pharmacology Flashcards
what 3 things are considered when considering a drug’s effects?
where the effect(s) are produced
the drug’s target
response produced after interaction with target
how would the effects of cocaine be described when considering the 3 main points (location of effect, target, response produced)?
overall: euphoric ‘high’
where effect takes place
- dopaminergic neurons in nucleus accumbens in brain
target of drug
- dopamine reuptake protein on pre-synaptic terminal
response produced
- cocaine blocks dopamine reuptake protein, preventing quick removal of dopamine from synapse (therefore more available to bind to receptor and activate it)
what is the key thing that allows a drug to produce an effect?
drug ‘binds’ to target
either enhances activation (“stimulation”) or prevents activation (block effect from being produced)
what are the 4 classes of drug target proteins? give an example of a drug that targets each one.
receptors (e.g. nicotine)
enzymes (e.g. aspirin)
ion channels (e.g. local anaesthetic)
transport proteins (e.g. Prozac)
how does aspirin act on enzymes (target protein) to bring about an effect?
aspirin binds to the enzyme cyclooxygenase
blocks production of prostaglandins
how does local anaesthetic act on ion channels (target protein) to bring about an effect?
block sodium ion channels
prevents nerve conduction
how does Prozac act on transport proteins (target protein) to bring about an effect?
block serotonin carrier proteins
prevents serotonin being removed from the synapse
how does nicotine act on receptors (target proteins) to bring about an effect?
binds to and activates nicotinic acetylcholine receptor
what characteristic must a drug display to be an effective therapeutic agent?
high degree of selectivity for particular drug target
why is it difficult to produce drugs with complete selectivity? what effect does this have?
many drugs and chemicals are structurally quite similar - therefore they all have some degree of specificity for the receptors of the other chemicals
when producing a drug, there is a chance that the drug will interact with receptors that aren’t the intended one, producing side-effects
how does drug dose relate to drug selectivity?
at lower dose, drug will interact with only one target to produce the intended effect
as dose increases, effects become less specific as drug begins to interact with other drug targets
what is an example of how drug dose affects selectivity?
Pergolide (treatment of Parkinson’s)
low dose
- target: dopamine D2 receptor
- effect: anti-Parkinsonian
medium dose
- target: serotonin receptor
- effect: hallucinations
high dose
- target: adrenergic receptor
- effect: hypotension
what are the 4 types of interaction between drugs and receptors?
electrostatic
hydrophobic
covalent bonds
stereospecific
what types of bonds are involved in electrostatic interactions between drugs and receptors?
(most common interaction)
includes hydrogen bonds and van del Waal’s forces
when are hydrophobic interactions between drugs and receptors important?
in use of lipid soluble drugs
why are covalent bond interactions the least common type of interaction between drugs and receptors?
irreversible
why is stereospecific interaction between drugs and receptors important?
many drugs exist as stereoisomers and interact stereospecifically with receptors
what is pharmacology?
study of how a drug interacts with living organisms and how this influences physiological function
what does the term ‘pharmacodynamics’ refer to?
what the drug does to the body
what does the term ‘pharmacokinetics’ refer to?
what the body does to the drug
how can the basic reaction between a drug and its receptor be represented?
equilibrium between drug and receptor, drug-receptor complex
for a specific concentration of the drug, a specific number of drug receptor complexes are formed
what happens to the equilibrium between and drug and receptor and the drug-receptor complexes when the concentration increases?
more drug molecules available to bind to free receptors
equilibrium shifts to the right
what happens to the equilibrium between and drug and receptor and the drug-receptor complexes when the concentration decreases?
more receptors become available due to lower drug concentration
shifts equilibrium to the left
what are the 2 categories of drug in terms of interaction with receptors?
agonist
antagonists
what is the difference between agonist and antagonists?
both bind to receptors, but only agonists bind and activate receptors
what are the 2 key properties of agonists?
affinity
efficacy
what does the affinity of a drug determine?
strength of binding of drug to receptor, the strength of each drug-receptor complex
therefore affinity is strongly linked to receptor occupancy
how is affinity linked to receptor occupancy?
each individual drug receptor interaction is transient, with many interactions only lasting milliseconds - at any given moment a particular drug molecule might be bound to a receptor, or it may have unbound and may currently be free with the potential to bind another receptor
therefore if two drugs were added to the tissue (i.e. same number of receptors available), the drug with the higher affinity will form stronger drug receptor complexes
thus at any given moment, it is more likely that more of this drug will be bound to receptors
what is efficacy?
ability of an individual drug molecule to produce an effect once bound to a receptor
what are the 3 types of drug with reference to efficacy?
antagonists
partial agonists
full agonists
how does an antagonist work with reference to efficacy?
drug has affinity for the receptor but no efficacy
effectively ‘blocking’ a receptor when bound to it
prevents an agonist from binding to the receptor and inducing activation
how does a partial agonist work with reference to efficacy?
drug has affinity for the receptor and sub-maximal efficacy
when bound to the receptor, it can produce a partial response, but cannot induce the maximal response from that receptor
how does a full agonist work with reference to efficacy?
drug has affinity for the receptor and maximal efficacy
produces the maximal response expected from receptor when bound to it
what is potency?
concentration or dose of a drug required to produce a defined effect
what is the standard measure of potency?
determine the concentration or dose of a drug required to produce a 50% tissue response
called EC50 (half maximal effective concentration) or ED50 (half maximal effective dose)
what is the difference between EC50 and ED50?
concentration that produced a 50% response is EC50
in some cases it is difficult to assess what a 50% response is (e.g. what does a 50% improvement in breathlessness look like?)
therefore dose of drug that produced the desired effect in 50% or the individuals tested is used (ED50)
how is potency related to dose?
the lower the dosage required to produce a particular effect, the more potent the drug is (often compared using ED50)
what is the relationship between efficacy and potency?
potency is related to dose, efficacy is not
highly potent drugs produce a large response at relatively low concentrations
highly efficacious drugs can produce a maximal response - effect not particularly related to drug concentration
what is the clinical relevance of the difference between potency and efficacy?
efficacy more important - drug should induce a maximal response
potency only gives dose needed to produce a response
if 2 drugs have equal efficacy, potency does not matter (maximal response with the less potent drug can be achieved by administering a slightly higher concentration)
what are the 4 major pharmacokinetic factors?
absorption
distribution
metabolism
excretion
how is absorption defined with regard to pharmacokinetics?
passage of a drug from site of administration into plasma
what is bioavailability (with regard to absorption in pharmacokinetics)?
fraction of the initial dose that gains access to the systemic circulation
what is the difference between absorption and bioavailability?
absorption deals with the process for drug transfer into the systemic circulation
bioavailability deals with the outcome of drug transfer into the systemic circulation (i.e. how much)
determined by site of administration-
e. g. IV administration of drug
- absorption (process for drug passage): injecting dose into circulation
- bioavailability: 100% (hypothetical)
what are some common forms of drug administration?
IV
oral
inhalational
dermal (percutaneous)
intra-nasal
what are the 2 ways that drugs move around the body?
bulk flow transfer (i.e. in the bloodstream)
diffusional transfer (i.e. molecule by molecule across short distances)
why is bioavailability likely to be less than 100% when drugs are not administered through an IV?
if IV is used, bulk flow transfer will deliver drug to intended site of action
other routes - in order for the drug to reach the bloodstream it is first going to need to diffuse across at least one lipid membrane
what are the 4 mechanisms by which chemicals diffuse across plasma membranes?
pinocytosis
diffusion across aqueous pores
diffuse across lipid membranes
carrier mediated transport
what is pinocytosis and and what is its relevancy in drug transport?
small part of cell membrane envelopes chemical molecule and forms a vesicle
chemical released on other side of membrane
e.g. insulin access to brain
but rarely used to transport drugs
why is diffusion across an aqueous pores not a major route for drug transport across membranes?
most pores are less than 0.5nm in diameter
very few drugs are this small
therefore there is little movement of drugs across this aqueous route
how do most drugs move across membranes?
diffusion across lipid membrane down concentration gradient
carrier mediated transport (transmembrane protein binds drug molecules on one side of membrane, transfers them across to the other side - can be against concentration gradient using ATP)
why are the majority of drugs more water soluble than lipid soluble?
large proportion of drug molecules are given orally
need to be water soluble to dissolve in the aqueous environment of GI tract and be available for absorption
what feature of a drug affects its lipid solubility?
ionisation
drugs are either weak acids (e.g. aspirin) or bases (e.g. morphine) - donate/accept protons respectively when ionised
unionised form of drug retains more lipid solubility - more likely to diffuse across plasma membranes
what 2 things affect the ionisation of a drug?
dissociation constant (pKa) for that drug
pH in that particular part of the body
how does a drug’s dissociation constant (pKa) and the pH in a particular area of the body affect a drug’s ionisation when the drug is a weak acid?
if drug pKa and tissue pH are equal, drug will be equally dissociated between the two forms (i.e. 50% ionised and 50% unionised)
as pH decreases below pKa (more acidic tissue): unionised form starts to dominate (equilibrium shifts to the left)
as pH increases above pKa (more basic tissue): ionised form starts to dominate (equilibrium shifts to the right)
how does a drug’s dissociation constant (pKa) and the pH in a particular area of the body affect a drug’s ionisation when the drug is a weak base?
if drug pKa and tissue pH are equal, drug will be equally dissociated between the two forms (i.e. 50% ionised and 50% unionised)
as pH decreases below pKa (more acidic tissue): ionised form starts to dominate (equilibrium shifts to the right)
as pH increases above pKa (more basic tissue): unionised form starts to dominate (equilibrium shifts to the left)
what is ion trapping?
weak bases poorly absorbed from stomach due to low pH causing high drug ionisation - ions are “trapped” in the stomach
weak acids can be absorbed from the stomach (low pH allows them to stay unionised) but when they become ionised due to higher physiological pH ions may become “trapped” in the blood
how is ion trapping overcome?
transport proteins
weak bases become “trapped” in the stomach - however, when the small intestine is reached, many transport proteins will allow absorption from GI tract
weak acids become “trapped” in blood - however, most tissues have transport proteins that could move the ionised drug out of the bloodstream into the tissue
what are the 4 places where the most important carrier systems for drug action are found?
renal tubule
biliary tract
blood brain barrier
gastrointestinal tract
what are carrier systems in the renal tubule, biliary tract, blood brain barrier and GI tract responsible for?
(overcoming ion trapping)
drug access to the bloodstream (absorption from GI tract)
drug access to certain tissues (absorption across blood brain barrier)
excretion of drugs from the body (excretion from the kidney of the GI tract)
what is distribution?
when a drug is absorbed it is then distributed to various tissues where they eventually take effect
what are the 4 factors that influence tissue distribution?
regional blood flow
plasma protein binding
capillary permeability
tissue localisation
how does regional blood flow affect tissue distribution?
different tissues receive different amounts of cardiac output
therefore more drug will be distributed to those tissues that receive most blood flow
distribution can change depending on circumstances:
- during exercise there is more blood flow to muscles
- after a large meal the stomach and intestines will receive more blood flow
how does plasma protein binding affect tissue distribution?
drugs often bind to plasma proteins (e.g. albumin) when they reach systemic circulation
only free drug is available to diffuse out of the blood and access tissues - bound drugs cannot leave the blood until they dissociate from the protein
free drug + protein binding site ↔ drug-protein binding site
what 3 factors affect the amount of drug that binds to plasma protein?
free drug concentration
affinity for the protein binding sites
plasma protein concentration
why are plasma proteins never saturated with drugs?
e. g. albumin
- albumin blood concentration: 0.6mmol/l
- each molecule has 2 binding sites
- therefore binding capacity: 1.2mmol/l
drug plasma concentration required for clinical effect is generally less than 1.2mmol/l
therefore plasma proteins are never saturated with drugs
what factor affects differences in the extent of plasma protein binding?
mostly due to particular affinity for protein binding sites for a particular drug
e.g. acidic drugs bind particularly well to albumin, therefore tend to be more heavily plasma protein bound
what are the 4 different types of capillary structure?
continuous
blood brain barrier
fenestrated
discontinuous
how does a continuous capillary structure affect capillary permeability and therefore drug distribution?
most capillaries in the body have the continuous structure
if drugs are very lipid soluble then they can diffuse across the endothelial cell and access the tissue
what does a continuous capillary structure look like?
endothelial cells aligned in single file with small gap junctions between the cells
what does the blood brain barrier’s capillary structure look like?
continuous structure, but with tight junctions between endothelial cells
what are the 4 different types of capillary structure?
continuous
blood brain barrier
fenestrated
discontinuous
how does a continuous capillary structure affect capillary permeability and therefore drug distribution?
most capillaries in the body have the continuous structure
if drugs are very lipid soluble then they can diffuse across the endothelial cell and access the tissue
what does a continuous capillary structure look like?
endothelial cells aligned in single file with small gap junctions between the cells
what does the blood brain barrier’s capillary structure look like?
continuous structure, but with tight junctions between endothelial cells
why is the brain the most difficult tissue in the body for drugs to gain access to?
blood brain barrier’s capillary structure
how are less lipid soluble drugs transported into the tissue?
if very small, can pass through gap junctions
otherwise, via carrier proteins
what is an example of a tissue with a discontinuous capillary structure?
liver
how does a fenestrated capillary structure allow the kidney to carry out its function?
kidney is a key tissue involved in excretion of chemicals (including many drugs)
fenestrations allow for some small drugs to pass from blood to kidney tubules which will enhance excretion of these drugs
what does a discontinuous capillary structure look like?
big gaps between capillary endothelial cells
what does a fenestrated capillary structure look like?
fenestrations - circular windows within endothelial cells that allow for passage of small molecular weight substances (including some drugs)
what is an example of a tissue with a fenestrated capillary structure?
kidney glomerulus
how does a discontinuous capillary structure allow the liver to carry out its function?
kidney is a key tissue involved in excretion of chemicals (including many drugs)
fenestrations allow for some small drugs to pass from blood to kidney tubules which will enhance excretion of these drugs
how does tissue localisation affect drug distribution?
both lipid and water soluble drugs diffuse out of the blood into the brain down a concentration gradient, establishing an equilibrium between the blood and brain
however, equilibrium position is different in lipid and water soluble drugs -
lipid soluble: equilibrium more heavily weighted towards retention in the brain as brain has higher fat content
water soluble: equilibrium more heavily weighted towards retention in the plasma as blood has the higher water content
therefore a larger proportion of the lipid soluble drug will be ‘localised’ in the brain as compared with the water soluble drug
what are the 3 main mechanisms of action of phase 1 of drug metabolism?
oxidation (produces electrophiles)
reduction (produces nucleophiles)
hydrolysis (produces nucleophiles)
what happens during oxidation in phase 1 of drug metabolism?
(most common mechanism)
all oxidation reactions start with a hydroxylation step using the cytochrome P450 system to incorporate oxygen into non-activated hydrocarbons
what enzymes within the liver are responsible for drug metabolism?
mostly cytochrome P450
what are the the 2 kinds of drug metabolism that act together to decrease lipid solubility?
phase 1 – introduce a reactive group to the drug
phase 2 – add a conjugate to the reactive group
what are the 3 main mechanisms of action of phase 1 of drug metabolism?
oxidation
reduction
hydrolysis
what happens in oxidation in phase 1 of drug metabolism?
(most common mechanism)
all oxidation reactions start with a hydroxylation step using the cytochrome P450 system to incorporate oxygen into non-activated hydrocarbons
what is the end result of phase 1 of drug metabolism?
incorporation of certain functional groups (-OH, -COOH, -SH, NH2) or unmasking existing groups in the parent drug
produces metabolites with functional groups that serve as a point of attack for conjugating systems of phase 2
what are pro-drugs?
phase 1 of drug metabolism often produces pharmacologically active metabolites
sometimes the parent drug has no activity of its own - will only produce an effect once it has been metabolized to the respective metabolite (i.e. pro-drugs)
what enzymes are used in phase 2 of drug metabolism?
transferases
transfer the substituent group onto the phase 1 metabolite
what occurs in phase 2 of drug metabolism?
attachment of a substituent group to functional groups
produces metabolites that are more water soluble and are usually inactive to facilitate excretion in the urine or bile
what are the common phase 2 conjugates that complement the usual phase 1 metabolites?
for electrophiles:
- glutathione conjugation
for nucleophiles:
- glucoronidation
- acetylation
- sulfation
what is first pass (pre-systemic) hepatic metabolism?
orally administered drugs are mostly absorbed from the small intestine and enter the hepatic portal blood supply - therefore pass through the liver before reaching systemic circulation
drug is heavily metabolised so not much active drug will reach systemic circulation
what are the 3 major routes for drug excretion via the kidney?
glomerular filtration
active tubular secretion (or reabsorption)
passive diffusion across tubular epithelium
what is the problem with the usual solution for first pass (pre-systemic) hepatic metabolism
extent of first pass metabolism varies amongst individuals, therefore the amount of drug reaching the systemic circulation also varies
therefore drug effects and side effects are difficult to predict
what are the 2 most important routes of excretion?
via kidney (in urine)
via liver (in bile)
what are some other routes of excretion (excluding the kidney and liver)?
via lungs
in breast milk
what are the 3 major routes for drug excretion via the kidney?
glomerular filtration
active tubular secretion (or reabsorption)
passive diffusion across tubular epithelium
why does excretion of different drugs vary so much?
extent to which drug use each of the 3 major routes for drug excretion in the kidney varies between drugs
also impacted by the rate of metabolism
why does urine pH affect the process of excretion by passive diffusion in the kidney?
urine pH varies from 4.5 to 8
acidic drugs are better reabsorbed at lower pH
basic drugs are better reabsorbed at higher pH
why is active tubular secretion the most important method of excretion via kidney?
only 20% of renal plasma is filtered at the glomerulus, the rest passes onto the blood supply to proximal tubule - more drug delivered to proximal tubule than glomerulus
what is the process of excretion by active tubular secretion in the kidney?
depends on transporters
2 active transport carrier systems within the proximal tubule capillary endothelial cells (one for acidic drugs, one for basic drugs)
both systems can transport drugs against a concentration gradient
why does drug metabolism affect the process of excretion by passive diffusion in the kidney?
phase 2 metabolites tend to be more water soluble than the parent drug
therefore less well reabsorbed
why does urine pH affect the process of excretion by passive diffusion in the kidney?
urine pH varies from 4.5 to 8
acidic drugs are better reabsorbed at lower pH
basic drugs are better reabsorbed at higher pH
what is the process of excretion by passive diffusion in the kidney?
leads to reabsorption from kidney tubule
as glomerular filtrate moves through the kidney most of the water filtered is reabsorbed
if drugs are more lipid soluble they will also be reabsorbed, diffusing across the tubule back into the blood
how are drugs excreted via the bile?
hepatocytes transport some drugs from plasma to bile
- mostly via transporters (similar to those in the kidney)
very effective at removing phase 2 glucuronide metabolites
drugs transported to bile are excreted into intestines, eliminated in faeces
how can enterohepatic recycling prolong drug effect?
glucuronide metabolite is transported into bile
metabolite is excreted into the small intestine and is hydrolysed by gut bacteria - releases glucuronide conjugate
loss of glucuronide conjugate increases molecule’s lipid solubility
increased lipid solubility allows greater reabsorption from small intestine back into the hepatic portal blood system for return to liver
molecule returns to the liver - a proportion will be re-metabolised, but a proportion may escape into the systemic circulation to continue to have effects on the body
what is the primary mechanism of action of metformin?
primary effect:
metformin activates AMPK in hepatocyte mitochondria
inhibits ATP production
blocks gluconeogenesis and subsequent glucose output
secondary effect:
blocks adenylate cyclase which promotes fat oxidation
both help to restore insulin sensitivity
what is the drug target of metformin?
5′-AMP-activated protein kinase (AMPK) (enzyme)
what is the primary site of action of metformin?
hepatocyte mitochondria
what are the side effects of metformin?
GI side effects (20-30% of patients)
- abdominal pain
- decreased appetite
- diarrhoea
- vomiting
particularly evident when very high doses are given - slow increase in dose may improve tolerability
high doses may produce high lactic acid levels
(low risk) low blood glucose
why may metformin accumulate the in the liver and the GI tract to produce therapeutic and side effects respectively?
highly polar structure, requires organic cation transporter-1 (OCT-1) to access tissues
when is metformin most effective?
in the presence of endogenous insulin
i.e. with some residual functioning pancreatic islet cells
what is an example of a DPP-4 inhibitor?
sitagliptin
what is the primary mechanism of action of DPP-4 inhibitors?
primary effect:
inhibiting DPP-4 action
(enzyme is present in vascular endothelium and can metabolise incretins in plasma)
what are the functions of incretins (e.g. GLP-1)?
secreted by enteroendocrine cells
help stimulate the production of insulin when it is needed (e.g. after eating)
reduce the production of glucagon by the liver when it is not needed (e.g. during digestion)
slow down digestion and decrease appetite
what is the drug target of DPP-4 inhibitors?
DPP-4 (enzyme)
what is the primary site of action of DPP-4 inhibitors?
vascular endothelium
what are the side effects of DPP-4 inhibitors?
upper respiratory tract infections (5% of patients)
flu-like symptoms (e.g. headache, runny nose, sore throat)
serious allergic reactions (skin rash, increased upper respiratory tract infections)/ avoid in patients with pancreatitis (less common)
what is a benefit of DPP-4 inhibitors as opposed to other anti-diabetic drugs?
do not cause weight gain
what is required for DPP-4 inhibitor effectiveness?
some residual pancreatic beta-cell activity
since they act mainly by augmenting insulin secretion
what is an example of a sulphonylurea?
gliclazide
what is the primary mechanism of action of sulphonylureas?
inhibit ATP-sensitive potassium (KATP) channel on the pancreatic beta cell (controls beta cell membrane potential)
inhibition causes depolarisation
depolarisation stimulates Ca2+ influx and subsequent insulin vesicle exocytosis
what is the drug target of sulphonylureas?
ATP-sensitive potassium channel (ion channel)
what is the primary site of action of sulphonylureas?
pancreatic beta cell
what are the side effects of sulphonylureas?
weight gain (likely)
hypoglycaemia (2nd most common)
what is required for sulphonylurea effectiveness?
some residual pancreatic beta-cell activity
since they act mainly by augmenting insulin secretion
how is the weight gain caused by sulphonylureas mitigated?
concurrent administration with metformin
when especially should the risk of hypoglycaemia associated with sulphonylureas be discussed with the patient?
when concomitant glucose-lowering drugs are prescribed
what is an example of a sodium-glucose co-transporter (SGLT2) inhibitor?
dapaglifozin
what is the primary mechanism of action of SGLT2 inhibitors?
reversibly inhibits sodium-glucose co-transporter 2 (SGLT2) in the renal proximal convoluted tubule
reduces glucose reabsorption, increases urinary glucose excretion
what is the drug target of SGLT2 inhibitors?
SGLT2 (transport protein)
what is the primary site of action of SGLT2 inhibitors?
proximal convoluted tubule
what are the side effects of SGLT2 inhibitors?
uro-genital infections due to increased glucose load (5% of patients)
slight decrease in bone formation
can worsen diabetic ketoacidosis (stop immediately)
what are some added benefits of SGLT2 inhibitors?
weight loss
reduction in BP
what is required for SGLT2 inhibitors effectiveness?
depends on normal renal function
less effective in patients with renal impairment
what drugs can be used in the treatment of diabetes?
metformin
DPP-4 inhibitors
SGLT2 inhibitors
sulphonylureas
what drugs can be used in the treatment of epilepsy?
lamotrigine
sodium valproate
diazepam
levetirecetam
what is the primary mechanism of action of lamotrigine?
blocks voltage gated Na+ channels, preventing Na+ influx
prevents depolarisation of glutamatergic neurones and reduces glutamate excitotoxicity
what is the drug target of lamotrigine?
voltage gated Na+ channels
what are the main (common) side effects of lamotrigine?
rash
drowsiness
what are the main (more uncommon but serious) side effects of lamotrigine?
Steven-Johnson’s syndrome
suicidal thoughts
how is lamotrigine used in treatment of allergic reactions?
lamotrigine introduced gradually - important in reducing frequency and severity of allergic skin reactions
what is the primary mechanism of action of sodium valproate?
inhibits GABA transaminase (prevents GABA breakdown)
directly increases GABA concentrations pre-synaptically in the synapse
indirectly prolongs GABA in the synapse (extraneuronal metabolism of GABA is slowed, slows GABA removal from synapse)
increased GABA availability
what is the drug target of sodium valproate?
GABA transaminase (inhibitory presynaptic terminal)
what are the main (common) side effects of sodium valproate?
stomach pain
diarrhoea
drowsiness
weight gain
hair loss
what are the main (serious) side effects of sodium valproate?
hepatotoxicity
teratogenicity
pancreatitis
how does sodium valproate interact with other drugs?
broad CYP (cytochrome P450) enzyme inhibitor
increases serum concentration of many co-administered drugs
what is the primary mechanism of action of diazepam?
increases Cl- influx in response to GABA binding at GABA A receptor
increased Cl- influx associated with hyperpolarisation of excitatory neurones
what is the drug target of diazepam?
benzodiazepine site on the GABA A receptor
what are the main (common) side effects of diazepam?
drowsiness
respiratory depression (if IV or at high dose)
what are the main (more uncommon but serious) side effects of diazepam?
haemolytic anaemia
jaundice
why is diazepam not used for long term suppression of seizures?
development of tolerance
why is diazepam
a Schedule 4 controlled drug?
addiction prone individuals more likely to become dependent on diazepam
what is the primary mechanism of action of levetiracetam?
inhibition of synaptic vesicle protein SV2A in excitatory presynaptic terminal, prevents vesicle exocytosis
reduction in glutamate secretion reduces glutamate excitotoxicity
why is levetiracetam favourable in terms of lack of drug–drug interactions?
metabolism of levetiracetam has no effect on cytochrome P450 enzyme system
what drugs are used in treatment of depression?
sertraline
citalopram
fluoxetine
venlafaxine
mirtazapine
what is the primary mechanism of action of sertraline?
serotonin reuptake inhibition causes accumulation
serotonin in CNS aids regulation of mood, personality, and wakefulness
what is the drug target of sertraline?
serotonin transporter
what are the main side effects of sertraline?
GI effects (nausea, diarrhoea)
sexual dysfunction
anxiety
insomnia
how does sertraline interact with CYP2D6 at high doses (150mg)?
partial inhibition
how does sertraline interact with dopamine transporters?
mild inhibition
how is sertraline discontinued?
gradually decreased
what is the primary mechanism of action of citalopram?
serotonin reuptake inhibition causes accumulation
serotonin in CNS aids regulation of mood, personality, and wakefulness
what is the drug target of citalopram?
serotonin transporter
what are the main side effects of citalopram?
GI effects (nausea, diarrhoea)
sexual dysfunction
anxiety
insomnia
how does citalopram interact with muscarinic and histamine (H1) receptors?
mild antagonism
how is citalopram discontinued?
gradually decreased
how is citalopram metabolised?
CYP2C19
what is the primary mechanism of action of fluoxetine?
serotonin reuptake inhibition causes accumulation
serotonin in CNS aids regulation of mood, personality, and wakefulness
what is the drug target of fluoxetine?
serotonin transporter
what are the main side effects of fluoxetine?
GI effects (nausea, diarrhoea)
sexual dysfunction
anxiety
insomnia
which receptors does fluoxetine antagonise?
mild antagonism of 5HT2A and 5HT2C receptors
which receptors does fluoxetine inhibit?
complete inhibition of CYP2D6
significant inhibition of CYP2C19
what does inhibition of CYP2C19 and CYP2D6 by fluoxetine contraindicate?
caution with warfarin
what is the primary mechanism of action of venlafaxine?
potent inhibitor of serotonin reuptake than norepinephrine reuptake
(noradrenaline in CNS implicated in emotional regulation and cognition)
what are the drug targets of venlafaxine?
serotonin transporter
noradrenaline transporter
what are the main side effects of venlafaxine?
GI effects (nausea, diarrhoea)
sexual dysfunction
anxiety
insomnia
(at higher doses) hypertension
how is venlafaxine discontinued?
gradually decreased
what is the primary mechanism of action of mirtazapine?
antagonises central presynaptic alpha-2-adrenergic receptors - causes increased serotonin and norepinephrine release
antagonises central 5HT2 receptors - leaves 5HT1 receptors unopposed, causing anti-depressant effects
what are the drug targets of mirtazapine?
alpha-2 receptor
5-HT2 receptor
(high affinity for H1 receptor causes sedation, low affinity for 5-HT3 receptor has anti-emetic effect)
what are the main side effects of mirtazapine?
weight gain
sedation
(low probability of sexual dysfunction)
how does mirtazapine affect REM sleep behaviour disorder?
causes exacerbation, suppresses REM sleep
beneficial impact on sleep continuity and duration
(sedation due to histamine H1 receptor blocking)
what drugs can be used in the treatment of hypertension?
angiotensin converting enzyme (ACE) inhibitors
calcium channel blockers
thiazide or thiazide-like diuretics
angiotensin receptor blockers
what are some examples of angiotensin converting enzyme (ACE) inhibitors?
ramipril (pro-drug)
lisinopril
perindopril
what is the primary mechanism of action of angiotensin converting enzyme (ACE) inhibitors?
inhibit angiotensin converting enzyme
prevent conversion of angiotensin I to angiotensin II
what is the drug target of angiotensin converting enzyme (ACE) inhibitors?
angiotensin converting enzyme (ACE)
what are the main side effects of angiotensin converting enzyme (ACE) inhibitors?
cough
hypotension
hyperkalaemia (care with K+ supplements or K+-sparing diuretics)
foetal injury (avoid in pregnant women)
renal failure (in patients with renal artery stenosis)
urticaria/angioedema
what must be monitored regularly when taking angiotensin converting enzyme (ACE) inhibitors?
eGFR
serum potassium
what kind of drugs are most angiotensin converting enzyme (ACE) inhibitors (not lisinopril)?
pro-drugs
require hepatic activation to generate active metabolites required for therapeutic effects
what are some examples of calcium channel blockers?
amlodipine
felodipine
what is the primary mechanism of action of calcium channel blockers?
block L-type calcium channels (predominantly on vascular smooth muscle)
causes decreased in calcium influx, with downstream inhibition of myosin light chain kinase and prevention of cross-bridge formation (i.e. muscular contraction)
resultant vasodilation reduces peripheral resistance
reduced cardiac contraction and cardiac output
what is the drug target of calcium channel blockers?
L-type calcium channel
what are the main side effects of calcium channel blockers?
ankle oedema
constipation
palpitations
flushing/headaches
what kind of calcium channel blockers demonstrate a higher degree of vascular selectivity?
dihydropyridine type
what are some examples of thiazide or thiazide-like diuretics?
bendro-flumethiazide (thiazide)
indapamide (thiazide-like diuretic)
what is the primary mechanism of action of thiazide or thiazide-like diuretics?
block Na+, Cl- co-transporter in early apical DCT
Na+ and Cl- reabsorption is inhibited
osmolarity of tubular fluid increases, decreasing the osmotic gradient for water reabsorption in the collecting duct
(decreased blood volume, decreased venous return, decreased cardiac output)
what is the drug target of thiazide or thiazide-like diuretics?
sodium/chloride cotransporter
what are the main side effects of thiazide or thiazide-like diuretics?
hypokalaemia
hyponatremia
metabolic alkalosis (increased hydrogen ion excretion)
hypercalcemia
hyperglycaemia (hyperpolarised pancreatic beta cells)
hyperuricemia
how long do the diuretic effects of thiazide and thiazide-like diuretics last?
lose diuretic effects within 1-2 weeks of treatment
thiazide and thiazide-like diuretics lose their diuretic effect within 1-2 weeks - what allows continuing anti-hypertensive action?
vasodilating properties (more pronounced for thiazide-like diuretics)
what are some examples of angiotensin receptor blockers?
losartan
irbesartan
candesartan
what is the primary mechanism of action of angiotensin receptor blockers?
these agents act as insurmountable (i.e. non-competitive) antagonists at AT1 receptor (found on kidneys and on the vasculature)
what is the drug target of angiotensin receptor blockers?
angiotensin receptor
what are the main side effects of angiotensin receptor blockers?
hypotension
hyperkalaemia (care with K+ supplements or K+-sparing diuretics)
foetal injury (avoid in pregnant women)
renal failure (in patients with renal artery stenosis)
how does the efficacy of angiotensin receptor blockers compare with angiotensin converting enzyme (ACE) inhibitors?
angiotensin receptor blockers are not as effective anti-hypertensive agents as ACE inhibitors
ACE inhibitors are cheaper
what kind of drugs are losartan and candesartan (angiotensin receptor blockers)?
pro-drugs
require hepatic activation to generate active metabolites required for therapeutic effects
what drugs can be used in the treatment of asthma?
salbutamol
fluticasone
mometasone
budesonide
montelukast
what is the primary mechanism of action of salbutamol?
β2 receptor agonist on airway smooth muscle cells
activation reduces Ca2+ entry - prevents smooth muscle contraction, prevents constriction
(adrenaline binds to β2 adrenergic receptor to cause bronchodilation)
what is the drug target of salbutamol?
beta 2 (β2) adrenergic receptor
what are the main side effects of salbutamol?
palpitations/agitation
tachycardia/arrhythmias
hypokalaemia (at higher doses)
what is salbutamol an example of?
short acting beta agonist (SABA)
what is the half life of salbutamol?
2.5 - 5 hrs
how does salbutamol produce cardiac side effects?
beta 2 selectivity is not absolute
beta 1 is also activated (causing cardiac side effects)
how does salbutamol produce hypokalaemia as a side effect?
via effects on sodium/potassium ATPase
how can hypokalaemia as a result of salbutamol administration be exacerbated?
co-administration with corticosteroids
what are the primary mechanisms of action of fluticasone?
(multiple actions on many different cell types)
directly decreases number of inflammatory cells (eosinophils, monocytes, mast cells, macrophages, dendritic cells etc.) and number of cytokines they produce
affects IL-5 to prevent growth, differentiation, and activation of eosinophils
what is the drug target of fluticasone?
glucocorticoid receptor
what are the main local side effects of fluticasone?
sore throat
hoarse voice
opportunistic oral infections
what are the main systemic side effects of fluticasone?
growth retardation in children
hyperglycaemia
decreased bone mineral density
immunosuppression
effects on mood
(etc.)
how does fluticasone’s affinity for the glucocorticoid receptor compare to that of cortisol?
greater affinity
why is any systemic delivery of fluticasone via the inhaled route predominantly through the pulmonary vasculature?
oral bioavailability <1%
what are the primary mechanisms of action of mometasone?
(multiple actions on many different cell types)
directly decreases number of inflammatory cells (eosinophils, monocytes, mast cells, macrophages, dendritic cells etc.) and number of cytokines they produce
what are the main local side effects of mometasone?
sore throat
hoarse voice
opportunistic oral infections
what are the main systemic side effects of mometasone?
growth retardation in children
hyperglycaemia
decreased bone mineral density
immunosuppression
effects on mood
(etc.)
how does mometasone’s affinity for the glucocorticoid receptor compare to that of cortisol?
greater affinity
why is any systemic delivery of mometasone via the inhaled route predominantly through the pulmonary vasculature?
oral bioavailability <1%
what are the primary mechanisms of action of budesonide?
(multiple actions on many different cell types)
directly decreases number of inflammatory cells (eosinophils, monocytes, mast cells, macrophages, dendritic cells etc.) and number of cytokines they produce
what is the drug target of mometasone?
glucocorticoid receptor
what is the drug target of budesonide?
glucocorticoid receptor
what are the main local side effects of budesonide?
sore throat
hoarse voice
opportunistic oral infections
what are the main systemic side effects of budesonide?
growth retardation in children
hyperglycaemia
decreased bone mineral density
immunosuppression
effects on mood
(etc.)
how does the potency of budesonide compare to that of fluticasone and mometasone?
less potent
why does inhaled budesonide result in some systemic absorption through the GI tract?
oral bioavailability >10%
what is the primary mechanism of action of montelukast?
antagonises CysLT1 leukotriene receptor on eosinophils, mast cells and airway smooth muscle cells
decreases eosinophil migration, bronchoconstriction, inflammation induced oedema
what is the drug target of montelukast?
CysLT1 leukotriene receptor
what are the main mild side effects of montelukast?
diarrhoea
fever
headaches
nausea or vomiting
what are the main serious side effects of montelukast?
mood changes
anaphylaxis
when should montelukast be administered for prophylaxis of exercise-induced bronchoconstriction?
at least 2 hours before initiating exercise
what drugs are used in treatment of GORD/peptic ulcer disease?
NSAIDS
PPIs
histamine (H2) receptor antagonists
paracetamol (aka acetaminophen)
what are some examples of NSAIDS?
ibuprofen
naproxen
diclofenac
what is the primary mechanism of action of NSAIDS?
inhibit cyclo-oxygenase enzyme (COX) - rate limiting step for production of all prostanoids (prostaglandins, thromboxanes) from parent arachidonic acid
prostanoids act through many prostanoid receptors, produces highly complex array of actions
how do the effects of NSAIDS vary depending on the type of COX inhibition?
anti-inflammatory (and most analgesic and antipyretic actions) related to COX-2 inhibition
unwanted effects mostly a result of COX-1 inhibition
what is the drug target of NSAIDS?
cyclo-oxygenase (COX) enzyme
what are the common side effects of NSAIDS?
gastric irritation
ulceration
bleeding
what are the more extreme side effects of NSAIDS?
perforation
reduced creatinine clearance, possible nephritis
bronchoconstriction in susceptible individuals (contraindicated in asthma)
skin rashes & other allergies, dizziness, tinnitus.
what are the side effects of NSAIDS following prolonged used/in patients with pre-existing cardiovascular risk?
adverse cardiovascular effects (hypertension, stroke, MI)
what is prolonged analgesic abuse over a period of years associated with?
chronic renal failure
what rare condition in children has aspirin been linked with?
post-viral encephalitis (Reye’s syndrome)
how can NSAIDS be used?
analgesics - mild to moderate pain relief (e.g. musculoskeletal pain, headache, dysmenorrhoea)
antipyretics - reduce fever
anti-inflammatory drugs - chronic control of inflammatory diseases (e.g. rheumatoid arthritis, osteoarthritis)
anti-aggregatory agent (aspirin only) - inhibit platelet aggregation in patients at risk of stroke or MI
what are some examples of PPIs?
omeprazole
lansoprazole
what is the primary mechanism of action of PPIs?
irreversible inhibitors of H+/K+ ATPase in gastric parietal cells
weak bases, so accumulate in acid environment of parietal cell canaliculi (concentrates and prolongs duration of action)
(omeprazole plasma half-life approx. 1 h but single daily dose affects acid secretion for 2-3 days)
PPIs inhibit basal and stimulated gastric acid secretion by >90%
what is the drug target of PPIs?
H+/K+ ATPase (‘proton pump’)
what are the main side effects of PPIs?
headache
diarrhoea
bloating
abdominal pain
rashes
symptoms of which condition may be masked by use of PPIs?
gastric cancer
omeprazole inhibits cytochrome P2C19 - what other drugs are affected by this?
reduced function in antiplatelet medication e.g. clopidogrel, when platelet function is monitored
how are PPIs administered?
generally given orally
degrade rapidly at low pH so administered as capsules containing enteric-coated granules
how do PPIs affect H+ ion transport in parietal cells?
PPIs are pro-drugs - converted into 2 reactive species at low pH
react with sulphydryl groups in H+/K+ ATPase responsible for transporting H+ ions out of the parietal cells
what are some examples of histamine (H2) antagonists?
ranitidine
cimetidine
what is the primary mechanism of action of histamine (H2) antagonists?
structural analogues of histamine are competitive antagonists of H2 histamine receptors
inhibit stimulatory action of histamine released from enterochromaffin-like (ECL) cells on gastric parietal cells surface
inhibit gastric acid secretion
(histamine receptors increase acid production via cAMP dependent activation of H+/K+ ATPase - less acid production means less corrosive environment, less irritation of stomach wall due to damaged mucosal barrier)
what is the drug target of histamine (H2) antagonists?
histamine H2 receptors
what are the main side effects of histamine (H2) antagonists?
diarrhoea
dizziness
muscle pains
transient rashes
why is cimetidine (histamine H2 antagonist) contraindicated with some drugs?
inhibits cytochrome P450
may retard the metabolism and potentiate the effects of a range of drugs
what are some drug categories contraindicated by cimetidine?
various - includes oral anticoagulants and TCAs
why does ranitidine only have 50% bioavailability?
undergoes first pass metabolism
why is twice daily dosing of ranitidine effective?
ranitidine plasma half-life 2-3 h - well tolerated
when do histamine (H2) antagonists not necessarily need to be on prescription?
low dose over-the-counter formulations available from pharmacies for short term use without prescription
what is the primary mechanism of action of paracetamol in GORD?
mechanism of action unclear
(current hypothesis)
both central and peripheral actions possibly involving interactions with a COX-3 isoform (inhibition of prostaglandin synthesis), cannabinoid receptors or the endogenous opioids
interactions at 5HT or adenosine receptors also proposed
where are the effects of paracetamol mostly restricted to?
nervous tissue
what is the drug target of paracetamol?
not yet well defined - COX-3 isoform?
what are some side effects of paracetamol?
few side effects at therapeutic doses
no gastric irritation but in overdose serious hepatotoxicity may occur
occasional allergic skin reactions
why is paracetamol not an NSAID?
little anti-inflammatory activity
what are the broad therapeutic effects of paracetamol?
good analgesic for mild-to-moderate pain
some antipyretic activity
what is step 1 of the 7 step process of prescribing?
identify the patient’s problem
what is step 2 of the 7 step process of prescribing?
specify the therapeutic objective
what is step 3 of the 7 step process of prescribing?
select a drug on the basis of comparative efficacy, safety, cost and suitability
what is step 4 of the 7 step process of prescribing?
discuss choice of medication with patient (and carer) and make a shared decision about treatment
what is step 5 of the 7 step process of prescribing?
write a correct prescription
what is step 6 of the 7 step process of prescribing?
counsel the patient on appropriate use of the medicine
what is step 7 of the 7 step process of prescribing?
make appropriate arrangements for follow up
BMI: 31
1st BP: 144/92 mmHg
2nd BP: 148/91 mmHg
HbA1c: 65mmol/mol
LDL: 5.18 mmol/L (200 mg/dL)
HDL: 0.8 mmol/L (30mg/dL)
triglycerides: 6.53 mmol/L (252 mg/dL)
glycosuria, no ketones
no polydipsia, polyuria or weight loss
what is the patient’s problem?
fasting glucose > 7
HbA1c > 48mmol/L (6.5%)
- diabetes
blood pressure high
- hypertensive
HDL < 50mg/dl
LDL > 100mg/dl, triglycerides > 150mg/dl
- dyslipidaemia
BMI 30-34.9
- obesity
overall, metabolic syndrome?
fasting glucose > 7
HbA1c > 48mmol/L (6.5%)
- diabetes
blood pressure high
- hypertensive
HDL < 50mg/dl
LDL > 100mg/dl, triglycerides > 150mg/dl
- dyslipidaemia
BMI 30-34.9
- obesity
overall, metabolic syndrome?
what are the therapeutic objectives for this patient?
lose weight – reduced adiposity should help reduce insulin resistance linked to diabetes
reduce blood pressure – reduce CVD risk
improve lipid profile – reduce CVD risk
reduce blood glucose – reduce complications (microvascular and (atherosclerotic) macrovascular) associated with prolonged elevated blood glucose
what should be done when HbA1c rises to 48 mmol/mol (6.5%) on lifestyle intervention? (adult with T2DM, can take metformin)
offer standard release metformin (500 mg per day, oral)
support person to aim for 48 mmol/mol
what is the first intensification (when HbA1c rises to 58 mmol/mol (7.5%)) for adults with T2DM that can take metformin?
consider dual therapy with:
- DPP-4 inhibitors e.g. sitagliptin (100 mg per day, oral)
- SGLT2 inhibitors e.g. dapaglifozin (5 mg per day, oral)
- sulphonylureas e.g. gliclazide (40-80 mg per day)
- pioglitazone (15-45 mg per day)
support person to aim for 53 mmol/mol (7.0%)
what is the second intensification (when HbA1c rises to 58 mmol/mol (7.5%)) for adults with T2DM that can take metformin?
consider triple therapy with:
- metformin, a DPP-4i and an SU
- metformin, pioglitazone and an SU - metformin, pioglitazone or an SU, and an SGLT-2i
or insulin-based treatment
support person to aim for 53 mmol/mol (7.0%)
what are the benefits of metformin treatment?
decreases glucose production by liver
increases insulin sensitivity of body tissues
anorexiant effect (appetite suppression, thereby reducing caloric intake)
expression of the organic cation transporter 1 (OCT-1) is highest in: liver hepatocytes (highest expression), small intestinal enterocytes and the renal proximal tubules.
why is this relevant to the pharmacokinetics of orally-administered metformin?
relation to absorption
- shows that metformin has a mechanism to leave small intestines and access the hepatic portal vein
relation to distribution
- shows that metformin has a mechanism to access the liver
- shows that metformin can access the kidney tubules
what is a side effect of pioglitazone?
increased incidence of heart failure
why may renal impairment cause problems for diabetic patients on metformin?
90% of standard dose (‘unchanged’,
active) of oral metformin excreted
via kidney
how should metformin administration be adjusted with an eGFR of >60?
no adjustment needed
how should metformin administration be adjusted with an eGFR of 45-60?
monitor eGFR in 3-6 months
how should metformin administration be adjusted with an eGFR of 30-45?
do not initiate metformin
if already taking metformin, consider 50% dose decrease
how should metformin administration be adjusted with an eGFR of <30?
contraindicated
how is depression screened for in primary care?
patient health questionnaire 9 (PHQ 9)
how is a PHQ-9 score related to depression severity?
0-4 - none/minimal
5-9 - mild
10-14 - moderate
15-19 - moderately severe
20-27 - severe
hypertension - losartan (angiotensin 2 receptor blocker) but BP still high (141/91 mmHg)
erythromycin for chronic prostatitis
uneasy
low mood
low self esteem
difficulty getting to sleep
inability to think clearly
strained personal relationship
job performance affected?
PHQ-9 score - 14
what is the patient’s problem?
indicative of moderate depression
major depressive disorder includes minor, moderate and severe depression
hypertension - losartan (angiotensin 2 receptor blocker) but BP still high (141/91 mmHg)
erythromycin for chronic prostatitis
uneasy
low mood
low self esteem
difficulty getting to sleep
inability to think clearly
strained personal relationship
job performance affected?
PHQ-9 score - 14
likely moderate depression
what are the therapeutic objectives?
alleviate depressive symptoms:
- improve mood
- help with sleep difficulties
- improve self-esteem
- improve ability to think clearly
reduce the likely functional impairment the depressive symptoms have on daily life:
- improve personal relationships
- improve job performance
the 3 most common SSRIs are sertraline, citalopram and fluoxetine - which is contraindicated with erythromycin?
citalopram
why is citalopram contraindicated with erythromycin?
both erythromycin and citalopram prolong QT interval - most manufacturers advise avoiding 2+ drugs that do this
severe interaction
what may be seen on an ECG if polymorphic ventricular tachycardia is occurring in the context of QT prolongation (e.g. interaction of citalopram and erythromycin)?
torsades de pointes
what are some factors that predispose to QT prolongation?
increasing age
female sex
disease
metabolic disturbance (notably hypokalaemia)
what is the optimal SSRI dose (normalised to fluoxetine) to cause 50% or greater reduction in depression rating after 8 weeks of treatment?
30 mg
what is the link between dropouts due to adverse effects and 50% or greater reduction in depression rating after 8 weeks of treatment?
as SSRI dose increases, dropouts due to adverse effects increases
reduction in depression rating begins at 1.0 at 0 mg, peaks at 30 mg, returns to 1.0 by 80 mg
20-30 mg is optimal dose to manage adverse effects
why does the plateau in therapeutic effect occur in anti-depressant action (based on action at serotonin transporter)?
limited receptor numbers
why is caution required when switching from one antidepressant to another?
risk of drug interactions
risk of serotonin syndrome
withdrawal symptoms
relapse
what is required before starting a new drug?
washout
high starting doses
why may venlafaxine be preferred to mirtazapine in a patient with hypertension?
noradrenaline mediates the sympathetic nervous system effects on the heart
> 150 mg per day - adrenergic effects
> 300 mg per day - increased BP, increased HR
rheumatoid arthritis for 9 years – awaiting total right knee arthroplasty
BP
- initial: 149/93mmHg
- subsequent: 147/92mmHg and 145/91mmHg
generally well
smokes (< 10 per day)
height: 167 cm
weight: 85kg
what is the patient’s problem? (check Q-risk score)
Q-risk = 14.9%
stage 1 hypertension
Q-risk = 14.9%
stage 1 hypertension
what are the therapeutic objectives for this patient?
set reasonable blood pressure reduction goals (previous case reduce below 140/90 mmHg)
reduce cardiovascular risk associated with increased morbidity and mortality (modifiable risk factors = obesity and smoking)
no new medication that interferes with upcoming procedures/other treatment
what is the Q-risk score?
shows risk of heart attack or stroke within 10 years
e.g. score of 12% - in a population of 100 all of whom have the same risk factors, 12 are likely to die of heart attack/stroke within 10 years
what is the procedure if ambulatory or home blood pressure monitoring (ABPM or HBPM) shows a BP under 135/85 mmHg?
monitor at least every 5 years
what is the procedure if ambulatory or home blood pressure monitoring (ABPM or HBPM) shows a BP between 135/85 - 149/94 mmHg? (stage 1 hypertension)
start drug treatment if there is:
target organ damage
CVD
renal disease
diabetes
10 year CVD risk >10%
what is the procedure if ambulatory or home blood pressure monitoring (ABPM or HBPM) shows a BP over 150/95 mmHg? (stage 2 hypertension)
start drug treatment
when is ambulatory or home blood pressure monitoring (ABPM or HBPM) offered?
clinic BP 140/90 mmHg or over
what is clearance?
measure of body’s ability to eliminate a drug
clearance by means of various organs of elimination is additive
elimination of drug may occur as a result of processes that occur in the liver, kidney, and other organs
what is elimination half life?
length of time required for drug concentration to decreasetohalf of itsstarting dose in the body
what is time to peak plasma levels?
time required for a drug to reach peak concentration in plasma
the faster the absorption rate, the lower the time to peak plasma concentration
why may amlodipine be better than felodipine considering BP tends to increase most rapidly in the morning after waking up?
felodipine has higher plasma clearance, shorter elimination half life and shorter time to peak plasma levels
therefore causes dose dependent decrease in systolic and diastolic BP along with reflex tachycardia
amlodipine has slow onset and longer half life - slow onset mitigates reflex tachycardia
what is the mechanism of action of ACE inhibitors in the treatment of hypertension?
inhibits angiotensin converting enzyme (ACE) on pulmonary and renal endothelium
prevents conversion of angiotensin I to angiotensin II
causes vasodilation, less salt and water retention, less aldosterone secretion
why may ACE inhibitors have a negative effect on eGFR?
angiotensin II causes efferent vasoconstriction (increased pressure for filtration) - helps maintain GFR when renal perfusion is low (renal artery stenosis, volume depletion, older people with congestive heart failure)
why may ACE inhibitors have a negative effect on serum potassium?
hyperkalaemia
usually aldosterone increases Na+ reabsorption and water in distal convoluted tubule at the expense of K+ (increasing plasma volume and blood pressure) A
increasing the gene expression and availability of:
- Na+ ion permease enzyme - more Na+ crosses from the lumen to the inside of the renal tubular cell
- Na+/K+ATPase on the peritubular side of the renal tubular cell - transfer increased cytosolic Na+ into peritubular fluid (so lower intracellular electronegativity)
- citrate synthase - more activity within the mitochondria for more ATP (for Na+/K+ATPase)
less aldosterone from the adrenal cortex means overall reduction Na+ and water reabsorption, allows K+ retention
thiazide-like diuretics are excreted unchanged in urine - why is this a vital part of their therapeutic action?
diuretic needs to move from the blood
it is transported on basolateral side, uses a transporter on apical side
only then can it access the sodium chloride transporter on the apical side of distal tubule
why do thiazides increase potassium excretion?
increase delivery from early distal tubule
why does the diuretic effect of thiazides only work for 1-2 weeks?
kidney becomes tolerant to the diuretics due to rebound activation of renin angiotensin system
consequent increasing sodium reabsorption counteracts diuretic effect
why do the antihypertensive effects of thiazides continue while the diuretic effect of thiazides only works for 1-2 weeks?
further vasodilating action (not as well understood)
how often should BP and medication be checked once stabilised?
6-12 months
how often should serum potassium and creatinine be checked once BP is stabilised?
yearly
3 yr old
great difficulty in breathing
whistle like wheeze when exhaling, occasional coughing
slight temperature (38.2°C)
history and physical examination reveal nothing
has had mild breathlessness before, usually when she has an infection of some type
what is the patient’s problem?
first presentation of asthma
no allergic trigger, and most likely precipitated by the viral infection
hard to objectively diagnose asthma in children < 5 years old
no evidence that this is atopic at the moment, based on history
first presentation of asthma
no allergic trigger, and most likely precipitated by the viral infection
what are the therapeutic objectives for this patient?
short term = relief
- relieve symptoms of breathlessness and expiratory wheeze during the acute asthma attack
long term = prevention
- dampen/prevent late phase of the asthma attack
- reduce the risk of further asthma attacks.
- attempt to improve lung function
what is the difference between the early phase and late phase of asthma?
early phase - bronchospasm
- immediate decrease in forced expiratory volume
some recovery in between
late phase - inflammation (up to 6 hours after early phase)
- further decrease in forced expiratory volume
what is the first line treatment for asthma in under 5s?
SABA (salbutamol)
what are the differences between oral and inhalation routes when taking salbutamol?
inhaled has local effects
oral has systemic effects (undergoes first pass metabolism etc.)
how does acetylcholine cause bronchoconstriction?
post ganglionic PSNS nerve releases acetylcholine
binds to M2 and M3 muscarinic receptor on bronchial smooth muscle
causes bronchoconstriction
why is a nebulizer the best method for delivering salbutamol in emergency situations?
many drug solutions
can deliver combinations
minimal patient co operation required
can deliver to all ages
concentration and dose can be modified
normal breathing pattern
what are the 5 places where are inhaled drugs lost?
1 - exhalation
2 - lack of absorption from lungs
3 - mucociliary clearance (trapped by cilia or mucous)
4 - swallowed (down oesophagus rather than trachea)
5 - some absorbed across mucous membrane in oral cavity and pharynx
due to drug loss and consequent difference between expected and actual dose, why is a spacer clinically useful (especially in children)?
inhalation indicator makes it easier to coordinate breathing in and pressing your puffer
increased space allows better delivery to lungs
why are eosinophils dangerous in asthma?
asthma can be exacerbated by viral infection
common viral infections (e.g. rhinovirus) release mediators that specifically activate eosinophils
eosinophils can induce epithelial damage (e.g. due to release of major basic protein)
increased susceptibility to viral infections (and therefore increased likelihood of asthma exacerbation)
why is the oral bioavailability (proportion of drugs reaching plasma via GI tract) of some inhaled drugs (e.g. fluticasone) low despite a significant proportion being swallowed?
first pass inactivation
what is the mechanism of action of montelukast?
targets CysLT1 receptor (Cysteinyl leukotriene receptor 1)
located on eosinophils/mast cells/airway smooth muscle
decreases smooth muscle constriction, eosinophil migration and oedema
why is the mechanism of action of montelukast useful in NSAID induced asthma?
NSAIDs generally work by blocking the production of prostaglandins (both leukotrienes and prostaglandins derive from arachidonic acid)
if the leukotriene pathway is blocked, more prostaglandin will be formed to combat NSAID effect
71-year-old man
osteoarthritis
- prescribed diclofenac gel (1%)
- regular paracetamol (500-1000mg orally every 6 hours when required) to help with the pain
bilateral knee pain diclofenac and paracetamol have reduced his pain, but he still has moderate pain when walking or carrying out strenuous activities such as gardening
pain is restricting his mobility and he has not been able to carry out the exercises that he has been advised to do
GP prescribes naproxen (250-500mg orally twice daily when required) as an additional analgesic
after taking the naproxen pain associated with his osteoarthritis is much improved
however, he has been suffering with intermittent upper abdominal pain for the last 2 weeks - described as a dull, gnawing ache, sometimes wakes him at night
what is the patient’s problem?
pain from osteoarthritis that limits daily activities
upper abdominal pain since starting naproxen
pain from osteoarthritis that limits daily activities
upper abdominal pain since starting naproxen
what are the therapeutic objectives for this patient?
treat pain from osteoarthritis to ensure it is not interfering with daily living (or at least minimising the effect on activities)
treat new stomach pain, ideally without impacting on treatment of osteoarthritis pain
(these objectives are trade-offs)
how does naproxen have an analgesic effect on joint pain?
target – COX enzymes (naproxen is non-selective i.e. inhibits COX1 & COX2)
location – peripheral nociceptive nerve endings (analgesia)
effect – COX produces prostaglandins that do not directly cause pain themselves, but sensitise peripheral nociceptors mediators (bradykinin and histamine) which causes pain (NSAIDs inhibit COX)
indirect effect on pain – PGs mediate inflammation therefore NSAIDs will reduce inflammation
how can opiates reduce pain?
increased activity in descending inhibitory pathways
decreased excitation of transmission neuron
desensitise peripheral nociceptors
how does naproxen have an adverse effect within the stomach?
target – COX I enzyme
location – gastric mucosal cells
effect – inhibited prostaglandin production means inhibition of prostaglandin mediated protection of gastric mucosa
how do prostaglandins in gastric mucosal cells protect from acid?
increase bicarbonate release
increase mucous production
increase blood flow
why would a patient be on oral naproxen and topical diclofenac? (topical drugs can cause systemic side effects)
GP mistake
communication failure
what changes should be made to a prescription of naproxen and topical diclofenac?
3 options:
stop the gel
switch to ibuprofen
stop NSAIDs completely
after an oesophago-gastro-duodenoscopy that leads to a diagnosis of peptic ulcer disase with no active bleeding and H. pylori negative, what treatment should be given?
stop NSAIDs where possible
offer full dose PPI therapy for 4-8 weeks
e.g. omeprazole 20 mg once daily
why do PPIs help with peptic ulcer disease associated with NSAIDs?
NSAIDs leave stomach wall exposed to the effect of acid, which is causing pain
PPIs reduce the acid production
what is the disconnect when comparing guidance for PPI treatment and what happens in practice?
treatment algorithm states that patients should be given 20mg omeprazole once a day for 4-8 weeks
data suggests that most patients prescribed PPIs are treated for at least 3 months (above the recommended treatment duration of 4-8 weeks) at twice the standard treatment dose i.e. 40mg versus 20mg.
nearly 50% are still on 40mg after 12 months
(data does include PPI use for indigestion or dyspepsia)
when suffering with osteoporosis as well as peptic ulcer disease, why is a histamine H2 receptor antagonist prescribed (as opposed to PPIs)?
PPIs increase fracture risk (worsens chances if patient has osteoporosis)
(mechanism of action is unclear- main theory)
absorption of calcium salts is pH dependent
change in pH induced by PPIs causes reduction in absorption and decrease in calcium available for bone
21 year old
single episode of collapse with jerking
lost consciousness, started convulsing before coming around
stressed and not much sleep
occasionally makes a quick jerk of her arms as she wakes up
similar episode 18 months ago
urea, electrolytes, calcium, glucose: normal
general and neurological exams: normal
EEG shows interictal epileptiform discharge (IED)
what is the patient’s problem?
generalised tonic-clonic seizures
EEG shows interictal epileptiform discharge (IED) - increased risk of seizure recurrence
generalised tonic-clonic seizures
EEG shows interictal epileptiform discharge (IED) - increased risk of seizure recurrence
what are the therapeutic objectives for this patient?
eliminate seizures or reduce their frequency to the maximum degree possible
avoid the adverse effects associated with long-term treatment
aid patients in maintaining or restoring their usual psychosocial and vocational activities, and in maintaining a normal lifestyle
how does epilepsy affect driving?
must document advice to contact DVLA that they cannot drive
what are the different types of seizure and how are they differentiated?
absence
focal
generalised tonic-clonic
myoclonic
what are the features of an absence seizure?
lose awareness of your surroundings for a short time
- stare blankly into space
- look like they’re “daydreaming”
- flutter their eyes
- make slight jerking movements of their body or limbs
what are the features of a simple partial focal seizure?
strange feeling that’s hard to describe
“rising” feeling in your tummy – like the sensation in your stomach when on a fairground ride
a feeling that events have happened before (déjà vu)
unusual smells or tastes
tingling in your arms and legs
an intense feeling of fear or joy
stiffness or twitching in part of your body, such as an arm or hand
remain awake and aware
how long does a typical absence seizure last?
up to 15 secs, will not remember
what can simple partial seizures indicate?
sometimes referred to as warnings or auras - can be a sign that another type of seizure is about to happen
what are the features of a complex partial focal seizure?
lose sense of awareness, make random body movements, such as:
- smacking your lips
- rubbing your hands
- making random noises
- moving your arms around
- picking at clothes or fiddling with objects
- chewing or swallowing
unresponsive to anyone, no memory of it
what are the features of a tonic-clonic seizure?
2 stages
tonic stage – lose consciousness, body goes stiff, may fall to the floor
clonic stage – limbs jerk about, may lose control of bladder or bowel, may bite tongue or the inside of cheek, might have difficulty breathing
how long does a typical tonic-clonic seizure last?
normally stops after a few minutes, some last longer
may have a headache, difficulty remembering what happened
may feel tired or confused afterwards
what are the features of a myoclonic seizure?
some or all of your body suddenly twitches or jerks, like you’ve had an electric shock (often happen soon after waking up)
how long does a typical myoclonic seizure last?
usually only a fraction of a second but many can occur in a short space of time
what is the difference between a tonic and atonic seizure?
tonic - all your muscles suddenly become stiff (like the first stage of a tonic-clonic seizure), may lose balance and fall over
atonic - all muscles to suddenly relax, so you may fall to the ground - tend to be very brief, usually able to get up straight away
what is the first line of treatment for a generalised tonic-clonic seizure in men and women with no child bearing potential?
sodium valproate
what is the first line of treatment for a generalised tonic-clonic seizure in men and women with child bearing potential?
lamotrigine or carbamazepine
what is the first line of treatment for an absence seizure in men and women with no child bearing potential?
ethosuximide or sodium valproate
what is the first line of treatment for an absence seizure in men and women with child bearing potential?
ethosuximide
what is the first line of treatment for a focal seizure in men and women with no child bearing potential?
lamotrigine or carbamazepine
what is the first line of treatment for a focal seizure in men and women with child bearing potential?
carbamazepine or levetiracetam
what is the first line of treatment for a myoclonic seizure in men and women with no child bearing potential?
sodium valproate
what is the first line of treatment for a myoclonic seizure in men and women with child bearing potential?
levetiracetam or topiramate
what is the first line of treatment for a tonic or atonic seizure in men and women with no child bearing potential?
sodium valproate
what is the first line of treatment for a tonic or atonic seizure in men and women with child bearing potential?
sodium valproate (pregnancy prevention programme)
why is there a difference in epilepsy treatment depending on childbearing potential?
sodium valproate: first line in absence, tonic-clonic, tonic/atonic, myoclonic
can cause: - neural tube defects - decreased IQ - autism after in utero exposure
how does lamotrigine interact with the combined oral contraceptive pill?
drug-drug interaction
COC appears to have an impact on lamotrigine blood levels – coadministration leads to a reduced level of lamotrigine in the blood
what are the effects of drug interactions between lamotrigine and the combined oral contraceptive pill?
reduced seizure control but no contraceptive failure
how may the combined oral contraceptive decrease lamotrigine concentrations in the blood?
reduce lamotrigine absorption - less gets into the blood in the first place
enhance lamotrigine metabolism - more cleared from the blood
enhance lamotrigine excretion - enhance clearance from the blood
how does lamotrigine affect blood ethinyl estradiol levels?
appears to have no effect
what prescription change should be made to lamotrigine if taken with the combined oral contraceptive?
increase lamotrigine dose
when on the combined oral contraceptive with lamotrigine, why may more seizures occur during the second and third week? why may someone feel drowsy in the fourth week?
oestrogen = “seizure promoting”
increased seizure frequency during oestrogen peak
COC taken over four weeks:
- first three weeks: active drug
- fourth week: nothing or ‘dummy’
fourth week - no COC affecting
liver enzymes (usually induces UDPGA):
- liver enzymes normalise
- lamotrigine levels increase
how can side effects in the fourth week of a combined oral contraceptive cycle when taken with lamotrigine be addressed?
decrease lamotrigine in fourth week
what are some side effects in the fourth week of a combined oral contraceptive cycle when taken with lamotrigine?
dizziness
drowsiness
diarrhoea
loss of balance
abnormal eye movement
trouble speaking
between lorazepam, diazepam and midazolam, which is best to administer out of hospital?
midazolam
others require IV access
how may pregnancy affect seizure frequency?
may increase
why may pregnancy affect seizure frequency (if on lamotrigine)?
lamotrigine dose may be reduced due to fears of harming the unborn child
pregnancy may lead to changes in liver metabolism - lamotrigine levels may decrease (so increased seizure risk)
how can increased seizure frequency be avoided in pregnancy (if on lamotrigine)?
check serum lamotrigine at the beginning of pregnancy and during the second and third trimester
dose could then be adjusted as described
how can increased seizure frequency during week 2-3 of the combined oral contraceptive cycle be addressed if lamotrigine is well tolerated?
change oral contraceptive to long-term progesterone implant (e.g. Implanon/Nexplanon)
progesterone = “seizure inhibiting”
what are the 2 ways in which variation in adverse effects of drugs can be considered?
differences in concentrations of drug reaching the tissues (i.e. factors affecting absorption, distribution, metabolism and excretion of the drug)
differences in response of the target tissues to the same degree of stimulation (i.e. factors such as variation in receptor sensitivity, number and distribution)
responses to a drug vary between individuals - how can the reasons for this be subdivided?
absolute differences in dose administered
relative overdose or underdose
how can an absolute difference in dose administered take place?
(deliberate or accidental)
error in prescription or dispensing
patient non-compliance
drug formulation
what are the 5 factors that may cause a relative overdose or underdose of a drug to produce variable effects?
environmental exposure to chemicals, including other drugs
food intake
fluid intake
age
disease
how can environmental exposure to chemicals, including other drugs, cause relative overdose or underdose of a drug to produce variable effects?
enzyme induction
enzyme inhibition
how can food intake cause relative overdose or underdose of a drug to produce variable effects?
drugs may interact chemically with components of food; this may alter their absorption (e.g. bisphosphonates chelated by Ca, Mg, Fe so not absorbed with food)
foods delay gastric emptying and alter gastric pH
how can fluid intake cause relative overdose or underdose of a drug to produce variable effects?
most drugs are better absorbed if taken with water e.g. may dissolve better
fluids may stimulate gastric emptying
how may newborn infants’ bodies cause relative overdose or underdose of a drug to produce variable effects?
more body water than adults
poorer renal function, with immature tubular secretion
an immature blood brain barrier
lower capacity for drug metabolism
how can changes in drug absorption in elderly people cause relative overdose or underdose of a drug to produce variable effects?
decreased absorptive surface of small intestine
altered gastric and gut motility
increased rate of gastric emptying
how can changes in drug distribution in elderly people cause relative overdose or underdose of a drug to produce variable effects?
reduced lean body mass and body water, relative increase in fat
lipid soluble drugs have increased volume of distribution and decreased blood levels
water soluble drugs have decreased volume of distribution and increased blood levels
reduced plasma albumin, so fewer plasma protein binding sites
how can changes in drug metabolism in elderly people cause relative overdose or underdose of a drug to produce variable effects?
splanchnic and hepatic blood flow decrease by 0.3 – 1.5%/year
liver size and hepatocyte number decrease
hepatic enzyme activity and induction capacity decrease
how can changes in drug excretion in elderly people cause relative overdose or underdose of a drug to produce variable effects? (most important in drug handling in elderly patients)
reduced renal mass
reduced renal perfusion
reduced glomerular filtration rate
reduced tubular excretion
(steady decline is normal - situation worsened in renal disease)
how can changes in organ sensitivity in elderly people cause relative overdose or underdose of a drug to produce variable effects?
elderly tend to be more sensitive to CNS active drugs
what are the 5 aspects of ageing that affect relative overdose or underdose to produce variable effects?
drug absorption
drug distribution
drug metabolism
drug excretion
organ sensitivity
what are the 6 aspects of disease that affect relative overdose or underdose to produce variable effects?
general nutritional status
GI disorders
congestive heart failure
kidney failure
liver failure
other acute or chronic disease states
how can changes in general nutritional status (disease) cause relative overdose or underdose of a drug to produce variable effects?
unbalanced diets may lead to deficiency states and enzyme abnormalities
starvation – decreased plasma protein binding and metabolism
obesity – increased lipid fraction
how can GI disorders (disease) cause relative overdose or underdose of a drug to produce variable effects?
e.g. achlorhydria, coeliac disease, Crohn’s disease
altered drug absorption
how can congestive heart failure (disease) cause relative overdose or underdose of a drug to produce variable effects, especially in the elderly?
reduced splanchnic blood flow
intestinal mucosal oedema
reduced hepatic clearance
how can kidney failure (disease) cause relative overdose or underdose of a drug to produce variable effects, especially in the elderly?
decreased drug excretion leading to toxicity
water overload leading to changes in drug concentrations in different body fluid compartments
how can liver failure (disease) cause relative overdose or underdose of a drug to produce variable effects?
reduced metabolism
reduced first pass metabolism (hence increased bioavailability)
decreased biliary secretion and hence decreased removal
decreased albumin synthesis and hence reduced plasma protein binding
how can other acute or chronic disease states (disease) cause relative overdose or underdose of a drug to produce variable effects?
varies
72-year-old
atrial fibrillation which could not be converted back to sinus rhythm
suffered a small stroke, warfarin prescribed (‘thins’ blood) to prevent a recurrence
warfarin dose stabilized (checked by clotting time), but later develops a chest infection and is given clarithromycin for one week
effectively treats the infection, but now has a severe nosebleed, bruises very easily
how has this adverse drug reaction been caused (by what mechanism)?
increased external bleeding (nose bleed)
increased internal bleeding (bruising)
warfarin metabolised by cytochrome P450 pathway
Cyt P450 inhibited by clarithromycin, so increased plasma levels of warfarin
72-year-old
atrial fibrillation which could not be converted back to sinus rhythm
suffered a small stroke, warfarin prescribed (‘thins’ blood) to prevent a recurrence
warfarin dose stabilized (checked by clotting time), but later develops a chest infection and is given clarithromycin for one week
effectively treats the infection, but now has a severe nosebleed, bruises very easily
what drugs might produce a similar effect to clarithromycin?
other antibiotics of same class (i.e. macrolides): e.g. erythromycin
some antibiotics of other classes: e.g. quinolones like ciprofloxacin
some systemic antifungal drugs: e.g. fluconazole
proton pump inhibitors (PPIs) - for peptic ulcers: e.g. omeprazole
some anti-HIV drugs, especially protease inhibitors
what is INR?
International Normalized Ratio (INR) - standardized measure of blood clotting time
how is INR calculated?
ratio of a patient’s prothrombin time (‘test’) to a control (‘normal’) sample, raised to the power of the ISI (International Sensitivity Index) value for the tissue factor used (usually 0.94 - 1.4)
(test PT / normal PT) ᶦˢᶦ
what does a raised INR signify?
increased bleeding (decreased clotting)
bleeding risk increased
what does a lowered INR signify?
less bleeding (increased clotting)
thrombosis risk increased
what are the reference ranges for INR?
normal: 0.9-1.2
normal in atrial fibrillation: 2.0-3.0
(thrombosis risk increases <2.0)
> 4.0 serious bleeding risk increases
why may self-medication with St. John’s Wort have an effect on warfarin requirement?
contains hypericin (inducer of cytochrome P450) (hyperforin also has this effect)
increases metabolism of warfarin, decreasing its concentration and making it less effective (less anticoagulant effect)
what drugs may have similar adverse effects to St. John’s Wort when administered with warfarin?
fewer enzyme inducers than inhibitors but drugs that induce Cyt P450 include:
rifampicin: antibiotic used in TB therapy (onset/duration of induction can depend on half-life)
carbamazepine and phenytoin, as well as older and largely obsolete antiepileptic drugs phenobarbitone and primidone
griseofulvin (antifungal drug)
what blood test should be done before increasing digoxin dose?
serum potassium
why does serum potassium have to be checked before increasing digoxin dose?
digoxin binds to the Na+/K+ exchange ATPase on cardiac myocytes and nodal tissue
competes with K+ for its binding site
hypokalaemia means more digoxin binding (less competition by K+) - therefore, enhanced therapeutic and adverse effects of digoxin (heart ‘block’)
how does hypokalaemia affect the effects of digoxin?
means more digoxin binding (less competition by K+)
therefore, enhanced therapeutic and adverse effects of digoxin (heart ‘block’)
how does hyperkalaemia affect the effects of digoxin?
indication of possible kidney disease - possible reduced kidney function and therefore reduced digoxin clearance
more digoxin in system, enhanced therapeutic and adverse effects of digoxin
how can you ensure that a dose of digoxin is correct?
measure plasma levels of digoxin directly – recognised target range for these
why may confusion be caused in older patients taking temazepam (benzodiazepine)?
(pharmacokinetic) metabolism by liver of some drugs is reduced in older patients – so more temazepam
(pharmacodynamic) older patients may have increased sensitivity to drugs, even if metabolism is normal (may relate to changes in receptor number or function or other)
why may INR increase as a consequence of malnutrition if a person is on warfarin?
metabolism of many drugs affected by malnutrition
warfarin: similar to a drug which inhibits cyt pathway (e.g. clarithromycin) – therefore, more warfarin
malnutrition also decreases plasma protein levels (warfarin is heavily plasma protein bound)
- decreases oxidative metabolism (warfarin is metabolised by oxidation)
- decreases GFR
(increased likelihood of adverse drug reaction)
