Mechanisms Of Drug Action Flashcards
What are the characteristics of physiochemical mechanisms of drug action?
Examples
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
How does sodium citrate work, why is it preferred to calcium bicarbonate
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
Why should sodium citrate not be used as a long term anti acid
High sodium load
How does protamine work
Fish protein with high arginine content which makes it highly basic
Forms a complex with acidic heparin with no anticoagulant effect
Example of an osmotic physiochemical drug
How does it work
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
Example of drug that works by physiochemical adsorption
Activated charcoal
How do chelating agents work?
High number of oxygen, sulphur and nitrogen atoms forming coordinate bonds with metal ions
Ideal chelating agent properties
Water soluble
Not undergone bio transformation
Low affinity for calcium
Forms non toxic compound that is readily excreted
What does penicillamine bind
Lead
Copper
Mercury
What does edta bind
Calcium
Lead
What is suggamadex
Structure
A gamma cyclodextrin
Oligosaccharide with eight sugar residues
Difference between alpha, beta and gamma cyclodextrins
Number of sugar residues
Alpha 6
Beta 7
Gamma 8
Types of ligand gated ion channels
Pentameric receptors
Ionotrophic glutamate receptors
Purinergic receptors
Structure of a pentameric ligand gated ion channel
4 full transmembrane domaines
Both terminals external
2 cystine bridges near the nh2 terminal
Examples of pentameric ligand gated ion channels
Nicotinic ach
GABAa
5-HT3
How does ach bind to the nicotinic receptor
Needs two molecules to bind to the alpha subunits cooperatively
What ions pass through nicotinic ach receptors when activated
Mainly na
Some k
Some ca (selectivity for divalent cations 5x less than monovalent)
How does suxamethonium work
What creates a similar picture to this pathologically
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.
Other than nmj where are nicotinic ach receptors found
Why are these effected differently to nmj receptors by cholinergic drugs
Autonomic ganglia in the CNS
Different subunit composition
What are the major inhibitory CNS neurotransmitters
Where are they located mainly
GABA - supraspinally
Glycine - spinal cord and hindbrain
Configuration of a GABAa receptor
Where does GABA bind?
2alpha, 2 beta, 1 gamma ( though can be different)
GABA binds in two locations between the alpha and beta subunits
Which drugs interact with the GABAa receptor
Where
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.
What drug inhibits 5HT3 receptors
Ondansetron
What sort of receptor is a 5HT3 receptor?
What are the other seratonergic receptors?
Pentameric ligand gated ion channel
3 others are ionotrophic, rest are all gpcrs
Where are 5HT3 receptors found - action on blocking?
Centrally in vomiting centre - antiemetic
Vagus nerve - blockage of vagal afferents stimulating vomiting reflex
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)
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
What ions are ionotropic glutamate receptors permiable too
Mainly calcium but also na and k
What drugs effect NMDA receptors
Where are NMDA receptors mainly found
Non-competitive inhibition from
Ketamine, N2O, and xenon
Hippocampus
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
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
Subclassifications of GPCRs
Gs - activates adenylyl cyclase
Gi - inhibits adenylyl cyclase
Gq - activates phospholipase c causing PIP to DAG and IP3
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
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
Opiate Type of receptor
What subcategory is effected by remifentanyl and pentazocin
All Gi
Remi = m
Pentazocin = k
Type of GPCR at gaba b receptor and agonist
Gi
Baclofen
Function of tyrosine kinase receptors
Cytoplasmic portion forms a catlytic site that is activated by external ligand binding
Which drugs act on voltage gated ion channels
Local anaesthetics
Phenytoin, lamotrigine, carbamazepine
Nifedipine, verapamil
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)
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
Examples of drugs interfering with enzyme function
Neostigmine and acetylcholinesterase
MAOIs and catecholamine metabolism
Sodium valproate and GABA transaminase
NSAIDS and COX
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
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
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
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
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.
Types of MAO
What inhibits each
MAOA - moclobemide (reversible short acting)
MAOB - selegiline
Both inhibited by non selective - tranylcypromine, phenelzine (both irreversible)
How long before surgery should irreversible moais be stopped
Examples
2 weeks
Tranylcypromine, phenelzine
What are. MOAB inhibitors used for
Example
Treatment of Parkinson’s
Selegiline
Example of reversible MAOI
Moclobemide
What drugs are contraindicated with MAOIs
Pethadine
Indirectly acting sympathomemtics eg ephedrine
How does sodium valproate work
Inhibits gaba transaminase which breaks down gaba thus increased gaba
What is arachadronic acid derived from
Membrane associated Phospholipase C
What is the distinction between COX1 and 2
COX 1 continuously active
COX 2 inducible (produced in response to inflammatory insult)
How does paracetamol exert its antipyretic action
Cox 3 inhibition
Which cox is associated with most side effects of non-selective cox inhibitors such as aspirin
COX1
Which drugs interact with transport proteins
SSRIs
Furosemide
PPIs
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
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).
What gaba antagonist antagonises the effects of propofol
Gabazine
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
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
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
What receptors does propofol effect
Excitatory at GABAa and glycine
Inhibitory at neuronal nicotinic ach
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
How do anaesthetic agents effect GABAa
Allosteric modulation resulting in increased channel opening time and increased Cl conductance causing hyperpolarisation
What is the glycine receptor
Where is it
A chloride channel similar to GABAa
Brainstem and spinal cord
What drugs act on NMDA receptors
Ketamine, n2o and xenon - inhibit
Mg - modulates
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
Subcatagories of predictable drug adverse effects
Physiochemical
Pharmacodynamic
Pharmacokinetic
Sub categories of idiopathic drug adverse effects
Hypersensitivity
Related to pharmacogenetics
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)
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
What mechanism can result in tachyphylaxis and tolerance
Receptor down regulation
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
At what point should sux be avoided after a denervation injury
48-72hrs
What pharmacokinetic adverse drug effects arise from
Alterations in distribution, metabolism or elimination of endogenous bioagents or from bio transformation of the drug itself
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
Examples of idiopathic adverse drug effects
Characteristics
Hypersensitivity,
Influenced by pharmacogenetics
Usually unpredictable and unrelated to dose
Distinction between anaphylactic and anaphylactoid reaction mechanism
Anaphylactic - has preexposure
Anaphylactoid - without preexposure
What results in most hypersensitivity reactions in anaesthetics
Muscle relaxants
Mainly sux and roc
What immune issues does halothane cause
Incidence and mortality
Immune mediated hepatitis
1:10,000, 50%
What idiopathic pharmacogenetic adverse effects can effect anaesthesia
Malignant hyperthermia
Sux apnoea
Cause of malignant hyperthermia
Inheritance pattern
Defect in ryanodine receptor
Triggered by sux or halagonated voletiles
Autosomal dominant
Issue in sux apnoea
What is effected
Inheritance pattern
Prolonged block post sux or mivacurium
Abnormal plasma cholinesterase (pseudocholinesterase, butyrylcholinesterase)
Autosomal codominant
Enzyme that metabolises codeine to morphine
Cyp2d6
What drugs would be effected by slow acetalor effect
Hydralazine
Isoniazid
Prolonged effect in both
Types of drug interactions
Physiochemical
Pharmacokinetic
Pharmacodynamic
What drugs are most effected by drug drug interactions
Low therapeutic index
Eg anticoagulant, antiarrhythmics, anticonvulsants, hypoglycaemics
Physiochemical reactions of thiopental
Implication for rsi
Precipitation with basic drugs eg sodium bicarb or sux! Must flush between.
Examples of drug absorption is effected by antacids
Ciprofloxacin
Rifampacin
Tetracycline
Ketoconazole
Examples of drug drug interactions effecting absroption
Overall effect
GI ph change eg antacids
GI stasis eg opioids
Slower peak and sometimes smaller peak
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
What is the key mechanism of most drug drug pharmacokinetic interactions
Induction or inhibition of metabolism usually by cyp450
What happens with administration of sux and neostigmine
Prolongation of block due to neostigmine inhibiting plasma cholinesterases!
What isoform of p450 is not inducable?
What drugs Inhibit it?
2d6
TCAs
What antiepileptic effects vecuronium duration, how?
Carbamazepine
Induction of cyp3a4 reducing duration of neuromuscular block
Examples of pharmacodynamic drug drug interactions
2 drugs having same effect eg sux and roc
Opposing effects eg nifedipine and phenylephrerine
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
