1.2 Drug Interaction and Toxicology Flashcards
Give the 4 general ways in which drugs may work
- Inhibition
- Activation
- Destruction
- Replacement
Most drugs interact with what?
endogenous proteins
(a few have unconventional mechanisms of action)
Compare an agonist with an antagonist
Agonists: activate endogenous proteins
Antagonists: block or inhibit endogenous proteins
Give the 6 main sites where drugs work
- Cell Surface Receptors
- Nuclear Receptors
- Enzyme Inhibitors
- Ion Channel Blockers
- Transport Inhibitors
- Inhibitors of Signal Transduction Proteins
Not all agonists elicit maximal responses in the same assay, what are the 2 types of agonist we can have?
Label each on the image below
Full and partial agonists
Full agonist
EC50 ___ Kd
+/- _________
Full agonist EC50 < Kd
+/- spare receptors
Is competitive antagonism surmountable or non-surmoutable and why?
Competes with agonist at receptor site thus Inhibition is SURMOUNTABLE
What would be seen on an agonist concentration-response curve for a reversible competitive antagonist
a parallel shift to the right
When does Non-Competitive antagonism occur?
Is it surmountable or non-surmountable and why?
Occurs when the antagonist dissociates slowly or not at all
NON-SURMOUNTABLE ➞ With increased [antagonist] or increased time more receptors are blocked by antagonist
Compare an ‘ideal drug’ vs a ‘real drug’
An ideal drug interacts at one site but not other sites preventing unwanted effects
A real drug acts at more than one binding site, may result in collateral effects ➞ adverse drug reactions
What is the advantage if a drug displays Selectivity?
The more selective a drug for its target, the less chance it will interact with different targets. Therefore it will have less undesirable side effects
What is the benefit of penicillan?
SELECTIVITY
The enzyme is involved in bacterial cell wall biosynthesis. As mammalian cells do not have a cell wall, penicillin has few side effects
What is the advantage of drug specificity?
The more specific a drug acts ___________
Targeting drugs against specific receptor subtypes often allows drugs to be targeted against specific organ.
The more specific a drug acts, the less action ther is on other organs
Give an example of drug targets for specific organs?
Adrenergic receptors:
- heart β1 receptors
- lungs β2 receptors
Define Therapeutic Window
The range of dosages that effectively treat a condition safely
Between the lowest dose that has a +ve effect, and the highest dose before the -ve effects outweigh the +ve effects
Label the Image
How do you calculate the Theraputic index?
Therapeutic index = Toxic Dose (TD50) / Effective dose (ED50)
Define Therapeutic index
Relationship between concentrations causing adverse effects and concentrations causing desirable effects
Compare drug version I and drug version II
**********
Define Affinity
The tendency of a drug to bind to a specific receptor type
The equilibrium dissociation constant is represented by _____, which is a measure of _____.
What is the relationship between the 2 blanks above?
Kd, affinity
Kd↓ then affinity↑
Define Efficacy and state what this tells us
Efficacy is the ability of a drug to produce a response as a result of the receptor or receptors being occupied
It describes the maximum effect of a drug
Define Potency and state what we are comparing
Potency is the dose required to produce the desired biologic response.
Potency compares doses of two drugs required to exact the same effect
What may increase the probability of drug interaction
Probability of drug interaction rises with the number of drugs patient uses
What occurs in each phase of hepatic metabolism of a drug and why?
Phase 1
- chemical changes
- CYP 450 family
- low substrate specificity
Phase 2
- conjugation
- ↑ solubility
- allows elimination
What is meant by low substrate specificity?
Can metabolise a range of substrates
Inhibition of CYP 450 is related to what 2 factors?
Is it a fast or slow process?
Related to:
- Half life and clearance of affected drug
- Plasma concentration at time of interaction
Relatively quick onset (several hours to days)
How can we induce enzymes?
Is this phase I or II and is it fast or slow?
By increasing the amount of enzyme present for a specific action
Normally a phase I processes and usually takes days to weeks to happen
Rate of enzyme Induction depends on what?
Drug and enzyme
Give 2 examples of enzyme induction and state how these function
Are these fast or slow onset and what is the implication of this?
Carbamazepine and warfarin (CYP 3A4)
- CBZ induces CYP3A4
- CYP 3A4 metabolises warfarin
So CBZ ⬆ metabolism of warfarin which ⬇ its effect.
Patient on both drugs will most likley be taking higher doses of Warfarin. However, as this process is slow onset (days-weeks), care must be taken when one drug is stopped to prevent over thinning of blood and risk of hemorrage
Give 2 examples of drugs that may show drug-food interactions with grapefruit juice
Explain why and a possible danger of this
Simvastatin and Amiodarone (long QT)
Grapefruit Juice Inhibits several CYP450 isoenzymes which ↓ the clearance of many drugs. This may lead to ↑ exposures to drug of up to 16 fold!
What is Cranberry Juice commonly use to treat and why?
Used therapeutically in UTI treatment by Inhibiting bacterial adherence to urothelium
What is the drug-food relation between cranberry juice and Warfarin?
What MUST we advise patients?
- ↓ Clearance of warfarin
- Enhanced anticoagulant effect
- ↑ Risk of haemorrhage
because It inhibits CYP2C9 isoform
Advise patients not to drink cranberry juice if on warfarin
Drug-Drug interactions either _____ or _____ therapeutic outcome through actions on the receptors
Drug interactions can occur via different _____ or different _____
enhance, reduce, receptors, tissues
Give 2 examples of agonism/antagonism acting at same receptor
1) Opiate analgesics and Naloxone
2) Beta blockers and Beta2 agonists
Give 2 examples of agonism/antagonism acting at different receptors
1) Amlodipine and Bendroflumethiazide
2) Warfarin and Aspirin
What is the risk of amlodipine and bendroflumethiazide being used togther?
amlodipine = calcium channel blocker
bendroflumethiazide = thiazide diuretic
Both act to decrease BP which can result in hypotension
What is a non-selective drug and give an example
They act on one or more receptors
Eg. Antidepressants interact with many receptor subtypes:
- adrenergic, noradrenergic, serotoninergic, cholinergic, Na channels
Give an example of how a drug may exhibit an enhanced effect
Digoxin toxicity enhanced by hypokalaemia caused by a loop diuretic (e.g. Furosemide)
Give 5 drug classes which are likley to cause drug-drug interactions
(Hint: 5A’s)
- Anticonvulsants
- Antibiotics
- Anticoagulants
- Antidepressants/Antipsychotics
- Antiarrhythmics
Drug Disease Interactions are most common in which age groups and why?
More common at the extremes of age ➞ Children or Elderly
Due to altered PK profile (renal and hepatic) and/or Co morbidities
Are drug disease interactions more common with chronic medical conditions or acute illness
Chronic medical conditions
Give 4 reasons why Renal Disease affects drug function
Incl drug examples
1) A falling GFR (acute or chronic) results in reduced clearance of renally excreted drugs:
2) Disturbances of electrolytes (esp K+) may predispose to toxicity
3) Nephrotoxins will further damage kidney function
4) CKD can affect Vd of drugs
Give 3 examples of renally excreted drugs
Digoxin, aminoglycoside, antibiotics
Give 4 reasons why Hepatic disease affects drug function
1) Reduced clearance of hepatic metabolised drugs
2) Reduced CYP 450 Activity
3) Much longer half lives
4) Toxicity
What ‘classic’ drug should NOT be given to patients with liver cirrhosis and why?
Opiates
Even small doses will accumulate which can lead to an coma. This is because metabolism of opiods in liver is not occuring normally.
Give 3 ways in which cardiac disease can affect drug function?
Falling cardiac output will lead to:
1) Excessive response to hypotensive agents
2) Reduced organ perfusion leading to reduced hepatic blood flow and clearance
3) Reduced organ perfusion leading to reduced renal blood flow and clearance
What is an adverse drug reaction? (ADR)
A noxious and unintended response to a medicine that occurs at normal therapeutic doses used in humans for prophylaxis, diagnosis, or therapy of disease, or for the modification of physiologic function.
How do we classify ADR’s?
Explain each + example
A-F
Give 3 reasons why ADRs are a serious problem
1) They increase morbidity, mortality and healthcare costs world wide.
2) They account for around 6-7% of admissions per year here in the UK
3) They cost the NHS £466,000,000
** ADRs are thought to occur in 10–20% of hospital in-patients AND they are avoidable!
Give 4 factors that cause high risk for ADRs
1) Ignorant, inappropriate or reckless prescribing
2) Polypharmacy
3) Patients at the extremes of age
4) Multiple medical problems
5) Use of drugs with narrow therapeutic indexes (↑risk of toxicity)
Why can use of drugs near their minimum effective concentration lead to ADRs
Increased risk of treatment failure if metabolism increased
How is severity of ADR’s classified?
Major (permanent / life threatening)
Moderate (requiring additional treatment)
Mild (trivial or unnoticeable)
Define Pharmacovigilance
The science and activities relating to the detection, evaluation, understanding and prevention of ADRs or any other drug related problem
Give 4 ways in which we can improve pharmacovigilance
1) Early detection of unknown safety problems
2) Detection of increases in frequency
3) Identification of risk factors
4) Preventing patients from being affected unnecesarily
What is the Yellow Card Scheme?
How adverse events regarding drugs or medical devices can be reported
How can we prevent ADR’s?
1) Careful patient history
2) Avoiding treatments in cohorts who are at increased risk
3) Report ADR’s using the Yellow Card scheme
