Pharmacokinetics and pharmacodynamics Flashcards
what is pharmacology?
the study of the effects of drugs
what is pharmacokinetics?
how the body affects the drug; Absorption, Distribution, Metabolism and Excretion (ADME)
what is pharmacodynamics?
how the drug affects the body
what is the role of zinc fingers in cytosolic/nuclear receptors?
can recognise discrete regions of DNA
what is potency?
measure of how well a drug works
what is EC50?
concentration (M) that gives half of the maximal response
what is an agonist?
a compound that binds to a receptor and activates it
what are types of normal response curves?
linear (normal scale) and sigmoidal (log scale)
what is a full vs partial agonist?
- full agonist can get a maximal response
- partial agonist cannot get maximal response when binding to receptor
what is Emax?
maximal response of a drug
what is intrinsic activity/efficacy? how is it calculated?
- the relative ability of a drug-receptor complex to produce a maximum functional response
- Emax of partial agonist ÷ Emax of full agonist
what is affinity?
how well a drug binds to a receptor
what is potency?
- a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity
- highly potent drug evokes a given response at low concentrations
- lower potent drug evokes same response only at higher concentrations
what is an antagonist?
- a compound that reduces the effect of an agonist
- does not activate receptors
- affinity of the antagonist for the receptor affects its activity
what is a competitive antagonist? what is its effect on the dose-response curve?
- bind to receptors at same binding site as the endogenous ligand or agonist, but without activating the receptor
- competes for same binding site with agonist
- sufficient concentrations of an antagonist will displace the agonist from the binding sites
- dose-response curve shifts to the right; more agonist is required to elicit the same response; decreased potency
what are the types of competitive antagonists?
- reversible (surmountable)
- irreversible (insurmountable)
what are reversible (surmountable) competitive antagonists?
- bind via noncovalent intermolecular forces
- will eventually dissociate from the receptor, freeing it to be bound again
what are irreversible (insurmountable) competitive antagonists?
- bind via covalent intermolecular forces
- there is not enough free energy to break covalent bones in the local environment, so the bond is essentially permanent, so the complex will never dissociate
- receptor remains permanently antagonised until it is ubiquinated and destroyed
what is a non-competitive antagonist? what effect does it have on the dose-response curve?
- type of insurmountable antagonist that binds to an allosteric (other) site of the receptor, or by irreversibly binding to the active site of the receptor
- reduce maximum response that can be attained by any amount of agonist
- effects cannot be negated, no matter how much agonist is present
- shift right and down of the dose-response curve
what is the agonist and antagonist of the mAChR receptor?
muscarinic ACh receptor
- agonist: muscarine
- antagonist: atropine
what is the agonist and antagonist of the nAChR receptor?
nicotinic ACh receptor
- agonist: nicotine
- antagonist: curare
what is the agonist for the histamine receptor? what are its effects?
agonist: histamine
- contraction of the ileum
- acid secretion from parietal cells
what is the antagonist for the histamine receptor? what are its effects?
antagonist: mepyramine
- reversed contraction of the ileum
- no effect on acid secretion
what is efficacy?
how well a ligand activates the receptor
what shows affinity?
shown by both antagonists and agonists
what shows efficacy?
- only agonists show efficacy
- antagonists show zero efficacy
what are factors governing drug action?
- affinity
- efficacy
- number of receptors at tissue
- signal amplification
how does the number of receptors at the tissue affect drug action?
- the less number of receptors at a tissue will result in more drug being required to illicit the same effect and vice versa
- in most cases it is possible to still get maximum response despite a reduction in receptor numbers meaning you only need a small number of receptors to get a full response
- example of drug that will inactivate a receptor is: bromoacetyl alprenolol menthane (BAAM) which is an
irreversible B-adrenoceptor antagonist - an equation called the Furchgott equation is used to calculate how many receptors are available
- receptor reserve/Spare receptors:
• many tissues have holds for a full agonist, this reserve can be large or small depending on the tissue
• there is no receptor reserve for a partial agonist
what is the Furchgott equation? what does it calculate?
used to calculate how many receptors are available in a tissue
what is signal amplification? how does it affect drug action?
- when a ligand binds to a receptor it sets off a signalling cascade
- signal amplification determines how powerful the response will be
- determined by the type of tissue the receptor is based in
what is allosteric modulation?
- substance binds to a receptor to change the receptor’s response to stimulus
- bind to allosteric site
- affinity modulation: change in EC50
- efficacy modulation: change in Emax
- modulation can be positive-allosteric or negative-orthosteric
what is an example of an allosteric ligand?
benzodiazepine
what is an inverse agonist?
a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist; <0% efficacy
what is a neutral antagonist?
has no activity in the absence of an agonist or inverse agonist but can block the activity of either; 0% efficacy
what is tolerance?
- the diminishing effect of a drug resulting from repeated administration at a given dose
- seen with continuous, repeated high concentration of drug over time
what is desensitisation of receptors?
- uncoupled - receptor can’t interact with G-protein
- receptor is internalised in vesicle of cell
- receptor becomes degraded
what is specificity?
- the ability of a protein’s binding site to bind specific ligands
- the fewer ligands a protein can bind, the greater its specificity
- describes the strength of binding between a given protein and ligand
what is selectivity?
- how a ligand may bind more preferentially to one receptor than another
- defined with respect to the binding of ligands to a substrate forming a complex
what are examples of selectivity in beta-adrenoceptors?
- isoprenaline is a non-selective B-adrenoceptor agonist so it activates both B1 (heart) & B2 (lungs) receptors
- whereas salbutamol is a selective B2-adrenoceptor agonist, but at very high concentrations it loses its specificity so will activate both B1 and B2
what catalyses the conversion of membrane phospholipid to arachidonic acid?
phospholipase A2
what is the action of phospholipase A2?
converts membrane phospholipid to arachidonic acid
what catalyses the conversion of arachidonic acid to prostaglandin H2?
cyclooxygenase
what is the action of cyclooxygenase?
converts arachidonic acid to prostaglandin H2
what are examples of NSAIDs?
include aspirin and ibuprofen but there are about 50
what are the actions of NSAIDs?
• analgesic
• anti-pyretic (reduces fever)
• anti-inflammatory
• they inhibit the enzyme
cyclooxygenase (COX) which is responsible for the breakdown of arachidonic acid to prostaglandin H2 (PGH2)
• NSAIDs work by preventing arachidonic acid from reaching the active site of the COX enzyme and thus from being broken down into prostaglandin H2 - this is achieved by competitive inhibition
what is PGH2 acted on? what does this generate?
PGH2 is acted on by specific synthases to generate prostanoids: • Prostaglandin D2 (PGD2) • Prostaglandin E2 (PGE2) • Prostaglandin I2 (PGI2) • Thromboxane A2 (TXA2)
what are some examples of prostanoids?
- Prostaglandin D2 (PGD2)
- Prostaglandin E2 (PGE2)
- Prostaglandin I2 (PGI2)
- Thromboxane A2 (TXA2)
what produces the different prostanoids?
- Prostaglandin D2 - mast cells
- Prostaglandin I2 - vascular endothelial cells
- Thromboxane A2 - platelets
- Prostaglandin E2 - macrophages (most widely found and mediates largest number of effects in the body)
what is the action of aspirin?
- prevents arachidonic acid from reaching the active site of the COX enzyme and thus from being broken down into prostaglandin H2 (competitive inhibition)
- irreversibly blocks the active site resulting in irreversible inactivation of the COX enzyme
what are the two isoforms of COX?
- COX-1: found normally and widely around the body (normal physiology)
- COX-2: this is induced and found mainly in inflammation only
what are examples of selective and non-selective drugs for COX?
- aspirin is non-selective so acts on both COX-1 and COX-2
* whereas celecoxib for example is COX-2 selective
what are examples of ACE inhibitors?
captopril and enalapril
what are actions of ACE inhibitors?
- anti-hypertensives
- work by inhibiting ACE thereby preventing the conversion of angiotensin I to
angiotensin II meaning there is less angiotensin II so less bind to angiotensin receptors (AT1) resulting in reduced vasoconstriction and thus
hypertension as well as less aldosterone release further reducing hypertension
what is the mechanism of action of ACE inhibitors?
- Captopril - mimic dipeptides; His and Leu
- Enalapril - mimic tripeptides; Phe, His and Leu
- both captopril and enalapril work by binding to ACE active site thereby meaning it is unable to convert angiotensin I to angiotensin II
what are examples of beta-lactam antibiotics?
penicillins, amoxicillin and cephalosporins
what is the action of beta-lactam antibiotics?
work by inhibiting cell wall biosynthesis of peptidoglycan bacterial cell walls by inhibiting the activity of certain enzymes
what is the enzymatic inactivation of drugs?
- most drugs are excreted by the kidneys but lipophilic drugs are not effectively
removed as they are passively absorbed because they can diffuse through cell membranes easily - in these cases Cytochrome P450 is required to introduce a hydroxyl (OH) group into the drug to enable it to be excreted more easily by the kidneys
- note: some drugs act to either inhibit or induce CYP450s to either make drugs remain in the system for longer or to be excreted quickly (e.g. quite toxic drugs)
what are examples of proton pump inhibitors?
omeprazole, lansoprazole, pantoprazole and rabeprazole
what are the actions of proton pump inhibitors?
- they are all activated in acidic (i.e. stomach) environments
- they act to inhibit acid secretion
- when prostaglandin E2 (PGE2) released from chromaffin cells, it binds to EP3 receptors on parietal cells, this causes a reduction in the concentration of H+ and thus acidity of the stomach by reducing the activity of the H+/K+ ATPase pump - PGE2
inhibits parietal cells - when histamine released from histaminocytes, binds to H2 receptors on parietal cells, this causes the H+/K+ ATPase pump to increase activity
resulting in a higher concentration of H+ being pumped into the gastric lumen thereby increasing acidity - histamine activates parietal cells - PPIs act to irreversibly inactivate the proton pump (H+/K+ ATPase) resulting in a marked reduction in acidity of the stomach, thereby helping with reflux etc.
what is the action of diuretics?
- act to inhibit symporters
- the increased excretion of water is useful for the treatment of hypertension and heart failure since the removal of water from the blood will reduce its volume and thus blood pressure
what is the action of furosemide?
furosemide can inhibit the NKCC2 pump on the thick ascending part of the loop of Henle thereby reducing the amount of Na+,Cl- and K+ ions able to enter the medullary interstitium thereby reducing hyperosomolarity meaning
that less water will diffuse out of the collecting ducts into the blood, resulting in more water loss in the urine and thus dehydration
what is the action of thiazides?
act to inhibit the Na/Cl cotransporter on the distal tubule of the nephron; this results in increased water loss
what neurotransmitters are subject to uptake?
dopamine, noradrenaline, serotonin and GABA
what do uptake inhibitors do?
cause an increased concentration of neurotransmitter in the synapse by preventing their re-uptake
what is the action of imipramine?
tri-cyclic anti-depressant that mostly inhibits the reuptake of noradrenaline (majority) and serotonin
what is the action of cocaine?
inhibits reuptake of dopamine
what is the action of tiagabin?
inhibits the reuptake of GABA (the inhibitory transmitter in CNS) thus useful for the treatment of panic disorders
what are examples of local anaesthetics?
lidocaine and procaine
what is the action of local anaesthetics?
- these local anaesthetics work by interrupting axonal neurotransmission in the sensory nerves
- they do this by blocking voltage dependent sodium channels thereby preventing the neurones from depolarising, meaning the threshold isn’t met and thus no action potential is developed to be propagated
- this rests in pain relief since pain isn’t transmitted to the brain to be perceived
- local anaesthetics can diffuse through mucus membranes easily thus
sometimes can act on muscles too
what is a drug?
any compound that is administered with an intended therapeutic effect
what are the three phases of plasma level?
- uptake into the plasma
- distribution from the plasma
- elimination from the plasma
what is the rate of diffusion like for a dissolved drug (in the plasma)?
- rate of diffusion is directly proportional to the concentration gradient - it is a first order process
- an increase in concentration will result in a higher rate of diffusion from plasma to tissue
- rate of diffusion is directly proportional to temperature (most drugs won’t work outside normal physiological temperature)
- rate is influenced by chemical reactions between the drug and solute (i.e. plasma)
what is a first order reaction?
rate is directly proportional to the concentration of drug (rate ∝ [drug])
what is a second order reaction?
rate is directly proportional to the square of the concentration of the drug (rate ∝ [drug]^2)
what is a third order reaction?
rate is directly proportional to the cube of the
concentration of the drug (rate ∝ [drug]^3)
what is a zero order reaction?
rate is unrelated to the concentration of the drug
rate ∝ [drug]0
what order process is diffusion?
first order
how is diffusion an exponential function?
where the rate of reaction is governed by one of the components involved in the reaction whose quantity or
magnitude is changing
what are features of plasma?
• the plasma is the fluid fraction or aqueous solution that remains when cells are
removed from the blood
• proteins (including antibodies) are found in the plasma as a result of their polar amino acid side chains
• the pH of the interstitium is reflected in the plasma
• plasma has a slightly higher pH than interstitium due to diffusion gradient
what does the pharmacokinetic theory consider the body as?
pharmacokinetic theory considers the body as 3 main compartments divided by tissue lipid rich barriers
what are the three main compartments of the body?
- plasma (5 litres)
- interstitial (15 litres)
- intracellular (45 litres)
what is the cellular tissue divided into?
- vessel rich viscera: muscle tissue
- vessel poor: fat stores/subcutaneous tissue
what are the 5 ways a drug can move from its site of administration to its target?
- simple diffusion
- facilitated diffusion
- active transport
- through extracellular spaces
- non-ionic diffusion
what are features of simple diffusion? what order process is it?
• movement of solutes from a region of their high
concentration to a region of
their low concentration through a lipid barrier
• first order process
what are features of facilitated diffusion?
• movement of solutes from a region of their high concentration to a region of their low concentration through protein channels • no energy required
what are features of active transport? what order reaction is it?
• movement of solutes from a region of their low concentration to a region of their high concentration using protein carriers • require energy • goes against the concentration gradient • first order reaction initially but when saturated it becomes zero order
what are features of movement through extracellular spaces?
- movement of solutes through pores in cell membrane
* protein typically cannot enter through these pores
what are features of non-ionic diffusion?
• the movement of ionic molecules (which find it difficult to diffuse across a lipid membrane) across a lipid membrane (such as that found in a cell) into the cell • ionised molecules are water soluble • un-ionised molecules are freely diffusable and lipid soluble • the mechanism of action of non-ionic diffusion is that an ionic molecule becomes less ionic and thus more non- ionic to enable it to cross the lipid membrane and enter the cell
what is the solubility of ionised and unionised molecules?
• ionised molecules are water soluble
• un-ionised molecules are
freely diffusable and lipid
soluble
what drug works by non-ionic diffusion?
aspirin
what affects non-ionic diffusion?
• the degree of ionisation of
weak acids and weak bases is influenced by pH
• non-ionic diffusion is enhanced if adjacent compartments have a pH difference
what is the effect of acids and bases when pH is increased?
weak acid: more ionised
weak base: less ionised
what is the effect on acids and bases when pH is decreased?
weak acid: less ionised
weak base: more ionised
what is bioavailability?
amount of drug taken up as a proportion of the amount administered
why does oral administration have the greatest variability?
has the greatest variability due to different factors involved; surface area of gut, diarrhoea (bioavailability is greatly decreased) and pH of
gut (alkaline at duodenum)
how do drugs move across the gut membrane?
simple diffusion of the lipid
soluble freely diffusible non ionised fraction
what are features of oral administration?
- has the greatest variability due to different factors involved; surface area of gut, diarrhoea (bioavailability is greatly decreased) and pH of
gut (alkaline at duodenum) - unpredictable
- movement across the gut membrane is simple diffusion of the lipid soluble freely diffusible non ionised fraction
- most tablets are either weak acids or weak bases
- water soluble tablets will not pass across the membranes of cells unless there is carrier mediated transport
what is the bioavailability of intramuscular administration?
close to 1
what is the bioavailability of IV administration?
should be 1
what are features of transcutaneous administration?
- such as a skin patch
- has a lower bioavailability than I.V.
what are types of routes of administration?
- oral
- intramuscular
- IV
- transcutaneous
- intrathecal (into CSF)
- sublingual
- inhalation
- topical
- rectal
is aspirin acidic or basic?
acidic
how is aspirin absorbed?
- aspirin is acidic
- in the stomach the acidic tablet dissolves but it then becomes less ionised due to the fact that a weak acid (such as aspirin) becomes less ionised in lower pH
- movement of the un-ionised aspirin across the gut is rapid
- in the plasma, aspirin is more ionised due to the higher pH
- gastric pH affects the amount of aspirin uptake
why is aspirin more ionised in the plasma?
due to higher pH
what affects aspirin uptake?
- in the plasma aspirin is more ionised due to the higher pH
* gastric pH affects the amount of aspirin uptake
why does aspirin become less ionised in the stomach?
- in the stomach the acidic tablet dissolves but it then becomes less ionised due to the fact that a weak acid (such as aspirin) becomes less ionised in lower pH
- movement of the un-ionised aspirin across the gut is rapid
how can gastric pH be increased?
- antacids act to increase pH e.g. treatment of ulcer
- omeprazole (PPI) and ranitidine (H2 blocker) acts to reduce acid secretion in stomach and thus increase pH
- ingesting alkali foods results in an increased pH
- a raised pH results in the reduced uptake of aspirin from the stomach and thus a reduction in bioavailability
what reduces aspirin uptake?
a raised pH results in the reduced uptake of aspirin from the stomach and thus a reduction in bioavailability
what is a drug distributed according to?
a drug is distributed in the plasma according to its chemical properties and
molecular size
what is found in the aqueous phase?
dissolved gases and small ionic molecules
where do lipophilic drugs adhere to?
hydrophobic areas of plasma proteins
what compounds are active in the three compartments of the body?
- proteins/large molecules are only active in the plasma compartment (5L)
- water soluble molecules are active in plasma and interstitial compartment
(5L + 15L) - lipid soluble molecules are only active in the intracellular fluid (45L)
what compartment are proteins/large molecules active in?
plasma compartment (5L)
what compartment are water soluble molecules active in?
plasma and interstitial compartments (5L + 15L)
what compartment are lipid soluble molecules active in?
intracellular fluid (45L)
what is the volume of distribution derived from?
derived value from steady state (where drug intake is in equilibrium with its
elimination) plasma level studies
what is the volume of distribution? how is it calculated?
- volume of distribution = total amount of drug in body ÷ concentration of drug in plasma
- it is the volume (litres) that the drug would occupy if it was distributed through all the compartments as if they were all plasma
what should be kept in mind when calculating the volume of distribution?
- the volume of distribution can appear to be larger than it actually is, this is because when calculating volume of distribution, concentration and volume is taken from the plasma (blood)
- however, when a drug is injected it can be taken up by organ systems (such as the liver, lungs and kidney etc.) this will mean its concentration in the blood will decrease
- thus when you calculate the volume of distribution after the drug has been partly taken up then the value you get can be much larger than it physically is
- drugs that are highly lipid soluble, enter the CNS and have a high volume of distribution
what is the volume of distribution of lipid soluble drugs?
drugs that are highly lipid soluble, enter the CNS and have a high volume of distribution
what drugs are found in the plasma?
- plasma expanders
- immunoglobulin
- warfarin
what drugs are found in the interstitial compartment?
- aspirin/ other NSAIDs
- antibiotics
- muscle relaxants
what drugs are found in the intracellular compartment?
- steroids
- local anaesthetics
- opioids
- CNS drugs
- paracetamol
- amiodarone (has a volume of distribution of 450L i.e. very easily taken up by tissue)
what is compartment modelling? what does it assume?
- assumes plasma is in equilibrium
- shows plasma concentration against time during the distribution of drug phase
- line of best fit to 1,2 or 3 compartment models of distribution
what is the 1 compartment model?
C = C0 e^-kt
what is the 2 compartment model?
C = C0 e^-kαt + C0 e^-kβt
what is the 3 compartment model?
C = C0 e^-kαt + C0 e^-kβt + C0 e^-kλt
what is the pattern of compartment modelling?
for every compartment you
add to the model you add
another “C0 e-kt”
what compartment model do lipid soluble drugs have?
most lipid soluble drugs have 3 compartment models - this suggests that the movement between the compartments is plasma > viscera > adipose
tissue
where is drug eliminated from?
plasma compartment
how are drugs eliminated?
- renal and/or hepatic elimination are the route for the vast majority of drugs
- in renal failure, a patient will not be able to eliminate for up to a week
what order process is elimination?
first order process
what are the two definitions of clearance?
- the volume of plasma that can be completely cleared of drug per unit time (mls minute^-1 (ml/min))
- the rate at which plasma drug is eliminated per unit plasma concentration (mls minute^-1 (ml/min))
what are features of clearance?
- the removal of drug from the plasma by either liver or kidney is clearance
- both definitions are measures of efficiency
- can influence the rate of elimination depending on plasma concentration of drug
how are units of clearance derived?
- the rate at which plasma drug is eliminated = mg per minute
- per unit plasma concentration = mg per ml
- total = mg per minute ➗ mg per ml
- cancel out the “mg”
- results in = mls minute^-1 (ml/min)
- thus the units of clearance are mls minute-1 (ml/min)
what are features of renal clearance? how are water soluble molecules processed?
• all of the factors affecting renal blood flow affect clearance most notably
blood pressure
• water soluble molecules which pass through the glomerular endothelial gap are eliminated by glomerular filtration
• larger water soluble molecules can be eliminated by active tubular secretion
how is renal clearance measured?
- the calculation assumes; rate of elimination = rate of appearance in urine
- plasma concentration measured during the clearance process is assumed to be constant
- clearance = rate of appearance in urine ➗ plasma concentration
- creatinine is used as a marker substance in kidney
what is used as a marker substance in the kidney?
creatinine
what is adult renal blood flow?
renal blood flow is 18% of cardiac output = 1L/min
what is the adult renal plasma flow?
renal plasma flow is 60% of blood flow = 600mls/min
what is the adult glomerular filtration rate?
glomerular filtration is 12% of renal blood flow = 130mls/min
what drugs are eliminated by renal clearance?
- many drugs are eliminated by the kidney either by glomerular filtration e.g digoxin and gentamicin or via active secretion e.g. penicillin, frusemide and thiazides
- many highly lipid soluble drugs metabolised to water soluble glucuronic acid conjugates are eliminated by active secretion e.g.
morphine 3 & 6 glucuronides - only free plasma is cleared
- highly protein bound drugs have little exposure to renal clearance
- most drugs eliminated by the kidney are water soluble and small molecules
what are most of the drugs eliminated by the kidney?
water soluble and small molecules
what is acute renal impairment often secondary to?
reduced pre-renal perfusion
what is chronic renal impairment caused by?
diabetes and hypertension
what will kidney damage result in?
reduced clearance and prolonged elimination of a large number of drugs
how does renal impairment affect drug clearance?
- for patients with renal impairment, choose drugs that are eliminated by the liver instead
- hypoalbuniaemia means lipid soluble drugs in the plasma have highly freely diffusable fractions and greater effects
- elevated plasma creatinine and urea compete for lipid binding sites on protein and displace more lipid soluble free drug
- patients with renal impairment have unpredictable reactions to drugs due to oedema in compartments
what is the management of renal impairment?
- choose alternatives not eliminated by the kidney
- avoid nephrotoxic drugs
- make corrections based on plasma creatinine which estimated the percentage reduction in clearance and then alter dose
- measure plasma concentrations if there is a toxicity risk
what are features of hepatic clearance?
- has no equivalent to glomerular filtration
- all hepatic clearance involves active transport
- there is active secretion (if water soluble) from the liver into the bile duct
what is the hepatic blood flow?
hepatic blood flow is 24% of cardiac output (3/4 from portal vein and 1/4 from hepatic artery)
what is the hepatic extraction ratio?
the proportion of drug removed by one passage through the liver
what does a high HER mean?
can be so high that clearance is only limited by hepatic blood flow - perfusion limited
what does a low HER mean?
the process is slow and not efficient with a low amount
removed - diffusion limited
what can affect HER? how does HER affect the liver?
- liver enzymes can alter the HER
- if the liver is exposed to a low HER drug then it will produce more enzymes to enable it to increase clearance
- high HER drugs have little effect on the number of new enzymes produced
what are features of drugs with a high HER?
drugs with a high HER are described as having a high first pass metabolism and thus have limited uptake from oral administration since they will first go to the liver before it can reach its target but by
that time most of it will have been eliminated - ineffective
how are different drugs eliminated from the liver?
- some large water soluble molecules are secreted unchanged in bile
- most large lipid soluble drugs are metabolised to increase their water solubility so that they may be excreted more easily by the kidney
- pro-drugs are activated in the liver, whereby the pro-drug is cleaved into the active drug via metabolism e.g hydrocortisone is broken down into the active drug cortisol
where do most phase I reactions happen in the liver?
95% of phase I reactions are in liver smooth endoplasmic
reticulum
what is the aim of phase I reactions?
aim is to make the drug more hydrophilic so that it can be excreted by the kidneys - it does this by adding a hydroxyl group to the drug
what happens in phase I reactions?
- they introduce or expose hydroxyl (-OH) groups or other reactive sites that can be used for conjugation reactions (the Phase II reactions)
- introduces reactive group to drug - attack point for conjugation
- hydrophilic molecules usually do not reach the metabolising enzymes since they are excreted easily
- oxidation
- reduction: add hydrogen (saturate unsaturated bonds)
- hydrolysis: split amide (peptide bond (between a carboxyl (COOH) and amino (NH) group) O=C-NH) and ester (the H from a COOH
(carboxylic acid) is replaced by some sort of hydrocarbon) bonds
what happens in oxidation reactions in phase I reactions?
- hydroxylation (add -OH)
- dealkylation (remove -CH side chains)
- deamination (remove -NH)
- hydrogen removal
what happens in reduction in phase I reactions?
add hydrogen (saturate unsaturated bonds)
what happens in hydrolysis in phase I reactions?
split amide (peptide bond (between a carboxyl (COOH) and amino (NH) group) O=C-NH) and ester (the H from a COOH (carboxylic acid) is replaced by some sort of hydrocarbon) bonds
what is functionalisation in phase I reactions?
- introduces reactive group to drug
- includes adding or exposing; -OH,-SH,-NH2,-COOH
- the product of the reaction is usually more reactive
- there is a small increase in hydrophilicity
where do phase I reactions occur? what are they catalysed by?
- mainly occur in the liver
- mainly catalysed by cytochrome P450 enzymes
what is cytochrome P450?
- type of microsomal enzyme i.e. found on liver smooth
endoplasmic reticulum - involved in Phase I reactions
what is the action of cytochrome P450?
- uses heme group (Fe2+) to oxidise substances
- products of P450 enzymes are more water soluble
- requires energy and molecular oxygen
what are examples of drugs that inhibit cytochrome P450?
some drugs act to inhibit cytochrome P450 such as amiodarone and cimetidine resulting in drugs lasting longer/not being eliminated as fast
what is involved in phase II conjugation reactions?
- also known as glucuronidation, used if drug is very hydrophobic
- essentially adding a glucuronic acid group (glucuronide) to the drug to make it more hydrophilic
- process forms covalent bonds
what enzymes are involved in phase II reactions?
- enzyme: glucuronosyltransferase (Uridine 5’-diphospho-
glucuronosyltransferase) (UGT) - microsomal enzyme, used in
phase II reactions, catalyses reaction - uridine diphospho-glucuronic acid (UDPGA) - essentially a co-
enzyme/donor compound required to conjugate glucuronic acid
what is the product of phase II reactions?
UDPGA + drug -> uridine diphosphate + drug-glucoronide
- catalysed by UGT
what happens to phase I water soluble metabolites and phase II glucuronides?
- phase I water soluble metabolites and phase 2 glucuronides enter the bile and then enter the gut via the cystic duct
- some phase I metabolites and phase 2 glucuronides also enter the blood and are actively excreted into the urine
- during cholestasis (stoppage of bile flow), increased amounts are excreted by the kidneys
- conversely biliary secretion may increase if renal function is reduced
how does the phase II glucuronide get metabolised in the enterohepatic circulation?
- large bowel flora tend to metabolise the glucuronic acid group on the phase 2 glucuronide
- this results in the liberation of the drug from the glucuronic acid
- the drug is then able to re-diffuse from the gut into the blood and then have a prolonged effect before going back to the liver to be re-conjugated and excreted again
- thus the enterohepatic circulation can prolong the action of some drugs
when does liver failure affect drug metabolism?
- isolated liver failure with no effects on other organs is unusual
- there is minimal effect on drug metabolism until at least 70% of functioning liver is lost
what is a disadvantage of prolonged duration of action of drug?
the prolonged duration of the action of a drug comes with the risk of drug accumulation and thus toxicity
how can liver failure lead to toxicity when metabolising drugs?
- the prolonged duration of the action of a drug comes with the risk of drug accumulation and thus toxicity
- hypoalbuminaemia means an increased free plasma levels of freely diffusable lipid soluble drugs
- pharmacodynamic (how drug affects body) alterations are often secondary to disease
- the nitrogen containing substances that are cleared by the liver contribute to toxicity
what are some drugs with active metabolites?
- Prednisone
- Isosorbide dinitrate
- Codeine
- Diamorphine
- L-dopa
- Cortisone
- Morphine
what are drugs that are given IV?
- Insulin
- Heparin
- Antibiotics
- Frusemide
- Anti-arrhythmics
- Sedation anaesthsia
why are IV infusions used?
- enables steady state plasma (where drug intake is in equilibrium with its elimination) levels to be maintained for as long as possible
- enables highly accurate drug delivery
- useful for drugs that are ineffective administered by other routes or those who cannot absorb oral medication
- is the quickest administration route
- guarantees 100% bioavailability (the gold standard)
what are advantages/disadvantages of oral administration?
- much less accurate drug delivery since bioavailability can be highly variable resulting in uncertainty or effectiveness of treatment
- however it does have excellent patient compliance with one tablet a day
what are advantages/disadvantages of IV infusion?
- requires constant monitoring of patency of IV access, replenishing of drug delivery and observation of response to therapy
- has the potential for serious calculation errors
- limited by the number of places a cannula can be inserted
what must be monitored in IV infusion?
patency of IV access, replenishing of drug delivery and observation of response to therapy
how are IV infusions dosed? what are the units?
- IV regimes lack standardisation of prescription
- units are mg hour-1 (mg/hour)
- drug dosage is based on body weight - problematic with extreme body weights
- monitoring necessary to look at therapeutic response
what are pharmacokinetic considerations for dosage of IV infusions?
- high volume of distribution means that there will be a small fraction in the plasma so it will take a long time to reach a steady state
- with high volume of distribution drugs, adjusting infusions rate takes ages to change the plasma concentration
- thus a ‘loading’ bolus dose is often recommended to speed up saturation of all the components
- steady state means that infusion dosage = rate of elimination from plasma
- increasing infusion rate aims to raise plasma level and maintain equilibrium
- if elimination becomes saturated then this will lead to the accumulation of the drug and thus toxicity
why is a loading bolus dose recommended for IV infusions?
- high volume of distribution means that there will be a small fraction in the plasma so it will take a long time to reach a steady state
- with high volume of distribution drugs, adjusting infusions rate takes ages to change the plasma concentration
- thus a ‘loading’ bolus dose is often recommended to speed up saturation of all the components
what does a steady state mean for IV infusions?
steady state means that infusion dosage = rate of elimination from plasma
what does increasing IV infusion rate aim to do?
increasing infusion rate aims to raise plasma level and maintain equilibrium
what happens if elimination becomes saturated in IV infusion?
if elimination becomes saturated then this will lead to the accumulation of the drug and thus toxicity
what is the ideal drug for infusions?
- one with a small volume of distribution so it is easy to reach steady state and so that the plasma concentration is responsive to dose rate
- one which is broken down by tissue/plasma enzymes irrespective of liver and renal function
- one with an obvious and predictable dose to response relationship
- one with a low risk of toxicity and that is easy to determine the concentration of it in the plasma
what are features of IV insulin infusion?
- insulin is infused with 10% dextrose for managing a diabetic who is nil by mouth
- there is a danger of hypoglycaemia if the insulin is not given alongside dextrose since plasma glucose can change rapidly
what are features of vacomycin IV infusion?
- type of antibiotic
- requires plasma level monitoring of peak (sample hour after drug given) and trough (sample hour before next dose) level after three doses
what are features of amiodarone IV infusion?
• anti arrhythmic drug
• has problem of returning arrhythmia when the infusion is turned off
• is a high volume of distribution drug and thus often steady state is not
achieved after 48hrs of IV infusion
what are features of heparin IV infusion?
- for emergency anticoagulation if at high risk of thrombosis
- chemical reaction works in minutes
what are features of noradrenaline IV infusion?
- alpha-1 agonist
- used as a vasoconstrictor
- given for the treatment of septic shock
what are examples of continuous/pulsatile drug delivery?
- GnRH (pituitary) when given in continuos infusion results in a contraceptive
effect - pulsatile GnRH however is a physiological fertility treatment
- desensitisation occurs with many agonist drug infusions, perhaps pulsatile delivery could avoid this
what are features of pulsatile IV gentamicin?
intermittent/pulsatile IV gentamicin results in a higher peak level than steady state infusion and thus has higher bactericidal activity
what are features of patient controlled morphine?
patient controlled morphine analgesia only requires a 1/3 of the normal IV dose if given as intermittent IM injections, this is very beneficial since there is less respiratory depression than with IV infusion
what does the peripheral nervous system consist of? what neurotransmitters are used here?
- somatic (NMJ) = voluntary = acetylcholine (ACh)
* autonomic = involuntary = ACh and Noradrenaline (NAd)
what does the autonomic nervous system consist of? what neurotransmitters are used here?
- parasympathetic - ACh
* sympathetic - NAd
what are the types of cholinergic receptors? what kind of receptors are they?
- nicotinic (nAChR) - ion channel receptors
* muscarinic (mAChR) - G-protein coupled receptor
what are the effects of ACh in the parasympathetic system mediated by?
muscarinic ACh receptors (M1, M2, M3 - most common)
what are the effects of ACh in the sympathetic nervous system?
ACh mediates the release of adrenaline (Ad) and
noradrenaline (NAd)
what are the effects of ACh in the somatic nervous system?
nicotinic receptors (nAChR) mediate the response of ACh in the somatic system at the neuromuscular junction
what receptors are found at the neuromuscular junction?
nicotinic ACh receptors (nAChR)
what is the process of ACh production, release and reuptake?
- choline acetyl transferase enzyme is required to make ACh from acetyl CoA and choline (substrate) in the neurone
- ACh is then packaged into a vesicle ready to be released when the neurone is stimulated
- after ACh has been used it is broken down in the synaptic cleft by acetylcholinesterase AChE into choline and acetate
- choline is taken up into the neurone where it can be used to make more ACh
what enzyme catalyses ACh production?
choline acetyl transferase enzyme makes ACh from acetyl CoA and choline (substrate) in the neurone
what enzyme breaks down ACh in the synaptic cleft?
after ACh is used, it’s broken down in the synaptic cleft by acetylcholinesterase into choline and acetate
what is botulinum toxin? what does it do?
- lethal toxin
* inhibits ACh release into the neuromuscular junction resulting in paralysis
what is the mechanism of action of botulinum toxin?
- uses protease to degrade vesicle proteins
* thereby preventing vesicle fusion and thus the release of ACh into the synaptic cleft
what is the use of botulinum toxin?
cosmetic and spasticity
what is a competitive nAChR antagonist?
curare
what is curare?
- competitive nAChR antagonist
- nAChR found at the neuromuscular junction
- arrow poison known as tubocurarine
- acts as a neuromuscular blockade by binding to the 2
nicotinic binding sites on the nAChR thereby preventing the
binding of ACh
what is the effect of curare?
- results in a muscle relaxant effect
- can result in being conscious but aware of pain and paralysed
how can the effect of curare be reversed?
can reverse the block using sugammadex which is a selective relaxant binding agent that encapsulates the blocker thereby preventing it from binding
what is the action of suxamethonium?
- suxamethonium is essentially 2 ACh stuck together
- acts to desensitise the receptor resulting in paralysis of skeletal muscle
- action is fast and short duration (less than 10 mins)
what happens to suxamethonium after its action?
remains in the NMJ for a while since it is a poor substrate for acetylcholinesterase; can only be broken down by plasma cholinesterase, not synaptic acetylcholinesterase
what is a reversible cholinesterase inhibitor?
neostigmine
what is the action of neostigmine?
- blocks cholinesterase reversibly
- resulting in an increase of ACh at the synaptic cleft since it isn’t broken down
- thus ACh remains for longer and thus signal stimulated
for longer
what is neostigmine?
reversible cholinesterase inhibitor
what is the therapeutic use of neostigmine?
useful in treatment of myasthenia gravis whereby the immune system produces antibodies against nAChR, resulting in less receptors and thus a weak skeletal muscle response - thus having ACh remain longer will result in stronger responses
what are some irreverible cholinesterase inhibitors?
organophosphates:
- insecticides (diazinon)
- nerve gas (sarin)
what is the action of organophosphates?
irreversibly inhibit acetylcholinesterase, meaning ACh remains indefinitely, leading to huge accumulation
what are some examples of organophosphates?
insecticides (diazinon) and nerve gas (sarin)
what are the effects of accumulation of ACh in nAChRs?
twitching, severe weakness and paralysis
what are the effects of accumulation of ACh on mAChRs?
salivation, defectation, urination, bradycardia and hypotension
what are the effects of accumulation of ACh in the CNS?
confusion, loss of reflexes, convulsions and coma
what is the overall function of the parasympathetic nervous system?
- normal physiological conditions
* rest and digest
what is the overall function of the sympathetic nervous system?
- stress
* fight or flight
what are therapeutic uses of muscarinic ligands?
- eye agonists
- lungs
- bladder
- GI tract
what is the therapeutic use of muscarinic ligands in the eyes?
- pilocarpine (stimulates saliva (dry mouth)) is a partial agonist of the muscarinic 3 receptor (M3)
- constrictor muscle and ciliary muscle contract, resulting in miosis (excessive constriction of pupil)
- leads to improved filtration of aqueous fluid
- lowers intraocular pressure (to treat glaucoma) which is associated with optic nerve damage
what is the therapeutic use of muscarinic ligands in the lungs?
• the intrinsic tone of the airways is governed by the
parasympathetic system
• mediated by cholinergic (ACh) muscarinic M3 receptors
• excessive parasympathetic activation can result in
bronchoconstriction mediated via the M3 receptor
• seen in COPD and asthma
• antagonists either short-acting (ipratropium) or long-acting (tiotropium) act as bronchodilators
what is a partial agonist of the M3 receptor in the eyes?
pilocarpine
what receptor is in the eye?
muscarinic 3 receptor
what is the effect of pilocarpine on the eyes?
- leads to contraction of the constrictor muscle and the ciliary muscle, resulting in miosis (excessive constriction)
- leads to improved filtration of aqueous fluid
- lowers intraocular pressure in glaucoma, which would lead to optic nerve damage
what is the intrinsic tone of the airways governed by?
parasympathetic system via cholinergic (ACh) muscarinic M3 receptors
what is the pathophysiology of COPD and asthma?
excessive parasympathetic activation of the M3 receptors in the lungs can lead to bronchoconstriction
what is a short acting antagonist of the M3 receptors in the lungs?
ipratropium
- acts as a bronchodilator
what is a long-acting antagonist of the M3 receptors in the lungs?
tiotropium
- acts as a bronchodilator
what is ipratropium?
short-acting antagonist of the M3 receptors in the lungs
- is a bronchodilator
what is tiotropium?
long-acting antagonist of the M3 receptors in the lungs
- is a bronchodilator
what is the effect of ACh on the bladder?
causes contraction of the bladder
what is the effect of a bladder agonist? what is an example?
a bladder agonist results in more contraction e.g. bethanechol - useful in urinary retention
what is the effect of a bladder antagonist? what is an example?
a bladder antagonist is used to relax the bladder e.g.
oxybutinin - useful in urinary frequency
what is the effect of ACh on the GI tract?
acts to increase GI motility
what are the actions and examples of GI antagonists?
GI antagonist such as mebeverine and scopolamine are useful at decreasing GI motility - especially useful in Irritable Bowel Syndrome (IBS)
what are the adverse effects of muscarinic agonists?
- Diarrhoea
- Urination
- Miosis (excessive pupil constriction)
- Bradycardia
- Emesis (vomiting)
- Lacrimation (tears)
- Salivation/sweating
- Remember by DUMBELS!
what is hexamethonium? what is its action?
- competitive antagonist at the nAChR at autonomic ganglia
- blocks both parasympathetic and sympathetic divisions of the
autonomic nervous system - has no effect on the neuromuscular junction
what are the effects of parasympathetic block by hexamethonium?
- secretions reduced
- constipation
- urinary retention
- blurred vision
what are the effects of sympathetic block by hexamethonium?
marked hypotension
what are the uses of hexamethonium?
the first antihypertensive drug
what are the uses of CNS antagonists in motion sickness?
- ACh stimulates the vomiting centre in the brain
* scopolamine (anti-muscarinic) used for motion sickness treatment
what are the uses of CNS antagonists in Parkinsons?
- dopamine is low in Parkinsons sufferers
- ACh stimulates the reuptake of dopamine
- benzatropine blocks the reuptake and thus increases the amount of dopamine at cleft
what are the uses of CNS antagonists in Alzheimers?
• there is a lack of cholinergic neurones and thus a reduction
in ACh
• donepezil acts to inhibit acetylcholinesterase and is specific to the CNS resulting in increased ACh in the CNS
what are noradrenaline and adrenaline?
NAd is a neurotransmitter and Ad is a hormone
what are the effects of the parasympathetic nervous system?
acetylcholine • rest and digest • constricts pupils • stimulates tears • stimulates salivation • lowers heart rate • reduces respiration • constricts blood vessels • stimulates digestion • contracts bladder • erection
what are the effects of the sympathetic nervous system?
noradrenaline • fight or flight • dilates pupil • inhibits tears • inhibits salivation • activates sweat glands • increases heart rate • increases respiration • inhibits digestion • release of adrenaline • relaxes bladder • ejaculation in males
what hormones are produced by the adrenal gland? in what proportion?
noradrenaline (20%) and adrenaline (80%)
what are catecholamines? what are some examples?
- monoamine neurotransmitter, an organic compound that has a catechol and a side chain amine
- noradrenaline, adrenaline, DOPA and dopamine
what is the synthesis pathway of catecholamines?
tyrosine -> DOPA -> dopamine -> noradrenaline -> adrenaline
what enzyme catalyses the conversion of tyrosine to DOPA?
tyrosine hydroxylase
what enzyme catalyses the conversion of DOPA to dopamine?
DOPA decarboxylase
what enzyme catalyses the conversion of dopamine to noradrenaline?
dopamine beta-hydroxylase
what enzyme catalyses the conversion of noradrenaline to adrenaline?
phenylethanolamine N-methyltransferase
what inactivates noradrenaline release?
monoamine oxidase and catechol-O-methyl transferase inactivate noradrenaline release by metabolising it thus reducing its stimulant effect
- metabolise other catecholamines too
what are classes of adrenoceptors? what types of receptors are they?
- alpha-1 and alpha-2
- beta-1, beta-2 and beta-3
- all are GPCRs
what are alpha-1 adrenoceptors coupled to?
- coupled with Gq protein and phospholipase C
- phosphatidylinositol is converted into DAG and IP3
- DAG activates protein kinase C
- IP3 triggers release of Ca2+ -> contraction
what are alpha-2 adrenoceptors coupled to?
- coupled with Gi protein
- Gi protein inhibits adenylyl cyclase, which would usually produce cAMP which would activate protein kinase A
what are the effects of activation of alpha-1 adrenoceptors?
- vasoconstriction
- pupil dilation
- bladder contraction
what are the effects of activation of alpha-2 adrenoceptors?
presynaptic inhibition of noradrenaline (negative
feedback) i.e. when blood sugar is low then alpha-2 in
pancreas will be stimulated to reduce noradrenaline
release thereby reducing insulin levels being released
from the pancreas
what are beta-1, -2 and -3 adrenoceptors coupled to?
- Gs protein and adenylyl cyclase
- converts ATP to cAMP
- cAMP activates protein kinase A
what are the effects of beta-1 adrenoceptors?
- increased force of heart contraction (positive inotropic effect)
- increased heart rate
- increased electrical conduction in heart
- increased renin release from the kidney
- increased blood pressure
what are the effects of beta-2 adrenoceptors?
- bronchodilation
- vasodilation
- reduced GI motility
what are the effects of beta-3 adrenoceptors?
- increased lipolysis
- relaxation of bladder
what is kind of compound is adrenaline?
- non-selective agonist
- non-selective since it works at any alpha or beta adrenoceptor
what are the uses of adrenaline?
• anaphylaxis - reduced blood pressure and increased
bronchoconstriction
• cardiac arrest
• acute hypotension
what are the targets of adrenaline?
- blood vessels (Alpha-1)
- heart (Beta-1)
- bronchial smooth muscle (Beta-2)
what are the effects of adrenaline?
- vasoconstriction (Alpha-1)
- positive inotropic effect (Beta-1)
- bronchodilation (Beta-2)
what are some selective adrenergic agonists for alpha-1? where are these receptors located?
- blood vessels and bladder
- phenylephrine and oxymetazoline
what are the effects of selective alpha-1 adrenergic agonists (phenylephrine and oxymetazoline)?
- results in vasoconstriction
* useful as a nasal decongestant since vasoconstriction results in less fluid leakage from vessels
what is a selective adrenergic agonist for alpha-2? where are the receptors located?
- pre-synaptic neurone
- clonidine
what are the effects of selective alpha-2 adrenergic agonists (clonidine)?
it inhibits noradrenaline release therefore is useful as an anti-hypertensive
what is a selective adrenergic agonist for beta-1? where are the receptors located?
- heart
- dobutamine
what are the effects of selective beta-1 adrenergic agonists (dobutamine)?
has a positive inotropic effect in the heart thus increases force of heart contraction
what is a selective adrenergic agonist for beta-2? where are the receptors located?
- lungs
- salbutamol
what are the effects of selective beta-2 adrenergic agonists (salbutamol)?
bronchodilation
what is a selective adrenergic agonist for beta-3? where are the receptors located?
- bladder
- mirabegron
what are the effects of selective beta-3 adrenergic agonists (mirabegron)?
relaxation of the bladder
what is a non-selective adrenergic agonist?
adrenaline (works on all alpha and beta receptors)
what are some indirect-acting adrenergic agonists?
- amphetamines and cocaine
- MAO and COMT inhibition
what is the action of amphetamines and cocaine on adrenoceptors?
- work by inhibiting the noradrenaline transporter on the pre-synaptic neurone thereby resulting in a build up of catecholamines, especially noradrenaline but dopamine too, in the synapse
- results in CNS overstimulation
what is the action of MAO and COMT inhibition on adrenoceptors?
- this results in the build up of noradrenaline as well as other catecholamines such as dopamine
- useful in the treatment of Parkinson’s and depression
what are some alpha-1 antagonists?
doxazosin and tamsulosin
what is the effect of doxazosin?
- alpha-1 adrenergic antagonist
- vasodilator; reduces blood pressure; is a anti-hypertensive
what is the effect of tamsulosin?
- alpha-1 adrenergic antagonist
- relaxes bladder neck and aids in urination
- useful in men with enlarged prostates who find it difficult to urinate
what is an alpha-2 adrenergic antagonist?
yohimbine
what is the effect of yohimbine?
- alpha-2 adrenergic antagonist
- blocks alpha-2 receptor
- noradrenaline inhibition does not occur, leading to an increase in noradrenaline and other catecholamines e.g. dopamine
what are the effects of beta-1 adrenoceptor antagonists?
- results in a reduction in cardiac output as well as a reduction in renin thus a reduction in blood pressure
- useful in treating hypertension, angina and arrhythmia
what is a non-selective beta-adrenoceptor antagonist?
propanolol; works on all beta receptors
what are some beta-1 adrenoceptor selective antagonists?
atenolol, metoprolol, bisoprolol, betaxolol
what is carvedilol?
non-selective beta and alpha-1 antagonist which affects the heart and causes vasodilation
what are additional properties of some beta adrenoceptor antagonists?
- partial agonists: intrinsic sympathomimetic activity
- membrane stabilising activity
what is intrinsic sympathomimetic activity in relation to beta blockers? what are some examples?
beta-blockers that are able to stimulate beta-adrenergic
receptors (agonist effect) as well as acting like antagonists too
- e.g. penbutolol and acebutolol
what are examples of beta blockers that have membrane stabilising activity?
• can inhibit the propagation of action potentials across a
membrane
• useful in the treatment of arrhythmias
• propranolol and betaxolol
what is the overall effect of alpha-1 adrenoceptor activation?
vasoconstriction and bladder contraction
what is the overall effect of alpha-2 adrenoceptor activation?
presynaptic inhibition
what is the overall effect of beta-1 adrenoceptor activation?
increased cardiac effects
what is the overall effect of beta-2 adrenoceptor activation?
bronchodilation
what is the overall effect of beta-3 adrenoceptor activation?
bladder relaxation and increased lipolysis
what are features of homeopathy? what are advantages/disadvantages?
- “to treat like with like”
- quite possible there is a placebo effect
- one advantage is that there are unlikely to be any drug interactions with homeopathic treatments
what are features of medical herbalism? what are advantages/disadvantages?
- medicine from plants
- can be medically effective
- but the industry is unregulated e.g. heavy metals found in asian herbal
products - also these medicines can interfere and interact with normal medication
what are examples of medical herbalism?
- digitalis from foxglove plant - for heart failure treatment
- morphine from poppy - analgesic
- atropine from deadly nightshade - scarlet fever treatment
- vincristine from periwinkle - cancer treatment
what is an example of medical herbalism for heart failure?
digitalis from foxglove plant
what is an example of medical herbalism for analgesia?
morphine from poppy
what is an example of medical herbalism for scarlet fever treatment?
atropine for deadly nightshade
what is an example of medical herbalism for cancer?
vincristine from periwinkle
what are approaches to drug design?
chance and rational drug design
what are examples of drugs that were developed by chance?
penicillin and sildenafil
what are examples of drugs that were developed rationally?
propanolol and ritonavir
how was penicillin developed?
- using fermentation
- led to discovery of other antibiotics e.g. streptomycin
what are some drugs that were developed via the fermentation approach?
- lovastatin (statin)
- cyclosporine (immunosuppressant)
- ivermectin (broad spectrum antibiotic)
what is chirality?
asymmetry; an object is chiral if it’s distinguishable from its mirror image; it cannot be superimposed onto it
- D (S form) or L (R form)
- may influence drug action
- some drugs have chiral centres (asymmetric carbon) e.g. salbutamol
what chirality do biological systems used?
L-amino acids (R form)
how was propanolol developed?
- rational drug design
- developer undertook physiochemical considerations such as solubility, electrostatic and bulk
- was developed as a antagonist to counter the agonist noradrenaline
- is a Beta-antagonist used in treatment of hypertension
how was cimetidine developed?
- was developed under rational drug design
- developed as a antagonist to counter the agonist histamine
- is a H2-antagonist used in the treatment of peptic ulcers
how was insulin first developed?
- extracted from beef/pork pancreas first
- then eventually engineered insulin analogues was developed
- second generation insulin analogues
what are some fast-acting second generation insulin analogues?
- Lispro
- Aspart
- Glulisine
what are some long-acting second generation insulin analogues?
- Degludec
- Detemir
- Glargine
what are some recombinant proteins in clinical use?
- insulin (recombinant human protein)
- erythropoetin
- growth hormone
- interleukin 2
- gamma interferon
- interleukin 1 receptor antagonist
what are therapeutic antibodies based on?
mAb (monoclonal antibody) technology
how are monoclonal antibodies produced?
• mouse is immunised against the antigen of interest
• B cells are isolated to check they are producing antibodies against the antigen
• if desired antibody is being produced then the mouse spleen is removed
• B cells in the spleen are removed and then cultured along with myeloma tumour cells (these cells can divide indefinitely but cannot produce antibodies)
• solution is added to fuse the B cells with the tumour cells to produce hybridomas (fused cells) that can divide indefinitely and produce
antibodies
• the hybridomas are then cloned and undergo clonal expansion
• then the monoclonal antibodies produced are extracted and then used for clinical purposes
what are features of 1st generation mAbs?
- these were mouse derived and thus tended to illicit immune responses against themselves since the human immune system recognised the antibodies as foreign
- also these antibodies had a poor half-life
what are types of 2nd generation mAbs?
- chimeric antibodies
- humanised antibodies
what are features of chimeric antibodies?
- have a mix of human and mouse antibody
- but since mouse antibody is still present still can illicit immune response
what are features of humanised antibodies?
- have 3 hypervariable regions (cutting edge of antigen recognition) and are less likely to illicit immune response
- reason why mAbs and humanised mABs recognise the same target e.g. TNF is due to similarities in hypervariable regions
what are examples of monoclonal antibodies?
- infliximab
- adalimumab
- trastuzumab
- omalizumab
what is the type, target and use of infliximab?
type: chimeric
target: TNF
use: RA, Crohn’s
what is the type, target and use of adalimumab?
type: humanised
target: TNF
use: RA
what is the type, target and use of trastuzumab?
type: humanised
target: HER2 (EGFR)
use: breast cancer
what is the type, target and use of omalizumab?
type: humanised
target: IgE
use: asthma
what are examples of humanised mAbs?
adalimumab, trastuzumab, omalizumab
what is an example of a chimeric mAb?
infliximab
what are features of gene therapy?
- delivery of nucleic acid polymer to cell
- DNA is delivered using a viral vector
- therapeutic gene administered to treat effects of mutated gene
- suppresses mutated gene gene expression
how are leads generated?
- biochemical modification of natural products
- tropical rain forest and the sea are important sources of natural products
- note: chemical modifications of natural products may be very difficult
what are examples of drugs developed by combinatoral chemistry?
- Penicillin
- Cyclosporine
- Quinine
- Morphine
what are features of combinatorial biosynthesis?
- large enzyme complexes generate natural products
- then manipulate biosynthetic machinery to generate structural analogues
what is the overall process of identifying compounds for drug development?
- combinatoral chemistry and biosynthesis
- huge library of compounds
- high throughput screening -> hits -> leads
how many compounds can high throughput screening screen?
can screen around 50,000 compounds a day, roughly 2.5 million a year
what is done in high throughput screening?
- looks a biological activity of compounds
- computers collate and retrieve data and analyse whether any compound has
clinical efficacy - rapid way to identify ‘hits’
what can high throughput screening not establish?
- bioavailability
- pharmacokinetics
- toxicology
these still need to be tested for using traditional methods
what is the path from a lead to a drug like?
the path from a lead to a drug is very long, expensive and has a high attrition rate
what is pain?
unpleasant sensory and emotional experience associated with actual or
potential tissue damage
what are the 3 components of pain?
- sensory
- emotional
- actual/potential tissue damage
what is the positive role of pain?
- warning of tissue damage
- immobilisation for healing
- protection of the species: establishment of memory
what are the physiological effects of pain?
- increased heart rate
- increased blood pressure
- increased respiratory rate
what is the classification of pain?
- acute pain
- cancer pain
- chronic non cancer pain
- nociceptive
- neuropathic
what are examples of acute pain?
post-op pain and non-surgical causes (most common)
what are examples of cancer pain?
palliative pain
what are examples of chronic non-cancer pain?
visceral and MSK pain
what is nociceptive pain?
inflammatory chemicals reach nerves to stimulate pain
what is neuropathic pain?
where the nerve is directly injured - pain originates in nervous system
what is acute pain?
- generally lasts less than a week
* results from the activation of sensory nerve fibres called nociceptors
what are nociceptors? what are some types?
- the nerve endings of the peripheral nervous system
- myelinated A delta fibres
- unmyelinated C afferent fibres
- located is most body tissues except the brain
what causes the experience of pain?
complex mix of activation of different afferent fibres types
what is the pain pathway?
- noxious stimulus
- nociceptors
- spinal cord (ascending pathway)
- spinal cord modulation
- thalamus
- cortical areas, somatosensory cortex and prefrontal cortex
- pain experience and memory
what is the excitatory neurotransmitter used in the pain pathway?
glutamate
what are noxious stimuli for pain?
- mechanical
- thermal
- chemical
how does tissue injury cause pain? what chemicals are involved?
- the breakdown of membrane lipids leads to the formation of arachidonic acid under the action of the enzyme phospholipase A2
- arachidonic acid is then converted to prostaglandins under the action of the enzyme cyclooxygenase (COX)
- prostaglandins are irritants to nerve fibres and stimulate pain
what do the products of arachidonic acid do to cause pain?
- prostaglandins
- act directly on the nociceptors (peripheral terminals of A delta and c fibres) and lower their threshold to thermal stimuli
- results in a sensation of burning at room temperature
what are the types of nerve fibres that transmit pain?
C fibres and A delta fibres
what are features of C fibres? what kind of sensation do they provide?
- unmyelinated
- characterised by diffuse dull intense pain
what are features of A delta fibres? what kind of sensation do they provide?
- small and myelinated
- conduct localised sharp sensation
what are the large nerve fibres that mediate pain?
A beta fibres
what are the small nerve fibres that mediate pain?
A delta fibres and C fibres
what is the gate control theory of pain?
- there is a balance of activity between large (A beta fibres) and small (A delta fibres and C fibres) fibres
- interneurons of the substansia gelatinosa regulate this input in Lamina V (dorsal horn of spinal cord)
- if A beta fibres are not stimulated by nociceptive stimulus then the pain signal goes through to the brain and is perceived
- if A beta fibres are stimulated then the pain signal is halted and does not reach the brain and is thus not perceived
- this means that low intensity stimulation of the skin or peripheral nerves or vibration in order to stimulate the A beta fibres will generate analgesia
what area in the spinal cord regulates nerve input of pain in the gate control theory?
interneurons of the substantia gelatinosa regulate the input in Lamina V (dorsal horn of the spinal cord)
what happens if A beta fibres are not stimulated, according to the gate control theory?
if A beta fibres are not stimulated by nociceptive stimulus then the pain signal goes through to the brain and is perceived
what happens if A beta fibres are stimulated, according to the gate control theory?
if A beta fibres are stimulated then the pain signal is halted and does not reach the brain and is thus not perceived
what stimulates analgesia, according to the gate control theory of pain?
low intensity stimulation of the skin or peripheral nerves or vibration which stimulates the A beta fibres will generate analgesia
what are applications of the gate control theory of pain?
- rubbing site of injury
- application of heat
- TENS - trans cutaneous nerve stimulation of A beta fibres
- spinal cord stimulation
what modulates gate control of pain?
higher centre inputs
what modulates higher centre inputs which modulate gate control of pain?
various neurotransmitters
what is the role of the periaqueductal grey and the locus cerulus in pain control?
- play key role in endogenous pain system
- they inhibit the firing of the dorsal horn neutron that
responds to noxious stimulus (gate control theory) - changing the levels of neurotransmitters at the level of synapses meaning less pain is transmitted
what is the role of periaqueductal grey in the endogenous pain control system?
- contains a high concentration of opiod receptors and endogenous opioids
- under situations of extreme stress this pathway can be
activated, resulting in the modulation of afferent noxious transmission - it projects to the dorsal horn
- once the dorsal horn is activated, opioid receptors are activated resulting in a reduction in pre-synaptic neuronal sensitivity (thereby reducing Substance P release) which in turn results in reduced pain sensation
- meaning less impulses travel up the first, second and third order neurones to the somatosensory cortex, meaning less pain is felt
what do opioid receptors do to control pain?
once the dorsal horn is activated, opioid receptors are activated resulting in a reduction in pre-synaptic neuronal sensitivity (thereby reducing Substance P release) which in turn results in reduced pain sensation
what is substance P’s role in pain?
release increases pain
how is the amount of pain felt reduced in endogenous pain control system?
- once the dorsal horn is activated, opioid receptors are activated resulting in a reduction in pre-synaptic neuronal sensitivity (thereby reducing Substance P release) which in turn results in reduced pain sensation
- meaning less impulses travel up the first, second and third order neurones to the somatosensory cortex, meaning less pain is felt
what are some endogenous opioid peptides?
- Enkephalin
- Dynorphine
- Beta endorphine: effect similar to morphine
what are examples of opioids?
opioids such as morphine, methadone, codeine and
oxycodone mimic this effect by binding to the opioid
receptors in the periaqueductal grey thereby conferring profound analgesia
what is the basis of pharmacological treatment of some pain?
- reducing excitatory neurotransmitters (glutamate) and excitation of the nerve (with respect to pain transmission)
- enhancing inhibitory neurotransmitters
what are examples of treatment which reduces excitatory neurotransmitters (glutamate) and excitation of the nerve (with respect to pain transmission)?
- basis for using anti epileptics
- local anaesthetics are Na+ channel blockers
what are examples of treatment which enhances inhibitory neurotransmitters?
- GABA is the main inhibitory neurotransmitter
- noradrenaline and serotonin are also inhibitory; used as basis for anti depressants
what are examples of inhibitory neurotransmitters?
- GABA is the main inhibitory neurotransmitter
- noradrenaline and serotonin are also inhibitory; used as basis for anti depressants
when are endorphins released?
in presence of pain
what are practical uses of endorphins?
- acupuncture - bearable pain
- placebo
- psychological modulation of pain
what are examples of pain medication?
• prostaglandins act directly on the nociceptors and reduce their threshold meaning normal stimuli can activate them resulting in a
sensation of pain (peripheral sensitisation)
• opioids
• local anaesthetics
what is the mechanism of action of local anaesthetics?
block the conduction of the nerve by blocking Na+ channels thereby preventing the depolarisation of the nerve and the propagation of an action potential
what is chronic pain?
ongoing persistent pain greater than 3-6 months
when does pain experience persist in chronic pain?
- beyond the usual course of an acute disease
- after healing/cure has taken place
what are features of chronic pain?
- ongoing persistent pain greater than 3-6 months
- recurs at intervals for months or years
- due to persisting stimulation in areas of ongoing tissue damage
- serve no useful biological function, but has profound effects on the patient and their family
what are the effects of chronic pain on the patient and their family?
- physical: immobility
- emotional: distress
- social: little social interaction leading to isolation
- economical: job issues
- day to day activity is severely affected
what are principles/aims of treatment of chronic pain?
- improve pain perception
- improve function/mobility
- improve sleep
- improve emotional and psychological consequences of pain
- improve quality of life
what is an adverse drug reactions?
a response to a drug which is noxious and unintended
what is the epidemiology of ADRs?
- occur in 10-20% of hospital patients
- cost the NHS £1 billion a year
- recognised as being associated with drug
what are features of a type A ADR?
Type A - augmented: • commonest • an extension of the clinical effect • predictable • dose related • self-limiting
what are examples of type A ADRs?
- diuretic causing dehydration
- anticoagulant causing bleeding
- drug for hypertension causing hypotension
who is more at risk for type A ADRs? why?
- those with renal or hepatic impairment are at a higher risk of ADR due to elimination difficulties i.e. have high blood plasma levels of the drug for longer
- also the elderly (above 65) are at higher risk since as you get older there is decreased glomerular filtration and hepatic impairment etc.
what are features of type B ADRs? what can cause them?
type B - bizarre • unexpected • unrelated to dosage and not expected from known pharmacological action • unpredictable • mostly immunological mechanisms • hypersensitivity • genetically linked
what is an example of a type B ADR?
heparin causing hair loss
when are type B ADRs more likely?
- those with predisposing factors such as; history of allergy, asthmatics and some family history are at greater risk
- can be seen in drugs that inhibit certain metabolic pathways
what are features of type C ADRs?
type C - chronic:
• occurs after long term therapy
• may not be immediately obvious with new medicines
what is an example of a type C ADR?
steroids predispose to hypoglycaemia - may result in diabetes
what are features of type D ADRs?
type D - delayed:
• also occurs after a long period of time after treatment (many years)
• common to see patient having treatment, then after 20-30 years they suffer an ADR
what are features of type E ADRs?
type E - end of use:
• relatively long term use (days/weeks)
• withdrawal reactions
• serious complication of stopping related to clinical effect
what does each letter of ABCDE ADRs stand for?
- A - Augmented
- B - Bizarre
- C - Chronic
- D - Delayed
- E - End of Use
what should be asked to identify what type of ADR it is? what does each thing indicate?
- is there a history of allergy? - Type B (Bizarre)
- is it predictable from the mechanism of action? does it seem dose-related? - Type A (Augmented)
- has the patient been using the medication for a long time? - Type C (Chronic)
- is the patient withdrawing from a medicine? - Type E (End of Use)
- has the patient uses a drug in the past that could be causing a problem now? - Type D (Delayed)
what patient history would indicate a type B ADR?
history of allergy
what patient history would indicate type A ADR?
reaction is predictable from mechanism of action and it seems dose-related
what patient history would indicate a type C ADR?
patient has been using medication for a long time
what patient history would indicate a type E ADR?
if patient is withdrawing from a medicine
what patient history would indicate a type D ADR?
if patient used a drug in the past that could be causing a problem now
what factors increase susceptibility to ADRs?
- age - elderly
- gender - more common in females
- pregnancy - negative effect on baby etc.
- disease - liver or renal in particular
- drug interactions
- diet or alcohol intake changes
- genetics
- hypersensitivity
what is a summary of the 4 types of hypersensitivity? what drugs can cause each?
- type 1: IgE-mediated drug hypersensitivity; anaphylaxis
- type 2: IgG-mediated cytotoxicity - some drugs can cause renal failure through this type
- type 3: immune-complex deposition; reacts with antibiotics
- type 4: T-cell mediated; usually substance containing metals
what is the mechanism of type 1 hypersensitivity?
- prior exposure to antigen (drug)
- virgin B lymphocyte activation to IgE producing plasma cells
- IgE becomes attached to mast cells, expressed as cell surface receptors
what are features of mast cells?
- monocyte in skin, sub mucosal, around blood vessels
- dormant indefinitely
- many are found in bronchial mucosa
- see a lot of mast cell activity beneath the skin, around lungs and blood vessels
what happens in mast cell degranulation?
cross linking of IgE receptors releasing:
- histamine
- thromboxanes, prostaglandins
- Tumour Necrosis Factor (TNF)
- all of above are acute inflammatory mediators
what does cross linking of IgE receptors release?
- histamine
- thromboxanes, prostaglandins
- Tumour Necrosis Factor (TNF)
- all of above are acute inflammatory mediators
what causes and features of non-immune anaphylaxis?
- not caused by any IgE antibodies
- due to direct mast cell degranulation
- previously called anaphylactoid reactions
- some drugs are recognised to cause this
- no prior exposure
- clinically identical to immune anaphylaxis
what are the main features of anaphylaxis?
- exposure to drug, immediate rapid onset
- rash with characteristic blotches
- swelling of lips, face, oedema, central cyanosis (go blue/purple)
- wheeze
- hypotension (Anaphylactic shock)
- cardiac arrest
what is an alternative presentation of anaphylaxis?
- cardiorespiratory arrest
- no skin changes
what is the management of anaphylaxis?
- commence basic life support: A (airway), B (breathing), C (circulation)
- specific/drug treatment
- effect of adrenaline
what are specific/drug treatments of anaphylaxis?
- stop drug if infusion
- adrenaline 1mg (10mls of 1:10,000 (IV)) 1ml IV increments - note: if cardiac arrest then may need to give cardiac massage in order to get drugs circulating
- IV anti-histamine (Chlorphenamine 10mg)
- IV Hydrocortisone (100 to 200mg) - note: unlikely to cause harm in excess so can’t really give too much
what are effects of adrenaline in anaphylaxis?
vasoconstriction, bronchodilation and increased cardiac output
what are medicine risk factors for drug hypersensitivity?
- protein or polysaccharide base macro molecules e.g. penicillin
- mono-clonal antibodies (proteins) can cause reactions
what are host risk factors for drug hypersensitivity?
- more common in females compared to males
* immunosuppression
what are genetic risk factors for drug hypersensitivity?
certain HLA groups (gene that encodes major histocompatibility complex (MHC))
why is drug allergy over-diagnosed?
- drug allergy is a highly specific term clinically; local rash, local swelling - specific
- GI upset (from NSAIDs) is not allergy
- type A (Augmented) is not allergy, but some people can be more sensitive e.g. more likely to develop hypotension with anti-hypertensives
what should be done if an ADR is suspected?
- elicit a full medication history and previous reactions
- check useful sources to find if ADR is described e.g BNF, eMC, Medicine Information Centres and MHRA (medical health regulation agency)
- identify markers
what are some identity markers of a type A ADR?
serum concentration - plasma monitoring
what are some identity markers of a type B ADR?
- tryptase - released from only mast cells; best test to confirm allergy based ADR
- urine methylhistamine; breakdown product of histamine
what can be done if a patient has an ADR?
- continue the drug and manage the ADR by other means
- reduce the dose of the drug
- stop the drug
how are type A ADRs managed?
- dose-related
- may respond to dose-reduction or temporary withdrawal
- severe reactions may require active treatment
how are type B ADRs managed?
- not usually dose-related
- should usually withdraw the medicine immediately
- give supportive treatment if the reaction is severe e.g. anaphylaxis
how are ADRs reported?
- MHRA Yellow-card scheme is the main method of surveillance of ADRs
- can complete it; online, by post or by telephone
what should you support in an ADR yellow card?
- all suspected ADRs for new medicines
- all ADRs in children
- all serious reactions, even if well-documented to include
what symptoms should be reported on an ADR yellow card?
- fatal
- life threatening
- disabling
- incapacitation or resulting in prolonged hospitalisation
what is synergy?
where the actions of 2 drugs combine
what are examples of synergy?
- clavulanic acid and amoxil to make augmentin
* paracetamol and codeine to increase analgesic effect
what is antagonism?
where one drug blocks the action of the other
what are patient risk factors for drug interactions?
- polypharmacy - on many different drugs
- old age
- genetics - e.g. slow/fast metabolism
- hepatic disease
- renal disease
what are drug risk factors for drug interactions?
- narrow therapeutic index
- steep dose/response curve
- saturable metabolism - e.g. paracetamol and alcohol are metabolised at a set rate
what are components of absorption in pharmacokinetics?
- motility
- acidity
- solubility
- non-absorbed complex formation
- direct action on enterocytes
how does motility in drug absorption affect drug interaction?
- erythromycin increases gut motility
- oral contraceptive pill and antibiotics have the commonest interaction causing motility changes
how does acidity in drug absorption affect drug interaction?
often with antacids and proton pump inhibitors - these change the pH of the stomach so if taking with other medication it can alter absorption of the drug
how does solubility in drug absorption affect drug interaction?
eating avocado (high in fat) and taking a fat soluble drug e.g. anti-coagulant then will dissolve the drug meaning there will be little or no drug absorption
how does non-absorbed complex formation in drug absorption affect drug interaction?
large complexes in intestinal lumen - cholestyramine and thyroxin, warfarin or digoxin
how does direct action on enterocytes in drug absorption affect drug interaction?
grapefruit juice inhibits P-glycoprotein resulting in the
increased uptake of certain drugs
how does protein binding in drug distribution affect drug interaction?
- affects drug concentration in plasma thus reduces distribution thus less available to have effect
- occurs with sulphonamide antibiotics and warfarin
how does CYP450 inhibition work?
- drug A (inhibits CYP450) blocks metabolism of drug B, leaving more free drug B in the plasma - increase effects
- note: in pro-drugs if metabolism is blocked then will be a decreased effect
how does CYP450 induction work?
- drug C induces CYP450 isoenzyme, leading to increased metabolism of drug D resulting in decreased therapeutic effects
- note: in pro-drugs if metabolism is increased then there will be increased therapeutic effects
how does grapefruit juice affect CYP450 metabolism?
affects CYP3A4 resulting in increased bioavailability thus this can make a drug more effective
where can drugs be excreted from?
renal and biliary
what are features of renal drug excretion?
- renal excretion is pH dependent
- weak bases - cleared faster if urine is acidic
- weak acids - cleared faster if urine is alkali
- can alter pH of urine to alter excretion
what are examples of drugs that are weak acids?
- aspirin - try to alkalinise urine to help increase excretion with aspirin overdose
- ibuprofen
- paracetamol
- warfarin
what are examples of drugs that are weak bases?
- amphetamine
- atropine
- propranolol
- salbutamol
what are types of pharmacodynamic mechanisms of drug interactions?
- receptor based
- signal transduction
- physiological systems
what are examples of agonists that cause drug interaction?
- bind to receptor
- for example, alcohol and benzodiazepine at GABA A receptor
what are examples of partial agonists that cause drug interaction?
- partially bind/activation at receptor
- for example buprenorphine for opioid addiction
what are examples of antagonists that cause drug interaction?
- block receptor
- can be competitive and non-competitive
- for example beta-blockers and asthma (competitive)
- never give beta-blockers to asthmatics since they will be on beta-agonists to help with bronchodilation, if using beta-blockers then will cause bronchoconstriction and increased risk of asthma attack
what are examples of signal transduction that causes drug interaction?
- rarer but examples exist
- commencing beta-blockers in a diabetic resulting in action at beta3 receptors in adipose tissues which normally detect and alter blood glucose, but action at B2 receptors can suppress hypoglycaemic awareness so they will not detect fall in glucose as well
what are examples of physiological systems that cause drug interaction?
- different drugs that effect different receptors, but in the same physiological system
- Ca2+ channel antagonists and beta-blockers
- ACE inhibitors and NSAIDs have a degree of nephrotoxicity
how do digoxin and furosemide interact?
- digoxin works on cardiac fibres and its effect is increased if there are low levels of potassium in blood plasma
- furosemide is a diuretic that lowers arterial pressure but
favours the loss of potassium - this could lead to hypokalaemia, which could increase the toxicity of digoxin
how can you avoid drug interactions?
- prescribe rationally
- BNF
- medicines information service
what antiarrhythmic agents have major drug interactions?
amiodarone
what antihistamines have major drug interactions?
terfenadine, diphenhydramine
what Ca2+ channel antagonists have minor drug interactions?
felodipine, nifedipine, nimodipine, nicardipine
what statins have major drug interactions?
simvastatin
what statins have minor drug interactions?
atorvastatin
what immunosuppressants have minor drug interactions?
cyclosporin, tacrolimus
what are some major drug interactions?
- amiodarone
- terenadine, diphenhydramine
- simvastatin
what are some major drug interactions?
- felodipine, nifedipine, nimodipine, nicardipine
- atorvastatin
- cyclosporin, tacrolimus
what is the effect of simvastatin in drug interactions?
rhabdomyolysis (muscle pain/breakdown)
what does simvastatin affect the breakdown of in drug interactions?
itraconazole, erythromycin, clarithromycin, diltiazem, verapamil, amiodarone
what is the advice for simvastatin in drug interactions?
20-200x increase in plasma concentrations
what is the effect of warfarin in drug interactions?
bleeding
what does warfarin affect the breakdown of in drug interactions?
erythromycin, clarithromycin, tramadol, amiodarone
what is the advice for warfarin in drug interactions?
monitor INR at day 3, then weekly, up to 4 weeks post commencement
what is the effect of SSRIs in drug interactions?
serotonin syndrome
what do SSRIs affect the breakdown of in drug interactions?
tricyclic antidepressants, tramodol
what is the effect of triple whammy drug interactions?
renal failure
what do triple whammy drug interactions affect the breakdown of?
NSAID or COX2 inhibitor, plus ACEi, plus dehydration or furosemide
what are examples of food and drug interactions?
- avocado reduces effectiveness of warfarin; could increase risk of blood
clots - grapefruit juice increases effectiveness of calcium channel blockers and anti-rejection medication
- garlic increases anti-platelet activity so can increase risk of bleeding
- soya increases effectiveness of NSAIDs and warfarin so can increase risk of bleeding
- ginger reduces effectiveness of anticoagulants so increases risk of bleeding
what is required for a prescription?
- diagnosis
- drug treatment
- indications and contraindications
- peculiar properties of either the diagnosis or drugs:
• does it require plasma monitoring?
• is there a risk of drug interaction? - patient name
- dose
- route
- frequency
- duration
- total number of tablets
- drug name
- date and signature
what is the prescribing pathway for patients at home and then in hospital admission?
- home: current medications, self prescribing?
- hospital admission: continue home meds, investigation, diagnosis
- inpatient: new treatment?
- discharge from hospital: pre-admission drugs, new prescription
what is the error potential in prescribing?
- home: drug history and pharmacy printout
- hospital admission: inpatient prescription chart
- inpatient: multi-disciplinary prescribing
- discharge from hospital: take home medication or not and discharge summary to GP
what are potential sources of error in prescribing?
- the number of different times the same information is translated or transposed
- information on admission
- duplication; paper, different teams
- clerical/legibility/ administration errors
- emergency situations
how can prescribing error happen?
- are avoidable; is classed as neglect
- carelessness since staff generally have the appropriate knowledge but do not use it at the time
- ward pharmacists check prescriptions carefully but only do daily checks - not continuous
- specify whether IV or intrathecal (spinal cord); can be confused easily leading to spinal cord damage
what drugs actually contain paracetamol?
beware that drugs with co-something-amol actually contain paracetamol, so inform patients of this because they might supplement this with more
paracetamol leading to a potential paracetamol overdose - need to be
careful
what drugs contain penicillin?
tazocin and augmentin
how can regular home medications be prescribed safely?
- withdrawal reactions if stopping most long term drugs; analgesics, anti
hypertensives and anti depressants - the vast majority of drugs should be continued unless there is a specific reason related to the presenting complaint
how should drugs be discontinued before surgery?
- nil by mouth policy for fluids is 2 hours, due to fear of aspiration under anaesthesia
- a sip of water with tablets is OK; can safely have a small drop of water for the taking of medications prior to surgery
what are the drugs which the patient should discontinue before surgery?
- ACE inhibitors, losartan (angiotensin receptor blocker)
- warfarin should be bridged to heparin (easier to manage dosage since injected)
- diabetes drugs - a detailed guidance proforma for this exists
how much of the population can’t metabolise morphine?
10%
what is morphine? what are features of it?
opioid receptor agonist
• the oral bioavailability of morphine is about 50% due to liver metabolism
• in 10% of the population codeine won’t work and in 10% it works too well
what are variants of morphine?
- naturally occurring opioids from the opium poppy (contains both morphine and codeine)
- simple chemical modifications
- synthetic opioids
- synthetic partial agonists
- antagonists
what are some naturally occurring opioids from the opium poppy?
- morphine
* codeine (weak)
what are some simple chemical modification variants of morphine?
- diamorphine (heroin)
- oxycodone
- dihydrocodeine (more predictable than codeine)
what are some synthetic opioids?
- pethidine
- fentanyl (very potent)
- alfentanil (very potent)
- remifentanil (very potent)
what are some synthetic partial agonists?
buprenorphine - if overdose there is no respiratory depression
what is a morphine agonist?
naloxone - give to reverse overdose
what are routes of administration of morphine?
- oral (simplest route)
- 10mg orally is equivalent to 5mg parenterally (subcutaneous, intramuscular and IV)
- single dose of morphine lasts 3-4 hours
- subcutaneous
- IV
what are features of oral administration of morphine?
• 50% of oral morphine is metabolised by first pass metabolism in the liver
• give half the dose if giving parenterally (sub-cutaneous,
intramuscular and intravenous (IV))
how long does a single dose of morphine last?
3-4 hours
what is the intravenous administration of morphine?
• fastest mode of administration, once given it will go around the whole
body in one minute
• will take 5 minutes for morphine to reach brain
what are features of IV patient controlled analgesia?
- dose can be self-administered by patient every 5 minutes with lockout
- safe since the patient will sleep before the onset of respiratory depression
- danger if somebody else presses the button for delivery e.g. grandchildren
what are features of diamorphine?
more potent and faster acting (crosses BBB quickly)
how do opioids work? how do they relieve pain?
- opioid drugs simply use the existing pain modulation system - natural endorphins (endogenous morphine) and enkephalins
- G protein coupled receptors act via second messengers
- they inhibit the release of pain transmitters at spinal cord and midbrain and modulate pain perception in higher centres - euphoria - to change the emotional perception of pain
- opioids block descending pain transmission
- they were never designed for sustained activation; designed only to be used for 30 minutes or so
- sustained activation leads to tolerance and addiction
what are the different opioid receptors?
- greek letter μ for morphine (MOP)
- soon after delta (DOP) and kappa (KOP) receptors were identified
- more recently the nociceptin opioid-like (NOP) receptor was identified
what is the aim of opioid development?
aim of opioid development is to develop opioid analgesic without the side effects of respiratory depression or addiction
what do kappa agonists cause?
mental depression instead of euphoria
where are opioid receptors located?
- midbrain
- spine
- GI tract - can get constipated with opioid use
- breathing centre - it communicates using opioid receptors, opioid use can cause respiratory depression
what is potency?
whether a drug is ‘strong’ or ‘weak’ - relates to how well the drug binds to the receptor - the binding affinity
what are the potencies of different opioids?
- diamorphine - 5mg (twice as potent as morphine)
- morphine - 10mg
- pethidine - 100mg (10 times weaker than morphine)
what is efficacy?
• is it possible to get a maximal response with the drug or not?
• or if all the receptor sites are occupied, do you get a ceiling
response?
• the concept of full or partial agonists (e.g. buprenorphine)
what is opioid tolerance?
• down-regulation of the receptors with prolonged use
• need higher doses to achieve the same effect
• can develop with continued morphine use due to the
desensitisation of μ receptors
how does naloxone affect morphine?
• morphine given with naloxone (antagonist) will reduce the efficacy of morphine since naloxone is a competitive receptor antagonist • given to correct morphine overdose
what is opioid dependence?
- psychological - craving of euphoria
* can be physical
what are features of opioid withdrawal?
begins within 24 hours, lasts about 72 hours - can give methadone to provide a slower and thus safer reduction in opioid
what are side effects of opioids?
- opioid receptors exist outside the pain system e.g. digestive tract and respiratory control centre
- respiratory depression
- sedation
- nausea and vomiting
- constipation
- itching
- immune suppression
- endocrine effects
- different patients have quite a range of sensitivity to opioids - start with small dose and titrate up as necessary
what is the treatment of opioid-induced respiratory depression?
- A (airway), B (breathing), C (circulation)
- administer naloxone - IV is fastest route - 400 micrograms per ml
- titrate to effect - don’t give all at once - once a drug has been injected you cannot get it back! - dilute 1ml in 10ml saline
- naloxone has a short half-life so give a depot of naloxone, some IV and some subcutaneous - so if the naloxone wears off then the depot will maintain levels
how are opioids used in chronic non-cancer pain?
- opioids for non-cancer pain start to lose effectiveness fairly quickly (within weeks)
- addiction to the drug leads to manipulative behaviour - easy to start but can be very difficult to get patient off them
what is the pharmacogenetics of codeine?
- codeine is a prodrug; it needs to be metabolised by cytochrome CYP2D6 to work
- CYP2D6 activity is decreased in 10-15% of the caucasian population, so
codeine will not be as effective - CYP2D6 activity is absent in 10% of the caucasian population meaning
codeine will have no effect - CYP2D6 is overactive in 5% of the caucasian population - these individuals may be at increased risk of respiratory depression with codeine; this is the reason why codeine is banned from children and breast feeding mothers in case they are in the 5%
what is the metabolism of morphine? what is its active metabolite?
- morphine is metabolised to morphine-6-glucuronide which is more potent than morphine
- morphine-6-glucuronide is renally excreted and will build up and cause respiratory depression in renal failure
what is the metabolism of pethidine? what is its active metabolite?
pethidine is metabolised to norpethidine which is epileptogenic and will build up and cause fits in renal failure
