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principles of disease > drug therapy week 9 > Flashcards

drug therapy week 9 Flashcards

1
Q

what is the pharmaceutical process in drug therapy

A

getting the drug into the patient

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2
Q

what is the pharmacokinetic process in drug therapy

A

getting the drug to the site of action

think kinetic = move to site

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3
Q

what is the pharmacodynamic process in drug therapy

A

producing the right pharmacological effect

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4
Q

what is the therapeutic process in drug therapy

A

producing the correct therapeutic effect

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5
Q

what is the difference between Pharmacokinetics and pharmacodynamics

A
  • pharmacokinetics is what the body does to medications (affected by absorption, distribution, metabolism and elimination)
  • pharmacodynamics is what the medication does to the body
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6
Q

what is the importance of studying pharmacokinetics and pharmacodynamics

A
  • individualise patient drug therapy
  • decrease the risk of adverse effects while maximising pharmacologic response to medications
  • so maximum benefit with minimum risk or toxicity
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7
Q

what are the four basic factors that determine drug pharmacokinetics

A
  • absorption
  • distribution
  • metabolism
  • elimination
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8
Q

what are some ways drugs can be absorbed to enter the blood stream

A
  • oral
  • subcutaneous
  • intramuscular
  • other GI = sublingual, rectal
  • inhalation
  • nasal
  • transdermal
  • IV is not absorbed!!!!!!!!! (bc it just goes straight into blood therefore not absorbed into blood)
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9
Q

what is the Tmax

A

time to peak concentration

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10
Q

what is the Cmax

A

peak concentration

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11
Q

what does the area under the drug concentration time curve tell you (AUC)

A
  • gives you an idea about the bioavailability of the oral drug which is the amount of the drug which is absorbed and reaches the blood stream
  • also tells us about the spread at which this happens
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12
Q

does increasing dose change the Tmax and Cmax

A
  • does not reduce the time at which peak concentration is reached (so does not reduce Tmax)
  • increases the peak concentration (increases Cmax)
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13
Q

what is the therapeutic index

A
  • a measure of the range over which a drug is safe and active
  • above the therapeutic range toxicity occurs
  • below the therapeutic range there will be insufficient or no pharmacological action
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14
Q

what does the area under the curve in drug therapy allow us to estimate

A

the amount of the drug which reaches the systemic circulation and which is available for action
(BIOAVAILABILITY)
- a drug which is given via IV has 100% bioavailability

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15
Q

what happens to the drug when it is swallowed

A
  • dissolution (when the tablet or capsule breaks down)
  • absorption
  • so when a drug is given orally some of it won’t be absorbed or some of it will be metabolised and so will not reach circulation
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16
Q

what are the factors affecting oral absorption bioavailability (amount of drug which reaches circulation)

A
  • formulation (whether capsule, solution, etc.)
  • ability of drug to pass physiological barriers (e.g. particle size, lipid solubility, degree of ionisation)
  • gastrointestinal affects (gut motility, food, illness, taking medicine with food or illness may decrease absorption)
  • first pass metabolism
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17
Q

what are the different types of transport across membranes

A
  • passive diffusion (remember ions can’t diffuse across membrane)
  • protein mediated transport
  • filtration (normally occurs through channels in membrane i.e. movement of water)
  • bulk flow (of liquid is through inter-cellular pores and is the major mechanism through which drugs cross the capillary walls)
  • facilitated diffusion
  • ion-pair transport
  • endocytosis
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18
Q

what is the effect of ionisation on the diffusion of drugs across the membrane

A
  • most drugs do not completely ionise in water
  • most drugs are weak acids or bases
  • both ionised and un-ionised forms will be present, the ionised drug does not cross the membrane
  • the un-ionised form should distribute across the membrane until equilibrium is reached
  • highly ionised drugs are not well absorbed across the membrane
  • although it isn’t that simple e.g. aspirin is weak acid so should be absorbed more easily from the stomach due to the pH but there are other factors to consider such as surface area, so aspirin is actually absorbed from the small intestine even though it is more ionised and less lipid soluble
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19
Q

what is the lipid-water partition coefficient

A

the ability of a drug to diffuse across a lipid barrier (must be lipid soluble to bass barrier)

  • a drug that is highly lipid soluble will rapidly diffuse across a cell membrane
  • a drug that is not lipid soluble may not be absorbed at all e.g. gentamicin
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20
Q

what are the gastrointestinal factors affecting the absorption of drugs

A
  • gut motility (speed of gastric emptying will affect speed at which drug reaches site of absorption, most drugs absorbed in the small intestine, if gastric emptying delayed then absorption delayed)
  • food (can enhance/impair rate of absorption)
  • illness (malabsorption, e.g. coeliac, can increase or decrease rate of absorption, migraine reduces rate of stomach emptying and therefore rate of absorption reduced)
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21
Q

what is first pass metabolism

A
  • the metabolism of drug prior to reaching systemic circulation
  • can be a limit on oral route for some drugs (e.g. insulin)
  • gut lumen (acid, enzymes)
  • gut wall (metabolic enzymes)
  • liver (cytochrome P450 enzymes)
  • these factors can be changed by drugs and disease
  • so first pass metabolism can occur in gut lumen, gut wall or liver
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22
Q

how can you avoid first pass metabolism

A
  • easiest way is giving patient drug that doesn’t undergo first pass metabolism
  • or change route of administration
  • subcutaneous and intra-muscular
  • inhalation and nasal
  • sublingual absorption from the buccal muscosa
  • rectal
  • transdermal
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23
Q

what is drug distribution

A
  • once a drug has been absorbed it must be available for biological action and distribution to the tissues
  • to be active a drug must then leave the blood stream and enter the inter or intra cellular spaces
  • drug distribution refers to the reversible transfer of a drug between the blood and the extra vascular fluids and tissues of the body (e.g. fat, muscle, brain tissue)
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24
Q

what are the mechanisms of distribution of drugs to the tissues

A
  • plasma protein binding
  • tissue perfusion
  • membrane characteristics (blood brain barrier, blood-testes/ovary barrier)(lipid soluble drugs, actively transported)
  • transport mechanisms
  • diseases and other drugs (esp. renal failure, liver disease, obesity
  • elimination
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25
Q

what is the important rule associated with plasma protein binding

A

only un-bound drug is active!!!!!!!

- drug that is bound to protein is inactive

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26
Q

what can the amount of unbound (active) drug be changed by in plasma protein binding in drug distribution

A

amount of unbound drug can be changed by:

  • renal failure
  • hypoalbuminaemia
  • pregnancy
  • other drugs
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27
Q

what is plasma protein binding in drug distribution

A
  • many drugs (e.g. phenytoin, warfarin, NSAIDs) bind to plasma proteins such as albumin or alpha 1 glycoprotein
  • only unbound drug is active
  • binding is reversible
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28
Q

why is plasma protein binding important to think about in drug distribution

A
  • for this to be an important factor, the drug must be more than 90% bound and the tissue distribution small
  • e.g. if a drug is 96% bound, only 4% of drug is free and available for action, if unbound drug levels change to 6% then plasma levels of free drug will increase by 50% which will result in toxicity
  • reasons for increase in level of unbound drug may be renal failure, acidosis, the addition of another medication which is also highly protein bound (e.g. adding NSAIDS to warfarin, NSAIDS displace warfarin from protein so too much warfarin active, women almost bleeds out because warfarin is blood thinner)
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29
Q

what is the apparent volume of distribution (Vd)

A
  • the volume of plasma that would be necessary to account for the total amount of drug in a patient’s body, if that drug were present as the same concentration as found in the plasma (expressed in litres per kilogram)
  • e.g. give patient 1000mg of drug, take blood sample, conc. is 50mg per litre, so Vd is 1000mg/50mg = 20 litres
  • the greater the Vd the greater the ability of the drug to diffuse into and through lipid membranes
  • if it stays in the extracellular fluid but can’t penetrate cells = 12 litres
  • if highly protein bound = 3 lites (warfarin)
  • if sequestered in extravascular lipid compartment > 40 litres (THC, lithium)
  • if the Vd is larger than 42 litres then the drug is thought to be distributed to all tissues in the body, especially the fatty tissue
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30
Q

what are important parameters relating to the therapeutic range

A
  • volume of distribution (Vd)
  • clearance (Cl)
  • half life (t1/2)
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31
Q

what is clearance (Cl) in drug distribution

A
  • the theoretical volume from which a drug is completely removed over a period of time
  • measured in ml/min
  • measure of drug elimination
  • dependent on drug conc. and urine flow rate for renal clearance
  • dependent on metabolism and biliary excretion for hepatic clearance
  • disease states and age (young and elderly) will reduce hepatic and renal clearance
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32
Q

what is half life in drug distribution

A
  • the time taken for the drug concentration in the blood to decline to half of the current value
  • if we know the volume of distribution and clearance we can show that half life, t1/2 = 0.693Vd/Cl
  • prolongation of half life will increase the plasma levels and hence the toxicity of a drug (due to reduction in clearance or due to a large volume of distribution)
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33
Q

what are the effects of chronic administration of a drug

A
  • to have a therapeutic benefit most drugs need to be given chronically
  • plasma levels of a drug take many doses before they stabilise, usually 4-5 half lives
  • to get the drug levels into the therapeutic range a loading dose may be necessary
  • with chronic dosing of a drug, plasma levels rise progressively until they reach a steady state (talking over the space of about 10 hours here not months)
  • key thing is to ensure the steady state is within the therapeutic range
  • this means that we have to be fairly certain of the dose and half life
  • so e.g. can’t give normal dose to someone who has impaired renal function because it will go into the toxic range
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34
Q

what factors can lead to an increase in the half life of a drug

A
  • age, obesity, pregnancy, malnourishment, hypoproteinaemia
  • liver disease, liver failure
  • renal disease, renal impairment, renal failure
  • congestive cardiac failure, hypotension
  • other medications
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35
Q

what is drug elimination

A
  • the removal of active drug and metabolites from the body
  • this determines the length and action of the drug
  • made up of two parts: drug metabolism (usually in liver) and drug excretion (usually in kidneys but also biliary system/gut, lung, milk)
  • so anything that disturbs drug metabolism or reduces drug excretion will lead to a build up of active drug metabolites in the body which will result in toxicity
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36
Q

what are the primary organs used for drug excretion and what are the mechanisms used by them

A

kidneys

  • three principal mechanisms used:
    1. glomerular filtration (most important)
    2. passive tubular reabsorption
    3. active tubular secretion
  • renal damage/impairment is therefore an important factor in causing drug toxicity
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37
Q

what is glomerular filtration

A
  • one of the mechanisms used for excretion of drugs via the kidneys (most important)
  • glomerulus filters about 190 litres of fluid a day
  • all unbound drugs will be filtered at the glomerulus as long as their molecular size, charge or shape are not excessively large
  • any factor that reduces the glomerular filtration rate will reduce the clearance of a drug and lead to prolongation of the half life and increasing bloods levels, hence toxicity
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38
Q

what is active tubular secretion

A
  • one of the mechanisms of drug excretion via the kidneys
  • some drugs are actively secreted into the proximal tubule (acidic and basic compounds)
  • this is the most important system for eliminating protein bound cationic and anionic drugs
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39
Q

what is passive tubular reabsorption

A
  • one of the mechanisms of drug excretion via the kidneys
  • as the filtrate moves down the renal tubule any drug present is concentrated as water is reabsorbed
  • passive diffusion along the concentration gradient allows the drug to move back through the tubule into the circulation
  • passive diffusion occurs in the distal tubule and collecting duct
  • only un-ionised drugs such as weak acids are reabsorbed
  • can also be affected by renal failure
  • the other key issue about this process is that drugs which are nephrotoxic, when filtered at the glomerulus may become increasingly concentrated as water is reabsorbed from the renal tubule and this in turn can lead to nephrotoxicity thus reducing renal function and so further prolonging the half life of the drug causing renal toxicity
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40
Q

what is biliary secretion

A
  • the liver secretes 1 litre of bile a day
  • drugs may be passively or actively secreted into the bile
  • biliary secretion accounts for 5-95% or drug elimination for many drugs
  • a number of drugs are then reabsorbed from the bile into the circulation, this is called enter-hepatic circulation
  • it continues until the drug is metabolised in the liver of excreted by the kidneys
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41
Q

what is one of the effects of a damaged liver in relation to conjugation and biliary secretion

A
  • metabolism in the liver often leads to conjugation of the drug to make it more water soluble
  • the conjugated drug is not reabsorbed from the intestine (so has to be excreted)
  • damage to the liver may reduce the rates of conjugation and biliary secretion so allow the build up or reabsorption of the drug with resultant toxicity
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42
Q

what is metabolism of drugs

A
  • an essential pharmacokinetic process which limits the life of a substance in the body
  • makes lipid soluble and non-polar compounds water soluble and polar so they can be excreted
  • this is because only water-soluble substances undergo excretion, whereas lipid soluble substances are passively reabsorbed from renal or extra-renal excretory sites back into the blood
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43
Q

what feature does a substance have to have to be excreted and not reabsorbed

A
  • substance has to be water soluble (and polar)

imagine pee out, pee water

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44
Q

where are the sites of metabolism

A

almost all drugs are metabolised before they are excreted, important sites are…

  • liver (main site)
  • lining of the gut
  • the kidneys
  • the lungs
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45
Q

what is the purpose of metabolism

A
  • deactivate compounds (may involve a number of steps)
  • to increase water solubility and so aid excretion
  • however some drugs need activation by metabolism (prodrugs) or form active metabolites following metabolism
  • some prodrugs are codeine, ramipril, simvastatin
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46
Q

what is a prodrug

A

a drug that needs activation via metabolism

e.g. codeine, ramipril, simvastatin

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47
Q

what is the active form of codeine and how does it become activated

A
  • active form of codeine is morphine
  • codeine is metabolised to form morphine and then in further metabolised to deactivate it
  • need enzyme called CYP2D6 to metabolise it
  • some individuals have absent CYP2D6 enzymes and so won’t be able to benefit from codeine
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48
Q

what is the enzyme need to metabolise codeine and what does codeine metabolise to

A
  • codeine metabolises to morphine

- CYP2D6 enzyme need to form morphine from codeine

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49
Q

what are the effects of metabolism

A
  • loss of pharmacological activity
  • decrease in activity, with metabolites that show some activity
  • increase in activity, more active metabolites (activation of a pro drug)
  • some metabolites can be toxic, carcinogens or teratogens (teratogens cause birth defects)
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50
Q

how many phases are there in metabolism

A 
2 phases (phase 1 and 2)
phase 1 = oxidation, reduction, hydrolysis 
phase 2 = glucuronidation
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51
Q

what is the result of phase 1 of metabolism

A

end up with activation or deactivation

52
Q

what is the result of phase 2 of metabolism

A

end up with conjugated products

water soluble

53
Q

what are the phase 1 metabolism reaction

A
  • oxidation
  • reduction
  • hydrolysis
54
Q

what is the most important super family of metabolising enzymes

A
  • cytochrome P-450 enzymes
  • drug specificity is determined by the isoform of the cytochrome P-450
  • involved in phase 1 metabolism
55
Q

what is CYP3A4

A
  • involved in phase 1 oxidative metabolism
  • CYP3A4 is the major constitutive enzyme in human liver and contributes to the metabolism of a wide range of drugs
  • it is also found in the gut and is responsible for the pre-systemic metabolism of several drugs such as diazepam, methadone, simvastatin, CCBs
56
Q

what is CYP2D6

A
  • involved in phase 1 oxidative metabolism
  • responsible for the metabolism of some antidepressants, antipsychotics and the conversion of codeine to morphine
  • reduced or absent expression is found in 5-10% of the population which means that 5-10% may be immune to the analgesic actions of codeine
57
Q

what is CYP1A2

A
  • involved in phase 1 oxidative metabolism
  • induced by smoking and is important in the metabolism of theophylline
  • therefore smokers require a higher dose of theophylline than non-smokers
58
Q

what enzymes in metabolism does smoking induce

A
  • CYP1A1
  • CYP1A2
  • CYP2E1
  • uridine diphosphate glucuronyl-transferase
  • induction by smoking may be important in psychiatric patients bc smoking is more common and the levels of their drugs will rise to toxic level bc too much metabolised
59
Q

what is phase 2 metabolism of drugs

A
  • involves conjugation
  • conjugation increases the water solubility and enhances excretion of the metabolised compound
  • conjugation involves the attachment of glucuronic acid, glutathione, sulphate or acetate to the metabolite generated by phase 1 metabolism
  • conjugation usually results in inactivation however a small number of drug metabolites may be active
  • pattern is either (parent molecule > phase 1 metabolism > phase 1 metabolite > phase 2 metabolism) or (parent molecule > phase 2 metabolism > phase 2 metabolite > phase 1 metabolism)
60
Q

what are some factors which affect metabolism

A
  • other drugs/herbals/natural substances
  • genetics
  • hepatic blood flow
  • liver disease
  • age
  • sex
  • ethnicity
  • pregnancy
61
Q

what happens if enzymes in drug metabolism are induced

A
  • induction of an enzyme involves increased enzyme synthesis and therefore increased activity
  • if enzyme activity is enhanced due to enzyme induction then the plasma concentration will fail to rise into the therapeutic range and will remain in the ineffective area causing failure of therapy
62
Q

what are some things that can induce metabolic enzymes

A
  • can be induced by medicines, herbal medicines, food stuffs
  • most common enzyme inducers are alcohol and smoking
  • many drugs and herbals such as phenytoin, carbamazepine, rifampicin and St. John’s wort can also induce metabolising enzymes
  • process may take weeks
63
Q

how long enzyme inhibition and induction take

A
  • enzyme inhibition is almost instantaneous

- enzyme induction may take weeks or months

64
Q

what happens if enzymes in drug metabolism are inhibited

A
  • if metabolism is inhibited plasma levels will rise into the toxic region
  • many commonly used drugs, herbal medicines and food stages may conversely inhibit drug metabolising enzymes
  • may be reversible of irreversible binding to the enzymes
  • common inhibitors include erythromycin, calrithromycin, CCBs, grapefruit juice
65
Q

what is the problem with grapefruit juice and the metabolism of drugs

A
  • grapefruit juice is an inhibitor and so causes increase in plasma levels
  • the enzyme inhibitory effects are cumulative, the more the patient uses grapefruit juice the greater the inhibition of felodipine metabolism and so the greater the blood levels
  • may rise into toxic range
66
Q

what is the importance of pharmacogenetics and genetic polymorphisms in prescribing drugs

A
  • there is a wide variability in response to drugs between individuals, consequences of this may be therapeutic failure or adverse reaction
  • genetic polymorphisms are drug metabolising enzymes that can be expressed in multiple forms
  • can be expressed in multiple forms within the same individual and between different people
  • gene mutations can result in excess, deficiencies or complete absence of a particular metabolising enzyme activity
67
Q

what are the types of CYP2D6 polymorphisms

A
  • approx. 70 nucleotide polymorphisms are known
  • four phenotype subpopulations of metabolisers:
    1. poor metabolisers (caucasians, 6-10%)
    2. intermediate metabolisers
    3. extensive metabolisers
    4. ultrarapid metabolisers (south asian/ethiopian, 20-30%)
  • ultrametabolisers will require higher doses
68
Q

what are the issues with CYP2C9 polymorphisms

A
  • metabolises some 16 commonly used drugs
  • warfarin, phenytoin and NSAIDS are among the substrates
  • two allelic variants known
  • warfarin clearance is greatly reduced in individuals possessing the allelic variants
  • dose adjustments are required for drugs in individuals who have the mutant enzymes
69
Q

what is the effect of age on drug metabolism

A
  • drug metabolising enzymes are often deficient or reduced in the foetus or premature infants
  • renal function is also deficient so drug and metabolites may rapidly build up to toxic levels
  • by the age of two children can metabolise many drugs more rapidly than adults
  • by puberty the rate of metabolism is greater than that of adults
  • in the elderly parameters such as plasma protein, lean body mass and liver weight decrease significantly and so alter drug metabolism
  • chronic disease in the elderly is also more common and so they are more likely to be on multiple drug therapy
70
Q

what is the effect of gender in drug therapy

A
  • sex-based differences have been found in all four pharmacokinetic areas: absorption, distribution, metabolism and elimination
  • responsiveness to certain drugs is different for men and women
  • pregnancy: the induction of certain drug metabolising enzymes occurs in second and third trimester
  • hormonal changes during development have a profound effect on drug metabolism
71
Q

what is the effect of race on drug metabolism

A
  • race may also effect drug metabolism

- there are many instances of racial differences in the genetic expression of cytochrome p450 isoforms

72
Q

what is a drug interaction

A
  • defined as the modification of a drug’s effect by prior or concomitant administration of another drug, herb, foodstuff, drink
73
Q

what is the ‘object drug’ and the ‘precipitant’ in drug interaction

A
  • the drug whose activity is altered by such an interaction is the object drug
  • the agent which precipitates an interaction is referred to as the precipitant
74
Q

what are the types of drug interaction

A
  • drug-drug interactions (DDI)
  • herb-drug interactions
  • food-drug interactions
  • drink-drug interactions
  • pharmacodynamic interactions (remember pharmacodynamics is response of body to drug)
75
Q

what are the different types of precipitants in drug interactions

A

factors (precipitants) which modify drug action include

  • drugs
  • food
  • smoking
  • alcohol
  • herbs
76
Q

what are some conditions that actually benefit from drug-drug interactions

A

commonly used in the treatment of:

  • hypertension
  • ischaemic heart disease
  • Parkinson’s with carbidopa and levodopa
77
Q

what are the risk factors for drug-drug interactions

A
  • advanced age
  • genetic polymorphisms
  • comorbidities
  • polypharmacy
  • narrow therapeutic range
  • dose
  • multiple prescribing physicians
  • self-prescription
  • prolonged hospital stay
78
Q

what are some possible types of pharmacodynamic interactions in drug interactions

A
  • antagonistic interactions
  • agonistic or synergistic interactions
  • indirect pharmacodynamic interactions
79
Q

what are some possible ways pharmacokinetic interactions can alter drug therapy in drug interactions

A

it is possible for one drug to alter:

  • absorption
  • distribution
  • metabolism
  • elimination of another drug
80
Q

how is absorption affected in drug interactions

A

Mechanisms:
- formation of insoluble complexes
- altered pH
- altered bacterial flora
- altered GIT motility
the interaction of drugs in the GI tract is complex
- most of these types of interactions result in changes in absorption rate rather than extent of absorption
- delayed absorption is important when a drug has a short half life or when we want to achieve therapeutic plasma levels rapidly
- most interactions result in delayed absorption which can be avoided if 2-4 hours are left between administration of the drugs

81
Q

how is distribution of drugs affected in drug interactions

A
  • after absorption drugs are distributed to site of action
  • protein binding to albumin and alpha 1-glycoprotein
  • protein binding displacement occurs when there is a reduction in the plasma protein binging of a drug caused by the presence of another drug
  • this results in increased bioavailability of the displaced drug which can result in toxicity
  • this type of interaction is common but patients may be protected from harm bu increased metabolism and excretion
82
Q

how is drug metabolism affected by drug interactions

A
  • metabolism commonly occurs in the liver via the cytochrome P450 system
  • drug interactions involving metabolism occur when one drug induces or inhibits the metabolism of another
  • induction may take weeks
  • inhibition usually takes hours
  • drugs such as clarithromycin, erythromycin, cimetidine, ketoconazole, omeprazole, CCBs inhibit the cytochrome P450 enzymes and so reduce or stop the metabolism of a large number of drugs
83
Q

what does st john’s wort do

A

induces CYP3A4

- so induces enzymes

84
Q

how is elimination/excretion affected by drug interactions

A
  • most drugs and metabolites are excreted in urine or bile
  • any changes in GFR or tubular excretion will result in altered drug levels
  • digoxin and lithium are toxic agents with a narrow therapeutic index which are eliminated by the kidney
  • inhibition of excretion leads to toxicity
85
Q

what are pharmacodynamic drug interactions

A 
- occur when the pharmacodynamic actions of a drug are changed due to the presence of another drug either acting directly on the same receptor or indirectly on different receptors
can be:
- direct 
- indirect 
- antagonistic 
- synergistic/agonistic
86
Q

what are direct antagonistic and synergistic pharmacodynamic interactions

A

direct antagonism:
- beta blockers such as atenolol will block the actions of beta agonists such as salbutamol
(direct means same receptor)
Synergistic interactions: when two drugs with the same pharmacological effect acting on different receptors are given concurrently (effects may be additive or multiplicative)

87
Q

what are indirect agonistic and indirect antagonistic pharmacodynamic interactions

A

indirect agonism:
- benzodiazepines and tricyclics or alcohol (profound sedation)
- warfarin and NSAIDS (profound bleeding)
- atenolol and verapamil (profound bradycardia)
Indirect antagonism:
- NSAIDS and anti-hypertensive medication
- NSAIDS and treatment for heart failure

88
Q

what is the difference between an adverse drug event and an adverse drug reaction

A
  • an adverse drug event occurs while a patient is taking a drug but is not necessarily attributable to it
  • an adverse drug reaction is a harmful of unpleasant reaction resulting from an intervention related to the use of a medicinal product
89
Q

what are the classifications of onset of an adverse drug reaction

A

onset of event:
acute - within 60 mins, e.g. bronchoconstriction
sub-acute - 1-24 hours, e.g. rash
latent - 2 days, e.g. eczematous eruptions

90
Q

what are the classifications of severity of an adverse drug reaction

A

mild - bothersome but requires no change in therapy, e.g. metallic taste
moderate - requires change in therapy, additional treatment or hospitalisation
severe - disabling or life threatening that result in persistent or significant disability or hospitalisation and that cause a birth defect

91
Q

what are the classifications of an adverse drug reaction

A
  • type A = augmented
  • type B = bizarre
  • type C = chronic
  • type D = delayed
  • type E = end of treatment
  • type F = failure of treatment
92
Q

what are the predisposing factors for an adverse drug reaction

A
  • multiple drug therapy
  • inter-current disease (e.g. additional disease, renal/hepatic impairment
  • race and genetic polymorphisms
  • age (elderly and neonates)
  • sex (ADRs more common in women)
93
Q

what it a type A adverse drug reaction

A
  • augmentation of the primary effect or there are secondary effects
  • easily reversible on reducing the dose or stopping the drug
  • not usually life threatening
  • type A reactions may be due to the secondary pharmacology of a drug unrelated to the therapeutic effect
  • e.g. dry mouth with tricyclic antidepressants or bronchospasm with beta blockers
94
Q

what are the reasons for having a type A adverse drug reaction

A
  • too high or low a dose
  • pharmacokinetic variation (ADME)(most type A are pharmacokinetic in nature)
  • pharmacodynamic variation
    (last two commonly occur as a result of disease)
95
Q

what is a type B adverse drug reaction

A
  • bizarre
  • unpredictable
  • rare
  • cause serious illness or death
  • may be unidentified for months or years
  • unrelated to the dose
  • not readily reversible
96
Q

what are some risk factors for type B adverse drug reactions

A
  • more common with macromolecules (proteins, vaccines, polypeptides)
  • patients with history of asthma and/or eczema
  • HLA status (HLA genes are highly polymorphic and presence increases risk for type B)
97
Q

what are the mechanisms for type B adverse drug reactions

A
  • idiosyncratic = inherent abnormal response to a drug, due to genetic abnormality such as enzyme deficiency (e.g. G6PD) or abnormal receptor activity
  • drug allergy or hypersensitivity = immunological, no relation to the pharmacological action of the drug, delay between exposure and ADR, manifests as rash, asthma, serum sickness, first dose acts as antigen then body produces antibody
98
Q

what is a type C adverse drug reaction

A
  • chronic/long term effects
  • related to duration of treatment as well as the dose and does not occur within single dose
  • it is semi-predictable (i.e if you treat a patient with high dose steroids for a long time they are likely to get Cushing’s disease)
99
Q

what is a type D adverse drug reaction

A
  • delayed effects
  • occur a long time after treatment
  • e.g. lymphomas increase in frequency in people who have had previous chemo for leukaemia
  • may be time related reactions i.e. due to prolonged use of a drug which doesn’t tend to accumulate
  • the delayed effects can be teratogens (birth defects), carcinogens (second cancers in those treated with alkylating agents or immunosuppressive agents)
100
Q

what are type E adverse drug reactions

A
  • end of treatment effects
  • adverse effects which occur when a drug treatment is stopped, especially suddenly, following long term use
  • e.g. unstable angina and MI when beta blockers are stopped, alcohol
101
Q

what is rebound phenomena

A
  • occur when a drug is suddenly withdrawn
  • alcohol
  • beta blockers
  • antidepressants
  • corticosteroids, etc.
  • so have to wean these patients off slowly
102
Q

what are type F adverse drug reactions

A
  • failure of therapy
  • common
  • dose related (dose often too low)
  • frequently caused by drug interactions
  • e.g failure of oral contraceptive when administered with hepatic enzyme inducers/antibiotics
103
Q

who is most at risk for an adverse drug reaction

A
  • age (children and elderly)
  • polypharmacy
  • comorbidity
  • inappropriate medication prescribing, use or monitoring
  • end-organ dysfunction
  • altered physiology
  • prior history or adverse drug reactions
  • genetic predisposition
104
Q

what is the yellow card reporting system/voluntary organised reporting system

A

allows anyone to report any adverse drug reactions

  • collects info on side effects, medical device adverse incidents, defective medicines, counterfeit or fake medicines or medical advice
  • anyone can report ADRs in yellow card system, doctors, parents, pharmacist, the public, etc.
105
Q

what is the intensive event monitoring system/green card system

A

chooses selective populations to be studied for a short time to see if there are any adverse drug reactions
- but it will only pick up ADRs for the medicines being studied at the time

106
Q

what are black triangle drugs

A
  • drugs which have been marked by the MHRA for data collection and adverse drug reaction reporting
107
Q

what does absorption or oral medication depend on and where does it occur most rapidly

A
  • absorption depends on gastric emptying

- occurs most rapidly in the small intestine

108
Q

what is a suspension formulation of a drug

A
  • drugs that don’t dissolve in liquid
  • dose can be contained in small volume
  • solutions and suspensions are absorbed rapidly
  • may be given via a nasogastric tube or PEG tube
109
Q

what is the rate limiting step in absorption of tablets and capsules and what are the advantages of tablets and capsules

A
  • dissolution or tablet/capsule breakdown is rate limiting step
  • advantages are: convenience, accuracy of dose, reproducibility of dose, drugs tend to be more stable in tablet/capsule form, ease of mass production
110
Q

what are enteric coated tablets

A
  • enteric coating delays disintegration of the tablet until it reaches the small intestine
  • tablets are enteric coated to protect the drug from stomach acid (omeprazole) or protect the stomach from the drug (aspirin)
111
Q

why is it important to use the same brand of medication

A
  • once patient is stable on long term medication important not to switch brands because risk of toxicity if you switch brands
112
Q

what is the advantage of prolonged or delayed release drug formulations

A
  • contains sufficient drug dose for 24hrs-4years
  • most disorders require prolonged therapy
  • maintains drug levels within the therapeutic range
  • reduces the need for frequent dosing
  • compliance is improved
  • improved nursing and doctor compliance
  • parenteral preparations mean administered anywhere but the mouth
  • surgical implant e.g. contraceptive
113
Q

what are the advantages of prodrugs

A
  • prodrugs are synthesised inactive derivatives of an active drug which need to be metabolically activated after administration
  • the advantages of prodrugs are prolongation of duration of action and avoidance of degradation of the drug in the gut
114
Q

what is the advantage of buccal and sublingual administration

A
  • buccal is inside of cheek in mouth
  • ideal method for drugs which have extensive pre-systemic or first pass metabolism
  • common example is GTN (angina medication)
115
Q

what is the advantage of the rectal route for drugs

A
  • drugs can be administered rectally to treat local conditions or to achieve systemic absorption
  • useful in patients unable to swallow
  • bypass pre-systemic metabolism
116
Q

what are the three injection based drug delivery systems

A
  • intravenous
  • intramuscular
  • subcutaneous
117
Q

when are drugs given intravenously

A
  • when we need a fast systemic effect bypassing first pass metabolism
  • the patient is unconscious or comatose
  • the drug must be infused continuously
  • we need careful control of plasma levels
  • IV can be given rapidly, slowly (to prevent toxic effects) or continuous infusion to ensure accurate control of blood levels especially when a drug has a narrow therapeutic index
118
Q

when is injection given intramuscular

A
  • the drug may be insoluble or formulated in an oil base (allows a more sustained duration of action up to months or good for stuff like contraceptives)
  • may be painful especially if frequent
    (no intramuscular to patients on anti-coagulants because they will bleed lots)
119
Q

when do you give injection subcutaneously

A
  • easy to use and bypasses need for venous access
  • used for insulin, heparin and narcotic analgesics
  • also used when gaining venous access has become difficult or distressing to the patient
  • dermojet is subcutaneous needleless injection
  • pellet implantation is solid pellet implanted under skin
120
Q

what is percutaneous drug administration

A
  • creams, ointments, skin patches
  • local effect or systemic effect
  • remember topical steroids may still have systemic effects even if given for local treatment
  • skin patches allow controlled sustained blood levels, allows bypass of first metabolism
121
Q

what are monoclonal antibodies

A
  • act directly when binding to a disease specific antigen and induce immunological response to cancer/immune cells
  • modified for delivery of toxin, cytokine or other active drug
  • wide applications in cancer therapy, rheumatoid arthritis, Crohn’s, psoriasis, etc.
122
Q

what are antibody drug conjugates

A
  • consist of a monoclonal antibody to a biologically active drug with a linker which is stable in the circulation
  • e.g. trastuzumab-emtansine targets HER2 and consists of the monoclonal antibody trastuzumab covalently linked to cytotoxic agent DM1 (treats breast cancer)
123
Q

what is liposomal drug delivery

A
  • drug inside hollow centre of liposome
  • prolongs serum and plasma half life
  • can achieve drug accumulation at disease sites and reduced distribution to sensitive tissues so enhanced efficacy and reduced toxicity
124
Q

what is nanoparticle based drug delivery

A
  • more specific drug targeting and delivery
  • reduction in toxicity
  • carbon nanotubes used in treatment of bronchial asthma (drug held inside tube)
  • gold nanoparticles used in cancer chemotherapy (drug on surface)
125
Q

what is CAR T cell immunotherapy

A
  • using patient’s own immune cells to treat their cancer
  • separate out T cells, then use disarmed virus, T cells are genetically engineered to produce receptors on their surface called chimeric antigen receptors (CARs) which target specific tumour antigens
126
Q

what are medication errors

A
  • broadly defined as any error in the prescribing, dispensing or administration of a drug, irrespective or whether such errors lead to patient harm
  • about 1/3 to 1/2 of adverse drug events are associated with medication errors
127
Q

how are medication errors classified into mistakes, slips or lapses

A

mistakes may be defined as errors in the planning of an action
- knowledge based = giving a medication without having established whether the patient is allergic
- rule based = misapplication of a good rule or application of a bad rule or the failure to apply a good rule
slips and lapses are errors in the performance of an action
- a slip = through an erroneous performance for instance writing up the incorrect medicine
- a lapse = through an erroneous memory such as giving a drug that a patient is already known to be allergic to

principles of disease (19 decks)

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