Pharmo Flashcards
What are some examples of problems with the patient and population that can result in poor prescribing?
Rapid patient turnover
Increased complexity of medical care
Increasingly older patients- more co-morbidities, on more medication, higher risk of side effects
Too many medical students needing to be trained with to enough staff
What are some examples of problems with the doctor that can result in poor prescribing?
No room for error
Expected to be perfect from day 1
Varying medical school experience- level of teaching or examination
On call medicine- results in sleep deprived, accident prone doctors
On call doctors- don’t know the patient, have to do routine boring jobs
Shift work- lack of continuity of care, working alone more often
Locum- doctors don’t have sufficient training, rules vary differently at different hospitals
What are some examples of problems with the pharmaceutical industry that can result in poor prescribing?
Vast numbers of new drugs
Clinical evidence for new drugs is usually with selected, healthier patients and/or young volunteers
Some side effects only come to light after the drug is on the market
Blind adherence to guidelines can lead to prescriptions where contraindications or serious interactions exist
What two models account for prescription errors?
Reasons model of error causation
Swiss cheese model of accident causation
What is Reasons model of error causation?
Latent conditions –> Error producing conditions –> Active failures –> Accident
(DEFENCES)
What is the Swiss cheese model of accident causation?
Cheese with holes in act as successive layers of defences, barriers and safeguards to hazards
Holes in the cheese represent active failures and latent conditions
When holes align and hazards persist you get losses
What is a latent condition?
Problem with the organisational processes and management decisions
What is an error producing condition?
Problems with the environment, team, individual and task factors that affect performance
What is an active failure?
Error- slips, lapses, mistakes
Violation
What are the defences?
Inherent within the system and the individual
Designed to protect against hazards and mitigate consequences of failure
Defences can be inadequate as a result of latent conditions
What is an error?
Failure of a planned sequence of actions to achieve a desired goal because an adequate plan was incorrectly executed (skill based slip or memory based lapse) or an inadequate plan was executed (rule based or knowledge based mistake)
What is a violation?
When rules of correct behaviour are consciously ignored
What is the basic checklist to reduce error? (15)
- Consider patient
- Correct chart for patient?
- Diagnosis and therapeutic aim?
- Right drug?
- Will illness affect drug distribution/elimination?
- Alternative drug?
- Patient on non-prescription medication?
- Appropriate route of administration?
- Correct dosage?
- Correct frequency and timing of drug?
- Duration of treatment?
- Most serious side effects?
- TDM required?
- How much info/ explanation does the patient need?
- Any special prescribing requirements for drug?
What things should we be clear on when deciding the right drug for a patient?
Avoid therapeutic duplication
Serious interactions that could lead to failure of treatment
Allergies
Drug spelt correctly
No abbreviation of drug names
Form of the drug- is it correct for the patient?
What is the role of the pharmacist in prescription administration?
Legal responsibility of pharmacist is to dispense according to prescription- if they suspect an error they must refer it back to the prescriber
What is formulary?
Previously was a list of formulae for compound medicines
Now is a List of recommended first line drugs for common medical conditions
What is the BNF?
More comprehensive listing all drugs currently licensed in the UK - widespread use in NHS
What three things must a drug show to be listed in the formulary?
Efficacy- how effective it is compared to similar drugs/ placebo
Safety- major and minor side effects
Cost- ONLY if efficacy and safety are equally equivalent
What is pharmacokinetics?
Study of the movement of a drug into and out of the body (what the body does to the drug)
What is pharmacodynamics?
Study of the drug effect and mechanism of action (what the drug does to the body)
What is pharmacogenetics?
Effect of genetic variability on the pharmacokinetics/ dynamics of a drug on an individual
What are the four broad stages of pharmacokinetics?
Absorption
Distribution
Metabolism
Elimination
Expand on absorption
In what form and route the drug is taken into the body and how this affects its action/effectiveness
How much of the drug is lost on entry into the body
BIOAVAILABILITY
What is bioavailability?
Fraction of a dose that finds its way into a body compartment (usually the circulation)
100% for IV bolus
How is bioavailability calculated?
For routes other than IV bolus (F= 100%)
Compare amount reaching the body compartment with IV bioavailability
F = AUC oral / AUC IV
What is bioavailability affected by?
Absorption- drug formulation, age, food (lipid sol > water sol), vomiting and malabsorption
First pass metabolism - gut lumens, gut wall, liver
What is first pass metabolism?
Any metabolism occurring before drug enters the systemic circulation
IN gut lumen (gastric acid, proteolytic enzymes, grapefruit juice, insulin), gut wall (P glycoprotein efflux pumps drugs out of intestinal enterocytes and back into the lumen - ciclorporin) and liver (propranolol)
Expand on distribution
A drugs ability to dissolve in the body
2 key factors- protein binding in systemic circulation and volume of distribution
What does protein binding refer to?
Drugs bind to albumin (acidic drugs), globulins (hormones), lipoproteins (basic drugs), acid glycoproteins (basic drugs)
Most drugs must be unbound/ free to have an effect
Changes in protein binding causes changes in drug distribution
- only important if: high protein binding, low Vd, narrow therapeutic ratio
Drugs bound or unbound to proteins are still ‘available’!!
What is meant by protein binding drug interactions?
Protein binding drug interactions - other drugs try to bind and displace drugs bound to proteins
What is protein binding affected by?
Hypoalbuminaemia
Pregnancy
Renal failure
Displacement by other drugs
What is the volume of distribution?
Drugs that are not bound to plasma proteins are available for distribution to tissues of the body - tissue fluid, or extensively bound to body tissues
Measure of how widely a drug is distributed in body tissues
Hypothetical but useful with dosing regimens
E.g. 100mg gentamicin dose –> peak plasma conc 5mg/ L has a Vd of 20L
Vd = dose (mg) / peak plasma conc (mg/L) [DRUG]t0
Half life is proportional to Vd
Apart from protein binding and Vd, what else is distribution affected by?
Specific receptor sites in tissues Regional blood flow Lipid solubility Active transport Disease states Drug interactions
Expand on drug metabolism
Phase 1 - make drug more reactive- oxidation, reduction, hydrolysis
Phase 2 - make drug more soluble- conjugation with glucuronic acid, glutathione, sulphuric acid
Either pharmacologically inactive –> active (PRODRUG)
Or pharmacologically active (codeine) –> another active (morphine)
What are some examples of CYP450 enzymes involved in phase 1 of drug metabolism?
3A
2D6
2C9
2C19
Where are CYP450 enzymes made?
In the liver (gut/lung)
What drugs do 3A enzymes metabolise?
Calcium channel blockers Benzodiazepines HIV protease inhibitors Most statins Cyclosporins
What induces 3A?
St. John’s wort
Phenytoin
Rifampicin
What inhibits 3A?
Macrolides
Cimetidine
Grapefruit juice
What drugs do 2D6 enzymes metabolise?
Codeine
B blockers
Tricyclics
What inhibits 2D6?
Fluoxetine
Paroxetine
Haloperidol
What drugs do 2C9 enzymes metabolise?
Most NSAIDs
Phenytoin
What induces 2C9?
Ethanol
What inhibits 2C9?
Fluconazole
What drugs do 2C19 enzymes metabolise?
Diazepam
Phenytoin
Omeprazole
What induces 2C19?
Rifampicin
What inhibits 2C19?
Omeprazole
Isoniazid
Expand on Elimination
Mostly by kidney (also by lungs, breast milk, sweat, tears, bile)
Elimination by the kidney is dependent on: glomerular filtration (affected by unbound drugs like gentamicin), passive tubular reabsorption (affected by urine flow rate and pH- aspirin), active tubular secretion (penicillin)
1st and 0 order kinetics
Clearance
What is 1st order kinetics?
Rate of elimination of drug is proportional to drug level
Constant fraction of drug eliminated in unit time
Half life can be defined and so multiple dosing is acceptable
What is 0 order kinetics?
Rate of elimination is a constant
Most drugs show this at high doses because receptors/ enzymes are saturated
Zero order drugs are likely to show toxicity at high doses (fixed rate/unit time) and so small dose change may cause large increase in dose and toxicity
No half life is calculable so will require TDM
What are the three broad categories of causes of poor prescribing?
Problems with the patient or population
Problems with the doctor
Problems with the pharmaceutical industry
What is clearance?
ability of the body to excrete drug (=GFR) / rate of elimination
Measure of hepatic, renal and other secondary forms of elimination such as sweating or biliary elimination
Volume of plasma that is completely cleared of the drug per unit time
Low GFR –> low clearance
Half life is inversely proportional to clearance (so lower the clearance or GFR, the higher the half life)
What is TDM?
Therapeutic drug monitoring
Important when- zero order kinetics, long half life, narrow therapeutic window, increased risk of drug-drug interaction
What is multiple dosing?
Repeated (first order) drug administration
Reach a steady state (Cpss) in 3-5 half lives (irrespective of dose/ frequency)
Require 4-5 half lived to completely eliminate most of a drug
What body systems can affect clearance and how?
HRH
HEART- circulation/ cardiovascular factors affecting blood flow to main organs of elimination
RENAL- factors affecting renal elimination (kidney failure, poor perfusion)
HEPATIC- factors affecting hepatic eliminations (enzyme inducers and inhibitors)
What is drug half life?
Amount of time over which the concentration of a drug in plasma decreases to one half the concentration value that it had when it was first measured
How is half life related to clearance and volume of distribution?
Half life is directly proportional to volume of distribution
Half life is inversely proportional to clearance
Half life = (0.693 x volume of distribution) / clearance
What is the therapeutic window?
Comparison of the concentration of drug with a therapeutic effect (minimal required concentration) to the concentration of drug with a toxic effect (maximal required concentration)
How does multiple dosing affect the therapeutic window?
Repeated drug administration means that a new steady state can be achieved so that levels stay within the therapeutic window
What is steady state equal to?
Steady state (Cpss) = dose rate / clearance
What is loading dose?
When a clinician wants to achieve a steady state quickly within the therapeutic window they can give a loading dose
Once the steady state is reached, it is maintained by the steady state equation: steady state = dose rate / clearance
Loading dose = volume of distribution x steady state (Cpss)
In what ways do drugs exert their effects on the body?
Interactions with enzymes Transport systems Secondary messengers Hormones Ion channels
What theory is pharmacodynamics based on?
Pharmacodynamics is based around the concept of the receptor theory, whereby the drugs act on receptors to target the molecules.
What are the key concepts of the receptor theory?
Agonists (partial) Antagonists (competitive and non competitive) Specificity Selectivity Affinity Efficacy Potency Therapeutic index and window
What is an agonist?
An agonist will bind to the receptor and stabilise it (whilst bound) into its active state.
What is an antagonist?
An antagonist will bind to the receptor and stabilise it (whilst bound) into its inactive state.
What is a partial agonist?
A partial agonist will bind to the receptor yet will not fit quite well as well and does not bring about the maximal response
What is a competitive antagonist?
Competitive antagonists bind to the site in which the natural ligand binds to and can completely remove all response from the receptor
Competitive antagonism occurs where the antagonist can be “out-competed” for the receptor site by simply increasing the agonist concentration, shown on curves by a shift to the right.
What is a non competitive antagonist?
Non-competitive antagonists bind to another site on the receptor (i.e. where the ligand does not bind) and will partially reduce the overall response of the receptor
Non-competitive antagonism can be either irreversible binding to receptor site or reversible or irreversible binding to a separate site, which is represented by the EC50 staying the same yet a reduction in overall response
What is specificity?
Specificity relates to the complementary drug and receptors (i.e. good specificity is only working on one receptor)
What is selectivity?
Selectivity relates to clinical effect of the drug and can be measured with specific therapeutic indices (i.e. good selectivity has minimal side effects)
What is affinity?
Affinity defines the ability of a drug to bind to a specific receptor type. The terms used to define this are Kd for agonists and Ki for antagonists. These terms indicate the concentration at which half the receptors are occupied at
What is efficacy?
Efficacy defines the maximal effect of a drug when bound to a receptor. Agonists have 100% efficacy, partial agonists will have reduced affinity, efficacy, or both, and antagonists have affinity yet no efficacy.
What is potency?
Potency defines the overall response seen by the receptor once the ligand has bound. It is measured by the EC50 which is the concentration where 50% of the maximal response is obtained. EC50 is rarely equal to Kd values. Antagonist potency can also be measured, which can be defined as the concentration that reduces maximal activation of a receptor by 50%.
What is the therapeutic index?
The therapeutic index is the relationship between concentrations causing adverse effects and concentrations causing desirable effects; it is calculated as LD50 / ED50 and a large therapeutic index is preferred.
What is the therapeutic window?
The therapeutic window is the range of drug concentrations where they exert a clinically useful effect but without exerting toxic effects; it is the range between the lowest dose that has a positive effect and the highest dose before the negative effects outweigh the positive effects.
What are some examples of drugs with a narrow therapeutic window?
- Warfarin
- Aminophylline
- Digoxin
- Aminoglycosides
Besides from pharmacokinetics and pharmacodynamics, what else can affect a drug or the body?
Drug interactions with other drugs
Drug interactions with food
Drug interactions with diseases
What 4 stages of pharmacokinetics are affected by drug-drug interactions?
ADME
How is absorption affected by drug-drug interactions?
Changes in gut motility can occur to affect absorption; for example, opiates and atrophine slow the gut down to increase Cmax and increase Tmax, whereas metoclopramide speeds the gut up to increase Cmax and decrease Tmax.
Other drugs will interfere with absorption, such as calcium salts bind to tetracyclines and reduce their absorption or cholestyramine binds to Warfarin and digoxin to reduce their absorption.
How is distribution affected by drug-drug interactions? (Class 1 and 2 drugs)
Class I (object) drugs are administered at a dose where the number of molecules of that drug is much lower than the number of binding sites available for that drug whereas class II (precipitant) drugs are used at much higher numbers than the number of binding sites available so displace the class I drugs. Administering a precipitant drug can cause free object drug concentrations to rise to toxic levels, pushing levels out of the therapeutic window. This can however be met with an increased clearance to achieve a similar steady state.
How is metabolism affected by drug-drug interactions?
Drugs can affect the metabolism of themselves or other drugs by two mechanisms of either induction or inhibition (described in previous lecture).
How is excretion affected by drug-drug interactions?
The primary mechanism affecting drug excretion includes changes in protein binding, inhibition of tubular secretion, and changes to urine flow / pH. Decreased protein binding increases the amount of free unbound drug which accelerates its removal, and inhibition of tubular secretion will result in increased plasma levels of the drug (NSAIDs can act to reduce tubular secretions).
How will drug-drug interactions affect the pharmacodynamics of a drug and the therapeutic outcome of the drug action?
Interactions will either enhance or reduce therapeutic outcomes through actions on the receptor, and these drug interactions can occur via different receptors or different tissues. This can have several categories.
For example, opiate analgesics and naloxone act antagonistically whereas digoxin toxicity is enhanced by hypokalaemia caused by loop diuretics (e.g. Furosemide). Even using aspirin with Warfarin will cause levels of unbound Warfarin to increase.
What are the 5 main classes of drugs that contribute to drug- drug interactions?
- Anticonvulsants
- Anticoagulants
- Antidepressants
- Antibiotics
- Antiarrhythmics
What are some examples of drug-disease interactions? (HRH)
The effects of hepatic, renal, or cardiac deficit on both PK and PD are common loci for drug-disease interaction. These drug-disease interactions often lead to exacerbation of systemic toxicity due to their close interdependence.
Renal Disease- Falling GFR will cause a reduced clearance of renally excreted drugs, e.g. digoxin or aminoglycoside antibiotics. Further reduction in GFR can be seen in patients on NSAIDs or ACEis, causing AKI and are considered to be nephrotoxic.
Hepatic Disease- Hepatic disease would cause reduced clearance of hepatically metabolised drugs by a reduced CYP 450 activity. This results in much longer half-lives of drugs resulting in toxicity. Good examples include opiates in cirrhosis, with small doses even resulting in accumulation causing coma.
Cardiac Disease- a falling cardiac output can cause reduced organ perfusion, resulting in both reduced hepatic blood flow and renal blood flow, reducing drug clearance.
Many drugs are bound to albumin, so any hypoalbuminaemia caused by liver failure, malnutrition, nephrotic syndrome, plus many more, higher free drug levels will be seen. This would affect PD and PK significantly.
What are some examples of drug- food interactions?
- Cranberry juice can be used therapeutically in UTI treatment, yet also acts to inhibit CYP2C9 so reduce clearance of Warfarin to cause raised INR and increased risk of haemorrhage.
- Grapefruit juice inhibits several CYP450 isoenzymes, so can reduce clearance of many drugs (e.g. simvastatin)
What is an adverse drug reaction?
In pharmacology, any unexpected or dangerous reaction to a drug. An unwanted effect caused by the administration of a drug. The onset of the adverse reaction may be sudden or develop over time.
What are two types of adverse drug reactions?
On target ADRs
OR
Off target ADRs
What are on target ADRs?
‘On target’ ADRs which are due to exaggerated therapeutic effect of the drug, most likely due to increased dosing or due to factors affecting the PK or PD. A simple example would be use of a certain drug to treat hypertension which could result in dizziness or syncope. Many ‘on target’ ADRs include effects on the same receptor type but found on other tissues.
What are off target ADRs?
‘Off target’ ADRs involves interaction of other receptor subtypes secondarily to the one intended for the therapeutic effect, which can also occur with metabolites that can subsequently act as a toxin. Inappropriate immune responses also constitute off target ADRs.
What increases the risk of ADRs?
Use of polypharmacy increases the risk of ADRs, due to effects of drug-drug interactions.
What are the 4 sites of actions of drugs?
Receptors
Ion channels
Enzymes
Transporters
How does a receptor function as site of action of a drug?
Receptors are the sensing elements in the system of chemical communication that coordinates the function of all the different cells in the body. Drugs can act by being agonists, partial agonists, or antagonists for known endogenous mediators.
How does a ion channel function as a an action site of a drug?
Some ion channels incorporate a receptor and open only when the receptor is occupied by an agonist. Thus drugs can act on ion channels indirectly (via G-protein coupled receptors) or directly (drug binds directly to ion channel) to alter its function.
How does an enzyme function as an action site for a drug?
Drugs can target certain enzymes to act as a competitive or non-competitive inhibitor of the enzyme, which can be reversible and irreversible. They can also act as false substrates, whereby drug molecules undergo chemical transformation to form an abnormal product that subverts the normal metabolic pathway. It should be mentioned that drugs may require enzymatic degradation to convert them from an inactive form (the prodrug) to their active form.
How do transporters function as an action site for drugs?
Transport of some ions and molecules requires carrier proteins, allowing for facilitated diffusion. Drugs can act to block these transporters, preventing these substances entering the cells.
What 4 stages of pharmacokinetics are affected by drug-drug interactions?
ADME
How is absorption affected by drug-drug interactions?
Changes in gut motility can occur to affect absorption; for example, opiates and atrophine slow the gut down to increase Cmax and increase Tmax, whereas metoclopramide speeds the gut up to increase Cmax and decrease Tmax.
Other drugs will interfere with absorption, such as calcium salts bind to tetracyclines and reduce their absorption or cholestyramine binds to Warfarin and digoxin to reduce their absorption.
How is distribution affected by drug-drug interactions? (Class 1 and 2 drugs)
Class I (object) drugs are administered at a dose where the number of molecules of that drug is much lower than the number of binding sites available for that drug whereas class II (precipitant) drugs are used at much higher numbers than the number of binding sites available so displace the class I drugs. Administering a precipitant drug can cause free object drug concentrations to rise to toxic levels, pushing levels out of the therapeutic window. This can however be met with an increased clearance to achieve a similar steady state.
How is metabolism affected by drug-drug interactions?
Drugs can affect the metabolism of themselves or other drugs by two mechanisms of either induction or inhibition (described in previous lecture).
How is excretion affected by drug-drug interactions?
The primary mechanism affecting drug excretion includes changes in protein binding, inhibition of tubular secretion, and changes to urine flow / pH. Decreased protein binding increases the amount of free unbound drug which accelerates its removal, and inhibition of tubular secretion will result in increased plasma levels of the drug (NSAIDs can act to reduce tubular secretions).
How will drug-drug interactions affect the pharmacodynamics of a drug and the therapeutic outcome of the drug action?
Interactions will either enhance or reduce therapeutic outcomes through actions on the receptor, and these drug interactions can occur via different receptors or different tissues. This can have several categories.
For example, opiate analgesics and naloxone act antagonistically whereas digoxin toxicity is enhanced by hypokalaemia caused by loop diuretics (e.g. Furosemide). Even using aspirin with Warfarin will cause levels of unbound Warfarin to increase.
What are the 5 main classes of drugs that contribute to drug- drug interactions?
- Anticonvulsants
- Anticoagulants
- Antidepressants
- Antibiotics
- Antiarrhythmics
What are some examples of drug-disease interactions? (HRH)
The effects of hepatic, renal, or cardiac deficit on both PK and PD are common loci for drug-disease interaction. These drug-disease interactions often lead to exacerbation of systemic toxicity due to their close interdependence.
Renal Disease- Falling GFR will cause a reduced clearance of renally excreted drugs, e.g. digoxin or aminoglycoside antibiotics. Further reduction in GFR can be seen in patients on NSAIDs or ACEis, causing AKI and are considered to be nephrotoxic.
Hepatic Disease- Hepatic disease would cause reduced clearance of hepatically metabolised drugs by a reduced CYP 450 activity. This results in much longer half-lives if drugs resulting in toxicity. Good examples include opiates in cirrhosis, with small doses even resulting in accumulation causing coma.
Cardiac Disease- a falling cardiac output can cause reduced organ perfusion, resulting in both reduced hepatic blood flow and renal blood flow, reducing drug clearance.
Many drugs are bound to albumin, so any hypoalbuminaemia caused by liver failure, malnutrition, nephrotic syndrome, plus many more, higher free drug levels will be seen. This would affect PD and PK significantly.
What are some examples of drug- food interactions?
- Cranberry juice can be used therapeutically in UTI treatment, yet also acts to inhibit CYP2C9 so reduce clearance of Warfarin to cause raised INR and increased risk of haemorrhage.
- Grapefruit juice inhibits several CYP450 isoenzymes, so can reduce clearance of many drugs (e.g. simvastatin)
What is an adverse drug reaction?
In pharmacology, any unexpected or dangerous reaction to a drug. An unwanted effect caused by the administration of a drug. The onset of the adverse reaction may be sudden or develop over time.
What are two types of adverse drug reactions?
On target ADRs
OR
Off target ADRs
What are on target ADRs?
‘On target’ ADRs which are due to exaggerated therapeutic effect of the drug, most likely due to increased dosing or due to factors affecting the PK or PD. A simple example would be use of a certain drug to treat hypertension which could result in dizziness or syncope. Many ‘on target’ ADRs include effects on the same receptor type but found on other tissues.
What are off target ADRs?
‘Off target’ ADRs involves interaction of other receptor subtypes secondarily to the one intended for the therapeutic effect, which can also occur with metabolites that can subsequently act as a toxin. Inappropriate immune responses also constitute off target ADRs.
What increases the risk of ADRs?
Use of polypharmacy increases the risk of ADRs, due to effects of drug-drug interactions.
What are the 4 sites of actions of drugs?
Receptors
Ion channels
Enzymes
Transporters
How does a receptor function as site of action of a drug?
Receptors are the sensing elements in the system of chemical communication that coordinates the function of all the different cells in the body. Drugs can act by being agonists, partial agonists, or antagonists for known endogenous mediators.
How does a ion channel function as a an action site of a drug?
Some ion channels incorporate a receptor and open only when the receptor is occupied by an agonist. Thus drugs can act on ion channels indirectly (via G-protein coupled receptors) or directly (drug binds directly to ion channel) to alter its function.
How does an enzyme function as an action site for a drug?
Drugs can target certain enzymes to act as a competitive or non-competitive inhibitor of the enzyme, which can be reversible and irreversible. They can also act as false substrates, whereby drug molecules undergo chemical transformation to form an abnormal product that subverts the normal metabolic pathway. It should be mentioned that drugs may require enzymatic degradation to convert them from an inactive form (the prodrug) to their active form.
How do transporters function as an action site for drugs?
Transport of some ions and molecules requires carrier proteins, allowing for facilitated diffusion. Drugs can act to block these transporters, preventing these substances entering the cells.
What are the main 2 classes of contraceptive drugs?
Progesterone only pills (POP)
Combined oral contraceptive pill (COCP)
