil

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39
Q

Types of intracellular receptors

A

Intracellular hormone receptors - react with lipid soluble hormones binding to dna regulating transcription
Adrenal steroid hormone receptors - mineralocorticoid or glucocorticoid, binding displaces an inhibitor on heat shock protein allowing dna binding facilitating transcription
Membrane bound - eg IP3 receptors triggered by Gq, ryanodine receptors (blocked by dantrolene)

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40
Q

What is the pharmacokinetic mechanism of drug action

A

Interference with pharmacokinetics (absorption, distribution, metabolism) or endogenous substances involved in biological processes, eg. enzymes and transporters

41
Q

Examples of drugs interfering with enzyme function

A

Neostigmine and acetylcholinesterase
MAOIs and catecholamine metabolism
Sodium valproate and GABA transaminase
NSAIDS and COX

42
Q

How is acetylcholinesterase arranged at the synapse?

A

Several enzymes associated into oligomers anchored to the post synaptic membrane with active sites facing into the cleft

43
Q

Why must some muscle activity be present before giving neostigmine to reverse neuromusclar blockade

A

If given when little or no activity the increase in ach will be insufficient to overcome the blockade completely

44
Q

How does ach bind to acetylcholinesterase

A

Anionic site attracts positively charged quaternary nitrogen of ach causing ach to approach esteratic site - this site contains a serine residue that causes bond breakage. Enzyme becomes acetylated in the process

45
Q

How does neostigmine effect acetylcholine

A

Bonds to both anionic and esteratic sties
It acts as a substrate but enzyme undergoes carbamylation instead of acetylation. The carbomyl group then is very slow to dissociate from the enzyme making the enzyme ineffective for a duration until the synaptic concentration of nmb has fallen sufficiently

46
Q

What is the effect on blood pressure control of methyldopa

A

Methyldopa enters natural catecholamine synthetic pathway and is converted to methylnoradreanline which is packaged into synaptic vessels in place of noradrenaline, however, it is less active so autonomic BP control is impaired.

47
Q

Types of MAO
What inhibits each

A

MAOA - moclobemide (reversible short acting)
MAOB - selegiline
Both inhibited by non selective - tranylcypromine, phenelzine (both irreversible)

48
Q

How long before surgery should irreversible moais be stopped
Examples

A

2 weeks
Tranylcypromine, phenelzine

49
Q

What are. MOAB inhibitors used for
Example

A

Treatment of Parkinson’s
Selegiline

50
Q

Example of reversible MAOI

A

Moclobemide

51
Q

What drugs are contraindicated with MAOIs

A

Pethadine
Indirectly acting sympathomemtics eg ephedrine

52
Q

How does sodium valproate work

A

Inhibits gaba transaminase which breaks down gaba thus increased gaba

53
Q

What is arachadronic acid derived from

A

Membrane associated Phospholipase C

54
Q

What is the distinction between COX1 and 2

A

COX 1 continuously active
COX 2 inducible (produced in response to inflammatory insult)

55
Q

How does paracetamol exert its antipyretic action

A

Cox 3 inhibition

56
Q

Which cox is associated with most side effects of non-selective cox inhibitors such as aspirin

A

COX1

57
Q

Which drugs interact with transport proteins

A

SSRIs
Furosemide
PPIs

58
Q

What is the broad effect of general anaesthetics

A

Depression of signals reaching the hippocampus and cortex so memories are not laid down and processing is interrupted with unconsciousness.
Spinal inhibition causing immobility
Sedative effect from tubomammillary nucleus inhibition

59
Q

Where are general anaesthetics thought to exert their effect

A

Lipophilic sites on ligand gated ionic channels and possibly voltage gated channels causing allosteric conformational changes resulting in enhancement of inhibitory or inhibition or enhancing currents (e.g. inhibitory at NMDA and enhancing GABAa).

60
Q

What gaba antagonist antagonises the effects of propofol

A

Gabazine

61
Q

What feature of an anaesthetic agent is associated with potency
More specifically?
Which anaesthetics are outliers in this regard

A

Lipid solubility
Lecithin solubility - a constituent of cell membranes

Ketamine

62
Q

What lipid sites in a cell might be sites of action of anaesthetics given the lecithin solubility potency link
How may these work.

A

Bilayer itself - alter relationship fluidising the membrane, disrupting membrane spanning ion channels
Annular lipids surrounding ionic channels
Lipophilic sites on proteins - binding to the protein inducing allosteric change - the most likely theory

63
Q

Evidence for proteins as a site of action for anaesthetic agents

A

Animal models
Enatomers of some anaesthetics show sterioselective differences proportional to the extent to which they alter ionic currents

64
Q

What receptors does propofol effect

A

Excitatory at GABAa and glycine
Inhibitory at neuronal nicotinic ach

65
Q

What supports the theory there is a specific binding site for agents such as etomidate, barbiturates and isoflurane on GABAa
Why do we think different agents effect different sites

A

Isomers have differing efficacy
Mutation studies

66
Q

How do anaesthetic agents effect GABAa

A

Allosteric modulation resulting in increased channel opening time and increased Cl conductance causing hyperpolarisation

67
Q

What is the glycine receptor
Where is it

A

A chloride channel similar to GABAa
Brainstem and spinal cord

68
Q

What drugs act on NMDA receptors

A

Ketamine, n2o and xenon - inhibit
Mg - modulates

69
Q

What sort of adverse effects of drugs are there (broad categories)
Which is dose dependant, which is dose independant

A

Predictable - dose dependant
Idiosyncratic - dose independant

70
Q

Subcatagories of predictable drug adverse effects

A

Physiochemical
Pharmacodynamic
Pharmacokinetic

71
Q

Sub categories of idiopathic drug adverse effects

A

Hypersensitivity
Related to pharmacogenetics

72
Q

Examples of physiochemical adverse effects

A

Sulphonamides - photo activated to cause skin discolouration and dermatitis
Alteration in metal ion valency interfering with physiological processes Eg nitrous oxide altering cobalt inhibiting Vit b12 causing megaloblastic anaemia (long term exposure)

73
Q

Principles of Pharmacodynamic drug adverse effects
Example of each

A

Often drug action at site different to that responsible for required effect - either same receptor just somewhere else or different subtype of receptor or indeed different receptor all together

Eg morphine respiratory depression and analgesia both associated with mu receptor
Eg salbutamol causing bronchodilation on beta 2 and tachycardia on beta 1
Eg cyclizine causing antihistamine effect of antiemetic and tachycardia from antimuscarinic

74
Q

What mechanism can result in tachyphylaxis and tolerance

A

Receptor down regulation

75
Q

What up regulation of receptors can cause issues with anaesthetics after denervation injury

A

Upregulation of ach receptors on muscles post denervation (and thus low ach)
These are fetal type rather than adult type so stay open longer allowing more k out.
Give sux and these are opened and k is extruded causing hyperkalaemia

76
Q

At what point should sux be avoided after a denervation injury

A

48-72hrs

77
Q

What pharmacokinetic adverse drug effects arise from

A

Alterations in distribution, metabolism or elimination of endogenous bioagents or from bio transformation of the drug itself

78
Q

Paracetamol metabolic pathway
Issue in overdose

A

Most metabolised by conjugation with sulphate and glucuronide
Some metabolised by cyp450 oxidising it to NAPQI. NAPQI detoxified by conjugation with glutathione but in overdose this can be overwhelmed

79
Q

Examples of idiopathic adverse drug effects
Characteristics

A

Hypersensitivity,
Influenced by pharmacogenetics
Usually unpredictable and unrelated to dose

80
Q

Distinction between anaphylactic and anaphylactoid reaction mechanism

A

Anaphylactic - has preexposure
Anaphylactoid - without preexposure

81
Q

What results in most hypersensitivity reactions in anaesthetics

A

Muscle relaxants
Mainly sux and roc

82
Q

What immune issues does halothane cause
Incidence and mortality

A

Immune mediated hepatitis
1:10,000, 50%

83
Q

What idiopathic pharmacogenetic adverse effects can effect anaesthesia

A

Malignant hyperthermia
Sux apnoea

84
Q

Cause of malignant hyperthermia
Inheritance pattern

A

Defect in ryanodine receptor
Triggered by sux or halagonated voletiles
Autosomal dominant

85
Q

Issue in sux apnoea
What is effected
Inheritance pattern

A

Prolonged block post sux or mivacurium
Abnormal plasma cholinesterase (pseudocholinesterase, butyrylcholinesterase)
Autosomal codominant

86
Q

Enzyme that metabolises codeine to morphine

A

Cyp2d6

87
Q

What drugs would be effected by slow acetalor effect

A

Hydralazine
Isoniazid
Prolonged effect in both

88
Q

Types of drug interactions

A

Physiochemical
Pharmacokinetic
Pharmacodynamic

89
Q

What drugs are most effected by drug drug interactions

A

Low therapeutic index
Eg anticoagulant, antiarrhythmics, anticonvulsants, hypoglycaemics

90
Q

Physiochemical reactions of thiopental
Implication for rsi

A

Precipitation with basic drugs eg sodium bicarb or sux! Must flush between.

91
Q

Examples of drug absorption is effected by antacids

A

Ciprofloxacin
Rifampacin
Tetracycline
Ketoconazole

92
Q

Examples of drug drug interactions effecting absroption
Overall effect

A

GI ph change eg antacids
GI stasis eg opioids

Slower peak and sometimes smaller peak

93
Q

What is the key drug drug effect influencing distribution
Why does it often not effect things even if there is an interaction
When is it significant

A

Competition for plasma protein binding
Interaction causes greater free fraction which causes greater elimination
Significant in very protein bound drugs (>95%) or when drug eliminated by zero order kinetics eg aminodarone and warfarin

94
Q

What is the key mechanism of most drug drug pharmacokinetic interactions

A

Induction or inhibition of metabolism usually by cyp450

95
Q

What happens with administration of sux and neostigmine

A

Prolongation of block due to neostigmine inhibiting plasma cholinesterases!

96
Q

What isoform of p450 is not inducable?
What drugs Inhibit it?

A

2d6
TCAs

97
Q

What antiepileptic effects vecuronium duration, how?

A

Carbamazepine
Induction of cyp3a4 reducing duration of neuromuscular block

98
Q

Examples of pharmacodynamic drug drug interactions

A

2 drugs having same effect eg sux and roc
Opposing effects eg nifedipine and phenylephrerine

99
Q

Differentiate additive effect and synergistic effect

A

Additive effect - same mechanism of action eg vec and roc together, or TCAs with SSRIs
Synergistic - different mechanism but same end goal eg acei and ccbs for htn

Primary Pharmacology (18 decks)

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