Pharmacology Flashcards
define pharmacokinetics
what the body does to the drug (process of absorption and distribution)
what happens when a drug is administered?
absorbed into the blood stream to systemic circulation where it is distributed to tissues
define pharmacodynamics
the effects of the drug on the body
what happens when the drug reaches it’s site of effect?
there is pharmacological effect leading to the clinical response
what two effects are seen in the clinical response to a drug?
toxicity
therapeutic effect
what does toxicity describe in relation to clinical response to a drug?
the side effects
when may an animal be given a drug even when there are contraindications?
if the quality of life is sufficiently affected then a cost benefit analysis will indicate that it is worthwhile giving the drug
what are the 2 key ways in which drugs work?
non-cellular mechanisms
cellular mechanisms
what are the 4 main non-cellular ways in which drugs work?
physical effects
chemical reactions
physicochemical mechanisms
modification of body fluid composition
why do fluids work through non-cellular mechanisms instead of cellular mechanisms?
because the effects that they have on cells isn’t direct, it is instead mediated by osmosis that is caused by changes if fluid composition
give an example of a drug with physical effects
eye lubricant
give an example of a drug which works to modify body fluid composition
hypertonic saline
what are the 4 main cellular mechanisms in which drugs work?
physicochemical/biophysical mechanisms
cell membrane structure and function modification
enzyme inhibition
receptor mediated effects
give an example of drugs which affect cell membrane structure and function
insulin
give an example of drugs that work through enzyme inhibition
NSAIDs
give an example of drugs that work through receptro mediated effects
opioids
what are the targets for drug action?
receptors enzymes transporters ion channels nucleic acid miscellaneous
how may receptors aid drug action?
transduce signal from drug to produce conformational change and influence flow of ions
how can enzymes be affected by drug action?
may be activated or inhibited
how are ion channels affected by drug action?
open or close
how are transporters influenced by drug action?
carry a molecule across the membrane
give an example of receptors which are targeted by drugs
mu opioid receptor
give an example of enzymes which are targeted by drugs
COX 1 and 2
give an example of a drug that may be moved by transporters
insulin
give an example of a drug that affects ion channels
local anaesthetics
define ligand
a substance that forms a complex with a receptor (biomolecule) to serve a biological purpose (e.g. analgesia in the case of opioids)
what is the role of a receptor?
interacts with extracellular physiological signals and converts them to intracellular effects
describe the 3 step process involved in a receptor converting extracellular signalling to intracellular effects
receives a signal
transduces signal to
effector mechanism
what are the 2 ways receptors will be targeted by drugs?
agonist or inverse agonist
antagonist
what are the main effects of agonists/inverse agonists on receptors?
direct through ion channel opening or closing
transduction mechanisms leading to enzyme activation/inhibition, ion channel modulation and DNA transcription
what is an example of a receptor agonist/inverse agonist?
dexmedetomidine
what is the effect of antagonists on receptors?
prevents binding of other agonists/antagonists
produces no effect and blocks endogenous mediators
give an example of a receptor antagonist
atipam
what are the 2 effects of drugs on ion channels?
blockers
modulators
what is the effect of blockers on ion channels?
permeation blocked so no entry or exit
what is the effect of modulators on ion channels?
increased or decreased opening probability
where do modulators and blockers sit within ion channels?
blockers sit within the channel itself
modulators sit in the sub-unit
what are the 3 ways drugs can affect enzymes?
inhibition
false substrate
prodrug
how does a false substrate affect the enzyme?
is structurally similar to substrate but not the same so an abnormal metabolite is produced
how does prodrug worth with an enzyme?
makes use of the enzyme function to convert prodrug to active drug. An active drug is produced by the reaction
how do transporters work to produce drug effects?
normal transport to allow drug to enter cell
inhibition of transporter to block transport
false substrate leading to accumulation of abnormal compounds
what are the 4 main types of receptors?
ligand gated ion channels
G-protein coupled receptors
kinase linked receptors
nuclear receptors
what are the fastest acting receptors?
ligand gated (milliseconds)
what are the slowest acting receptors?
nuclear receptors (hours)
how do ligand gated ion channels work?
lead to hyperpolarisation or depolarisation and therefore cellular effects
how do G-protein coupled receptors work?
change in cell excitability leads to activation of second messengers which cause protein phosphorylation. This leads to cellular effects
how do kinase linked receptors work?
receptor phosphorylates protein leading to gene transcription, protein synthesis and then cellular effects
how do nuclear receptors work?
receptors in the nucleus cause gene transcription this then leads to protein synthesis and cellular effects.
give an example of a ligand gated ion channel
nicotinic ACh receptor
give an example of a G-protein coupled receptor
muscarinic ACh receptor
give an example of a kinase linked receptor
cytokine receptor (linked to inflammation)
give an example of nuclear receptors
oestrogen receptors
define affinity
how well/avidly a drug binds to it’s receptor
define intrinsic activity/ efficacy
magnitude of a drugs effect once bound (0-1)
what is a full agonist able to do once bound to the receptor?
generate a maximal response
describe the affinity and intrinsic activity of full agonists
high affinity and high intrinsic activity
give an example of a full agonist drug
morphine is a full agonist at the mu opioid receptor
what type of receptor is a mu opioid receptor?
G-protein coupled receptor
what is a partial agonist drug?
one that has intrinsic activity of less than 1
what does receptor occupancy of a partial agonist drug lead to?
a sub maximal effect even if receptors are fully bound
give an example of a partial agonist drug
buprenorphine binds to the mu opioid receptor but does not produce a maximal effect even if the dose is increased
what is an inverse agonist?
drug binds and exerts an opposite effect to the endogenous agonist
give an example of an inverse agonist
antihistemines
define antagonist
exhibits affinity but no intrinsic activity
give an example of an antagonist
atipam antagonises a-2 adrenoreceptor against dexmedetomidine
define potency
the dose of a drug required to produce a response (more potent = less drug required for response)
what is therapeutic index a measure of?
maximum non-toxic dose divided by minimum effective does
what is the issue with using therapeutic index?
based on data that may not be clinically relevant
effective dose can be extremely variable depending on what is being treated
doesn’t account for idiosyncratic reactions
what does ADME stand for?
absorption
distribution
metabolism
excretion
what is ADME involved with?
what the body does to the drug
why is it important that drugs can cross cell membranes?
to enable them to reach their site of action so they may have an effect
what are the 5 main ways that drugs cross cell membranes?
aqueous diffusion passive lipid diffusion facilitated diffusion pinocytosis active transport
what is the law which governs the rate of transfer of drug across biological membranes?
Fick’s law of diffusion
what are the 5 elements of Fick’s law of diffusion?
diffusion coefficient surface area of tissue membrane thickness partition coefficient concentration gradient
what is the partition coefficient?
how drugs distribute themselves in water vs in oil
what sort of molecules are drug molecules usually?
small weak acids or weak bases
what is the level of ionisation of a drug determined by?
pKa of drug and pH of the surrounding tissue
how do non-ionised drugs cross biological membranes?
passive diffusion
how do ionised drug molecules cross biological membranes?
selective transport mechanisms, facilitated diffusion or pinocytosis
what process in the body may affect drug absorption?
infection/inflammation can change tissue pH and make it more acidic
what is drug absorption mainly influenced by?
route of administration and drug formulation
peripheral shutdown if present
define bio-availability
the fraction of a dose reaching the systemic circulation after administration IM compared to the same does administered IV
what are the 8 key routes of drug administration?
IV IM SC oral inhalational epidural transmucosal (oral and rectal) transepithelial (skin, cornea, nasal mucosa)
where does drug absorption primarily take place after oral administration?
small intestine
what types of drug molecules are usually poorly absorbed through oral administration?
low lipid soluble and strong acids and bases
what are the 4 main factors which affect GI absorption?
gastrointestinal motility
splanchnic blood flow
particle size and formulation
physicochemical factors
how can gastrointestinal motility affect GI absorption of drugs?
fast and slow can mean that not enough of the drug is absorbed
how may splanchnic blood flow be reduced and so reduce drug absorption?
dehydration and reduced BP
what is first pass metabolism of drugs?
enzymes in gastrointestinal wall and liver that metabolise drugs
what is the fastest route of drug administration?
IV
what is challenging about IV drugs?
access can be difficult
what influences the rate of IV injection?
peak concentration (faster admin = higher peak concentration)
define peak concentration of drugs
maximum serum concentration of a drug in a specific area
what can be used to maintain plasma concentrations of IV drugs?
constant rate infusions (CRI) or target controlled infusions (TCI)
describe the basic path of IV drugs once administered
right heart - lungs - systemic circulation
why is IM injection variable?
local blood flow
diffusion through tissue
why may IM injections produce an adverse response?
they are often painful but varies from drug to drug
what must happen on administration of IM drugs before injection?
aspirate (draw back)
how does absorption of SC injection compare to IM?
slower and more unpredictable
what influences absorption of SC injections?
injection site, temperature of skin, dehydration and shock
what drugs are given through inhalation?
drugs that can be vapourised or aerosolised
what is a benefit of epidural, transmucosal or transepithelial administration of drugs?
direct to site of action so doses can be lower
define apparent volume of distribution
amount of drug administered / plasma concentration
what are the 5 key factors which determine drug distribution?
protein binding tissue binding organ blood flow membrane permeability drug solubility
what are the 2 proteins involved in plasma protein binding?
albumin
alpha-1 acid glycoprotein
what does albumin bind to during plasma protein binding of drugs?
weak acids
what does alpha-1 acid glycoprotein bind to during plasma protein binding of drugs?
weak bases
what is the effect of plasma protein binding of drugs during distribution?
doesnt elicit a response. It takes up drug and removes it from circulation so preventing it from working on receptors
what happens to the unbound/free fraction of the drug that is not plasma protein bound?
can interact with receptors/diffuse across membranes
why may plasma protein binding vary from patient to patient?
those with low albumin will have a larger unbound/free fraction
what are the 2 types of tissue binding of drugs?
specific and non-specific
where are drugs initially distributed to?
organs with high blood flow
what is an advantage of drugs being initially distributed to organs with high blood flow?
good for anaesthetics as they go to the brain first
what is a disadvantage of drugs being initially distributed to organs with high blood flow?
anaesthetic drugs will negatively affect the heart quickly as this also has good blood flow
how does membrane permeability affect drug distribution?
higher membrane permeability = faster effect
what may happen to highly lipid soluble drugs?
accumulate in fat and then be released as the fat is metabolised. This can lead to the ‘hangover’ effect and keep the plasma concentration of a drug higher for longer leading to prolonged recovery
what must be assumed about all drugs with regards to pregnant or lactating animals?
drugs will cross placenta and be secreted into milk
define drug clearance
the volume of plasma from which a drug is completely removed per unit time
define half life of a drug
the time taken for plasma drug concentration to fall to 50% of it’s initial value
what is the equation used to calculate drug half-life?
K= clearance / volume of distribution
what is the termination of drug effects caused by?
primarily biotransformation then excretion
where does biotransformation usually occur?
in the liver
where does excretion of drugs usually happen?
the kidneys
what compounds does the kidney excrete most easily?
polar water soluble compounds
why is biotransformation in the liver so crucial?
most drugs are lipophillic and highly plasma protein bound which the kidneys cannot excrete easily. Biotransformation converts them into easily excreted molecules
what is the primary organ of metabolism?
the liver
what are the 2 stages of hepatic metabolism?
I: conversion of drug to polar metabolite
II: conjugation with substrates
what reactions are used in phase I of hepatic metabolism?
oxidative, hydrolytic or reductive
what is required in phase II of hepatic metabolism?
energy
what is the aim of phase II hepatic metabolism?
to make resultant polar compound more readily excreted
what reaction does not occur in phase II hepatic metabolism of cats that can cause longer lasting effects of propofol?
glucuronidation
what reaction does not occur in phase II hepatic metabolism of dogs?
acetylation
what are the 4 effects of hepatic metabolism?
drugs may be activated
drugs may have active metabolites
drugs may have toxic metabolites
enzymes involved in metabolism may be inhibited or induced (long term drug use)
what type of excretion of drugs is most common?
renal excretion
what are the 3 other types of excretion of drugs from the body?
biliary
exhalation
GI tract
what are the 2 types of renal excretion of drugs?
active
passive
where does active renal excretion of drugs occur?
tubular secretion
where does passive renal excretion of drugs occur?
glomerular filtration
what may need to happen to drug doses in animals with renal compromise?
may need to be altered
what happens during enterohepatic circulation of drugs?
drug is metabolised (often through glucuronidation)
billiary excretion
deglucuronidation by gut microflora
reabsorption from gut
what can be explained by enterohepatic circulation of drugs?
longer lasting effects of drugs
how long does enterohepatic circulation continue for?
until plasma concentration drops
how may antimicrobial agents be classified?
according to the type of organism against which they are effective
what do bacteriostatic antimicrobials do?
arrest bacterial multiplication so stop proliferation and allow individuals immune system to clear the infection
what do bacteriocidal antimicrobials do?
act by primarily killing bacteria so useful for immunocompromised animals
what is the outcome of concentration dependent antibiotics related to?
peak antibiotic concentration achieved at the site of infection relative to the MIC
what is MIC?
minimum inhibitory concentration (HIGH DOSE)
what is the outcome of time dependent antibiotics related to?
concentration of drug being kept above MIC for high proportion of time between each dose (SUSTAINED DOSE)
what are the 3 mechanisms of action of antibiotics?
interference with cell wall leading to cell rupture due to osmotic pressures
interference with structure of the plasma membrane
interference with microbial DNA or its replication or repair
what are the 6 principles of antimicrobial therapy?
make a diagnosis remove barriers to cure decide whether chemotherapy is necessary select the best drug administer the drug in optimum dose and frequency and by the optimum route test for cure
how should be the best drug be selected?
specificity
pharmacokinetic factors
the patient
what are pharmacokinetic factors?
right dose at the right time
what could be involved in removing barriers to cure?
holistic approach e.g. debriding wound
what affects the breakdown of local anaesthetics?
whether there are ester and amide linkages
where are side effects of local anaesthetic seen?
CVS
CNS
when are the 5 main occasions for local anaesthetics to be used?
part of balanced anaesthesia (e.g. epidural under GA)
Anaesthesia in a standing/conscious patient
Post-operative pain relief
Desensitisation for procedures (e.g. EMLA)
Lameness investigation in horses
what is the difference between epidural and spinal anaesthesia?
epidural - injected into the epidural space via a catheter
spinal - injected directly into CSF via a much smaller needle
give an example of when local anaesthesia may be used
infraorbital block for dental surgery
give an example of when topical local anaesthesia may be used
desensitisation of feline larynx prior to endotracheal intubation
what is potency a measure of in pharmacology?
drug activity expressed in terms of the amount required to produce an effect of given intensity
what increases as local anaesthetic potency increases?
toxicity
what 4 factors affect the duration of local anaesthetic action?
ease of penetration into nerve cell and amount of drug reaching the sodium channel
strength of binding to the sodium channel
speed of removal
metabolism of the local anaesthetic
what is ease of penetration into nerve cell and amount of drug reaching the sodium channel of local anaesthetics due to?
lipid solubility
what is speed of removal of local anaesthetic dependent on?
tissue perfusion
what may be added to local anaesthetics to reduce speed of removal?
vasoconstrictors (e.g. adrenaline)
how are ester links in local anaesthetics hydrolysed?
plasma esterases
does CSF contain esterases?
no - esters cannot be broken down there and must diffuse out into other tissues
what are amide linkages broken down by?
cytochrome P450 enzymes
what may prolong or limit metabolism of amide local anaesthetics?
hepatic disease
what can increase the breakdown of amide local anaesthetics?
drugs such as barbiturates induce enzymes which will increase breakdown
what can decrease the breakdown of amide local anaesthetics?
drugs that inhibit the P450 enzymes e.g. midazolam
what are the 3 main formulations of Lidocaine?
sterile solutions for parenteral use
aerosol sprays for nasal/airway use
topical patches
how water soluble are local anaesthetics?
poor
how is the low water solubility of local anaesthetics over come?
making a salt solution
what is the effect of making a salt solution to increase water solubility of local anaesthetics?
lowers pH of solution if a hydrochloride salt which can cause stinging on injection
what is baricity?
weight of one substance compared with the weight of an equal volume of another substance
what is the baricity comparator for spinal anaesthesia?
CSF
why is baricity essential in spinal local anaesthetics?
because we don’t want anaesthetics to spread higher into epidural space, as it would effect respiration
how are solutions made heavier to address issues baricity in local anaesthetics?
glucose is added
what are the key effects of vasoconstrictors in local anaesthetics?
reduces risk of toxicity
reduces bleeding at the injection site
reduces speed of systemic absorption and so prolongs duration of action
what happens when local anaesthetics are absorbed systemically?
they are available for systemic effects
what must happen to a local anaesthetic drug for it to be systemically active?
must be unbound and unionized
what types of local anaesthetics have a longer duration of action and lower risk of toxicity?
those which bind more easily to plasma proteins
what is the effect of lower pH on local anaesthetic binding?
reduces affinity for protein binding and increases risk of toxicity
what are the 2 levels of toxicity of local anaesthetics?
neurotoxicity
cardiovascular toxicity
what must be considered when injecting local anaesthetic?
dose
injection site
care with smaller patients
what effect does site of injection of local anaesthetic have?
determines the rate of uptake into the systemic circulation
at what concentrations of local anaesthetic is CNS toxicity often seen?
lower than CVS
what are the symptoms of generalised CNS depression that are proportional to the unbound drug?
minor behavioral changes
muscle twitching and tremors
tonic-clonic convulsions
CNS depression/respiratory depression and death
how is CNS toxicity treated?
symptomatic treatment
Benzodiazapines to control seizures
O2 supplementation
intubation and control of ventilation if respiratory seen/needed
what are the 2 main symptoms of CVS toxicity due to local anaesthetic?
hypotension
dysrhythmias
how does CVS toxicity from local anaesthetic lead to hypotension?
depression of myocardial activity
direct relaxation of vascular smooth muscle
loss of vasomotor sympathetic tone
how does CVS toxicity due to local anaesthetic cause dysrhythmias?
commonly seen with bupivacaine
lipophilicity means that there is rapid entry to open sodium channels during systole
drug remains bound to sodium channel during diastole
presents as re-entrant arrythmias
how is CVS toxicity from local anaesthetic treated?
symptomatic treatment
manage bradycardias with an anticholinergic
fluid therapy with inotropic support if needed
intralipid IV could be used to mop up local anaesthetic
how can local anaesthetic toxicity be prevented?
don’t exceed ‘safe’ maximum dose
if a greater volume is needed dilute the local anaesthetic with 0.9% NaCl
use appropriately sized syringes to draw up dose (accuracy)
use appropriately sized needles to minimise tissue trauma
aspirate before injection to confirm you are not in a blood vessel
what volatile agents are licensed for use in dogs and cats?
isoflurane and sevoflurane
what was suggested by CEPSAF to do with gas induction of anaesthesia?
gas induction was associated with increased risk of anaesthetic related death
describe the characteristics of the ideal inhalational agent
non-irritant to mucous membranes minimal effects on CVS and respiratory function rapid uptake and elimination non-toxic non-flammable and chemically stable easily vaporised good analgesia and muscle relaxation
what does MAC stand for?
minimum alveolar concentration
what is MAC?
concentration of VA required to prevent response to supramaximal noxious stimuli
what can MAC be used to compare?
potency of agents
what is the difficulty of using MAC as a reliable measure of potency?
measured in a lab and there are factors which affect it
what factors can MAC be reduced by?
other drugs (e.g. premed) hypothermia pregnancy extremes of age (geriatric and neonatal) hypothyroidism
what factors can MAC be increased by?
hyperthermia
neonates
hyperthyroidism
administration of catecholamines and sympathomimetics
define vapour
gaseous state of a substance that at ambient temperature and pressure is a liquid
define gas
exists in gaseous form at room temperature at sea level
define partial pressure
pressure that individual gas exerts in a mixture of gases
define partition coefficient
ration of the concentration of a compound in two solvents at equilibrium
how does concentration of VA in inspired air affect uptake of anaesthetic gases?
drugs move down their concentration gradient, higher concentration of inspired air VA will lead to faster uptake
what is the mechanism of action of anaesthetic agents?
unclear - site of action is the brain
how does alveolar ventilation affect uptake of anaesthetic gases?
good alveolar ventilation leads to enhanced uptake of agent
how does alveolar ventilation affect recovery?
increased alveolar ventilation improves recovery as anaesthetic gas is blown off
is panting effective in alveolar ventilation?
no - just moves animals dead space air so exchange is not occurring
how does blood gas solubility affect distribution of anaesthetic gases?
lower blood gas solubility leads to faster onset and recovery from anaesthesia
how does cardiac output affect distribution of anaesthetic gases?
lower cardiac output leads to faster onset
how does blood tissue solubility affect distribution of anaesthetic gases?
impacts how well distributed agent is (increased solubility = better distribution)
how can concentrations of anaesthetic gases be reduced so their side effects are reduced?
provision of effective analgesia so that less VA is required during surgery to keep patient comfortable
what are the main side effects of inhalant anaesthetics?
dose dependent respiratory and cardiovascular depression
what is the role of balanced anaesthesia?
reduction of side effects while benefiting from desired effects of drugs
why is monitoring of anaesthetic so essential?
supportive therapy of any issues can be provided quickly (e.g. fluids or ventilation)
