S2) Pharmacodynamics, Drug Interactions and Toxicology Flashcards
What is pharmacokinetics?
Pharmacokinetics is the study of the movement of a drug into and out of the body
“What the body does to the drug”
What is pharmacodynamics?
Pharmacodynamics is the study of drug effect and mechanisms of action
“What the drug does to the body”
What is pharmacogenetics?
Pharmacogenetics is the effect of genetic variability on the pharmaco- kinetics/dynamics of a drug on an individual
What are agonists?
Agonists are drugs which activate endogenous proteins
What are antagonists?
Antagonists are drugs which antagonise, block or inhibit endogenous proteins
What are competitive antagonists?
- Competitive antagonists are drugs which compete with the substrate to antagonise, block or inhibit endogenous proteins
- They bind at the same site as the substrate and are surmountable
What are non-competitive antagonists?
- Non-competitive antagonists are drugs which bind irreversibly to endogenous proteins to antagonise, block or inhibit their actions
- They bind at the allosteric site and are non-surmountable
Identify 5 locations where drugs work
- Cell surface receptors
- Nuclear receptors
- Enzyme inhibitors
- Ion channel blockers
- Transport inhibitors
Identify 5 unconventional mechanisms of drug action
- Disrupting structural proteins
- Acting as enzymes
- Covalently linking to macromolecules
- Reacting chemically with small molecules
- Binding free molecules/atoms
What is drug selectivity?
Drug selectivity refers to a drug’s ability to preferentially act at its target, reducing the chances of its interaction with different targets
What is drug specificity?
Drug specificity refers to a drug’s ability to bind to specific receptor subtypes, often allowing drugs to be targeted against specific organ
What is affinity?
Affinity is the tendency of a drug to bind to a specific receptor type
What is efficacy?
- 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
What is potency?
Potency is the dose required to produce the desired biological response of a drug
What is the therapeutic index?
The therapeutic index is the relationship between concentrations causing adverse effects and concentrations causing desirable effects
How does one calculate the therapeutic index?
Therapeutic index = Toxic Dose (TD50) / Effective dose (ED50)
What is the therapeutic window?
- The therapeutic window is the range of dosages that can effectively treat a condition while still remaining safe
- It is the range between the lowest dose that has a positive effect, and the highest dose before the negative effects > positive effects
In terms of the therapeutic window, what do the following mean:
- MEC
- MTC
- MTC = Minimum toxic concentration
- MEC = Minimum effective concentration
What is the probability of drug interaction?
The probability of drug interaction rises with the number of drugs a patient uses
In terms of absorption, explain how pharmacokinetic drug-drug interactions can occur
⇒ Altered P-Glycoprotein activity
⇒ Inducable/inhibitable active transporter
In terms of distribution, explain how pharmacokinetic drug-drug interactions can occur
Protein-binding interactions, important for:
- IV drugs
- Drugs with short half-life (rapidly cleared)
- Drugs with narrow therapeutic index
In terms of metabolism, explain how pharmacokinetic drug-drug interactions can occur
Changes in blood flow (first pass metabolism)
Explain how CYP450 inhibition occurs
- Related to:
I. Half life and clearance of affected drug
II. Plasma concentration at time of interaction
- Relatively quick onset (several hours to days)
Explain how CYP450 induction occurs
- Increase the amount of enzyme present for a specific action
- Usually phase 1 processes
- Rate depends on drug and enzyme (takes days/weeks)
What are the effects of pharmacodynamic drug-drug interactions?
Interactions either enhance or reduce therapeutic outcome through actions on the receptors
Describe two types of pharmacodynamic drug-drug interactions and how they occur
- Agonism/antagonism at same receptor e.g. beta blockers and β2 agonists
- Agonism/antagonism at different receptors e.g. warfarin and aspirin
Which drugs commonly produce pharmacodynamic drug interactions?
- Anticonvulsants
- Antibiotics
- Anticoagulants
- Antidepressants/Antipsychotics
- Antiarrhythmics
In three steps, explain how the falling GFR in renal disease leads to drug interactions
⇒ Reduced clearance of renally excreted drugs
⇒ Disturbances of electrolytes may predispose to toxicity
⇒ Nephrotoxins will further damage kidney function
In four steps, explain how hepatic disease leads to drug interactions
⇒ Reduced clearance of hepatic metabolised drugs
⇒ Reduced CYP 450 activity
⇒ Much longer half lives
⇒ Toxicity
In four steps, explain how the falling cardiac output in cardiac disease leads to drug interactions
⇒ Excessive response to hypotensive agents
⇒ Reduced organ perfusion
⇒ Reduced hepatic blood flow and clearance
⇒ Reduced renal blood flow and clearance
In three steps, explain how grapefruit juice leads to drug interactions
⇒ Inhibits several CYP450 isoenzymes
⇒ Decreases clearance of many drugs
⇒ May lead to increased exposures to drug of up to 16 fold
In four steps, explain how cranberry juice leads to drug interactions
⇒ Inhibits CYP2C9 isoform
⇒ Decreases clearance of warfarin
⇒ Enhanced anticoagulant effect
⇒ Increased risk of haemorrhage
How can the inter-patient variability in drug response be explained?
Pharmacogenetics – the variation in CYP450 expression accounts for a great deal of inter-patient variability in drug response
Provide two examples of drugs showing variations in CYP450 pharmacogenetics
- Warfarin response (CYP2C9)
- Codeine response (CYP2D6)
What is an adverse drug reaction (ADR)?
An adverse drug reaction is an unwanted or harmful reaction which occurs after the administration of a drug(s) and is suspected or known to be due to the drug(s)
Identify and describe the three types of ADRs
- Major – permanent / life threatening
- Moderate – requiring additional treatment
- Mild – trivial or unnoticeable
Identify 5 causes of variability in the drug response related to the biological system
- Body weight and size
- Age and sex
- Pharmacogenetics
- Condition of health
- Placebo effect
Describe 3 causes of variability in drug response related to conditions of administration
- Dose, formulation, route of administration
- Repeated administration of drug – drug resistance; drug tolerance-tachyphylaxis; drug allergy
- Drug interactions – GI absorption, protein binding / distribution, metabolism (stimulation/inhibition), excretion (pH/transport processes)
