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Mechanisms Of Drug Action Flashcards

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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
Where are 5HT3 receptors found - action on blocking?
Centrally in vomiting centre - antiemetic Vagus nerve - blockage of vagal afferents stimulating vomiting reflex
26
What are the ionotrophic glutamate receptors What is their structure
NMDA, AMPA, kainite 4 subunits, 2 transmembrane forming a pore, 2 regulatory (one transmembrane, 1 cshaped on cytoplasmic side)
27
What is the ligand binding in physiology to the NMDA glutamate receptor
Glutamate binds to pore forming subunits Glycine binds to the regulatory subunits as a coactivator
28
What ions are ionotropic glutamate receptors permiable too
Mainly calcium but also na and k
29
What drugs effect NMDA receptors Where are NMDA receptors mainly found
Non-competitive inhibition from Ketamine, N2O, and xenon Hippocampus
30
What drug effects purinergic ionotropic receptors Where are they located and native activation Effect Structure
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
31
Structure and mechanism of a GPCR
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
32
Subclassifications of GPCRs
Gs - activates adenylyl cyclase Gi - inhibits adenylyl cyclase Gq - activates phospholipase c causing PIP to DAG and IP3
33
What sort of receptor types are muscurinic ach receptors Drugs effecting them
M1 M3 and M5 - Gq M2 and M4 - Gi All effected by atropine and glycopyrronium, only M2 and M4 by ipratropiu
34
Adrenoreceptor classification Specific agonists and antagonists
Alpha 1 - Gq - phenylephrine, phentolamine Alpha 2 - Gi - clonidine, yohimbine Beta 1 and 2 - Gs - isoprenaline + salbutamol, beta blockers
35
Opiate Type of receptor What subcategory is effected by remifentanyl and pentazocin
All Gi Remi = m Pentazocin = k
36
Type of GPCR at gaba b receptor and agonist
Gi Baclofen
37
Function of tyrosine kinase receptors
Cytoplasmic portion forms a catlytic site that is activated by external ligand binding
38
Which drugs act on voltage gated ion channels
Local anaesthetics Phenytoin, lamotrigine, carbamazepine Nifedipine, verapamil
39
Types of intracellular receptors
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)
40
What is the pharmacokinetic mechanism of drug action
Interference with pharmacokinetics (absorption, distribution, metabolism) or endogenous substances involved in biological processes, eg. enzymes and transporters
41
Examples of drugs interfering with enzyme function
Neostigmine and acetylcholinesterase MAOIs and catecholamine metabolism Sodium valproate and GABA transaminase NSAIDS and COX
42
How is acetylcholinesterase arranged at the synapse?
Several enzymes associated into oligomers anchored to the post synaptic membrane with active sites facing into the cleft
43
Why must some muscle activity be present before giving neostigmine to reverse neuromusclar blockade
If given when little or no activity the increase in ach will be insufficient to overcome the blockade completely
44
How does ach bind to acetylcholinesterase
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
How does neostigmine effect acetylcholine
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
What is the effect on blood pressure control of methyldopa
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
Types of MAO What inhibits each
MAOA - moclobemide (reversible short acting) MAOB - selegiline Both inhibited by non selective - tranylcypromine, phenelzine (both irreversible)
48
How long before surgery should irreversible moais be stopped Examples
2 weeks Tranylcypromine, phenelzine
49
What are. MOAB inhibitors used for Example
Treatment of Parkinson’s Selegiline
50
Example of reversible MAOI
Moclobemide
51
What drugs are contraindicated with MAOIs
Pethadine Indirectly acting sympathomemtics eg ephedrine
52
How does sodium valproate work
Inhibits gaba transaminase which breaks down gaba thus increased gaba
53
What is arachadronic acid derived from
Membrane associated Phospholipase C
54
What is the distinction between COX1 and 2
COX 1 continuously active COX 2 inducible (produced in response to inflammatory insult)
55
How does paracetamol exert its antipyretic action
Cox 3 inhibition
56
Which cox is associated with most side effects of non-selective cox inhibitors such as aspirin
COX1
57
Which drugs interact with transport proteins
SSRIs Furosemide PPIs
58
What is the broad effect of general anaesthetics
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
Where are general anaesthetics thought to exert their effect
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
What gaba antagonist antagonises the effects of propofol
Gabazine
61
What feature of an anaesthetic agent is associated with potency More specifically? Which anaesthetics are outliers in this regard
Lipid solubility Lecithin solubility - a constituent of cell membranes Ketamine
62
What lipid sites in a cell might be sites of action of anaesthetics given the lecithin solubility potency link How may these work.
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
Evidence for proteins as a site of action for anaesthetic agents
Animal models Enatomers of some anaesthetics show sterioselective differences proportional to the extent to which they alter ionic currents
64
What receptors does propofol effect
Excitatory at GABAa and glycine Inhibitory at neuronal nicotinic ach
65
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
Isomers have differing efficacy Mutation studies
66
How do anaesthetic agents effect GABAa
Allosteric modulation resulting in increased channel opening time and increased Cl conductance causing hyperpolarisation
67
What is the glycine receptor Where is it
A chloride channel similar to GABAa Brainstem and spinal cord
68
What drugs act on NMDA receptors
Ketamine, n2o and xenon - inhibit Mg - modulates
69
What sort of adverse effects of drugs are there (broad categories) Which is dose dependant, which is dose independant
Predictable - dose dependant Idiosyncratic - dose independant
70
Subcatagories of predictable drug adverse effects
Physiochemical Pharmacodynamic Pharmacokinetic
71
Sub categories of idiopathic drug adverse effects
Hypersensitivity Related to pharmacogenetics
72
Examples of physiochemical adverse effects
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
Principles of Pharmacodynamic drug adverse effects Example of each
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
What mechanism can result in tachyphylaxis and tolerance
Receptor down regulation
75
What up regulation of receptors can cause issues with anaesthetics after denervation injury
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
At what point should sux be avoided after a denervation injury
48-72hrs
77
What pharmacokinetic adverse drug effects arise from
Alterations in distribution, metabolism or elimination of endogenous bioagents or from bio transformation of the drug itself
78
Paracetamol metabolic pathway Issue in overdose
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
Examples of idiopathic adverse drug effects Characteristics
Hypersensitivity, Influenced by pharmacogenetics Usually unpredictable and unrelated to dose
80
Distinction between anaphylactic and anaphylactoid reaction mechanism
Anaphylactic - has preexposure Anaphylactoid - without preexposure
81
What results in most hypersensitivity reactions in anaesthetics
Muscle relaxants Mainly sux and roc
82
What immune issues does halothane cause Incidence and mortality
Immune mediated hepatitis 1:10,000, 50%
83
What idiopathic pharmacogenetic adverse effects can effect anaesthesia
Malignant hyperthermia Sux apnoea
84
Cause of malignant hyperthermia Inheritance pattern
Defect in ryanodine receptor Triggered by sux or halagonated voletiles Autosomal dominant
85
Issue in sux apnoea What is effected Inheritance pattern
Prolonged block post sux or mivacurium Abnormal plasma cholinesterase (pseudocholinesterase, butyrylcholinesterase) Autosomal codominant
86
Enzyme that metabolises codeine to morphine
Cyp2d6
87
What drugs would be effected by slow acetalor effect
Hydralazine Isoniazid Prolonged effect in both
88
Types of drug interactions
Physiochemical Pharmacokinetic Pharmacodynamic
89
What drugs are most effected by drug drug interactions
Low therapeutic index Eg anticoagulant, antiarrhythmics, anticonvulsants, hypoglycaemics
90
Physiochemical reactions of thiopental Implication for rsi
Precipitation with basic drugs eg sodium bicarb or sux! Must flush between.
91
Examples of drug absorption is effected by antacids
Ciprofloxacin Rifampacin Tetracycline Ketoconazole
92
Examples of drug drug interactions effecting absroption Overall effect
GI ph change eg antacids GI stasis eg opioids Slower peak and sometimes smaller peak
93
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
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
What is the key mechanism of most drug drug pharmacokinetic interactions
Induction or inhibition of metabolism usually by cyp450
95
What happens with administration of sux and neostigmine
Prolongation of block due to neostigmine inhibiting plasma cholinesterases!
96
What isoform of p450 is not inducable? What drugs Inhibit it?
2d6 TCAs
97
What antiepileptic effects vecuronium duration, how?
Carbamazepine Induction of cyp3a4 reducing duration of neuromuscular block
98
Examples of pharmacodynamic drug drug interactions
2 drugs having same effect eg sux and roc Opposing effects eg nifedipine and phenylephrerine
99
Differentiate additive effect and synergistic effect
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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