Week 1 Flashcards
List target sites for drug action
Enzymes, Carrier Molecules, Ion Channels, Receptors, Structural Proteins, DNA
Define and explain the terms agonist, antagonist and partial agonist
- Agonist – molecule/drug that binds and activates the receptor
- Full agonist – 100% activation each time drug interacts with receptor
- Partial agonist - <100% activation even with maximum occupancy of receptors
- Inverse agonist – Reduces activation of a receptor, has negative efficacy
- Antagonist – Molecule/ drug that binds a receptor without activation (have zero efficacy)
Define IC50
• IC50 – concentration of antagonist to inhibit 50% of the agonist maximal effect , used to measure drug potency
Describe what is meant by dose-response curve
• Typically used to plot the concentration of a drug against its “response”
• Can be useful to compare drugs for affinity, efficacy and safety margins
(see notes for image of curve)
Explain affinity
• Affinity – tendancy of drug to bind to the receptor
Explain efficacy
• Efficacy – tendancy of drug to activate receptor once bound
Explain EC50
• EC50- Effective concentration – dose required for 50% maximal effect (in vitro)
Explain ED50
• ED50- Effective dose – Dose for 50% of the population to to obtain the therapeutic effect (in vivo)
Explain Therapeutic index
• Therapeutic index = toxic dose (TD50)/effective dose (ED50)
o You want a high therapeutic index as this indicates a large difference between the toxic dose and the effective dose – don’t have to worry about killing the patient by administering drug for therapeutic purposes
Explain Potency
Potency – Amount of drug required to produce 50% of its maximal effects
Explain Specificity
• Specificity – Capacity of a drug to cause a particular action in a population
Explain Selecticity
• Selectivity – The drugs ability to target only a selective population in preference to others
Define Tachyphlaxis
• Tachyphylaxis- “Rapid Protection” – Reduction in drug tolerance which develops after a short period of repeated dosing (reduced response)
Define self antagonism
• Self antagonism – Drug that becomes antagonistic to its own effect
Describe the potential outcomes of drug interactions
• Altered pharmacologic response to one drug caused by the prescence of a second drug • Outcomes include: o Enhanced action o Development of new effects o Inhibitory action o No change
Describe pharmaceutical interactions
o Pharmaceutical – related to physiochemical propertied and formulation (chemical/physical incompatibility/interation)
Describe pharmacokinetic interactions
o Pharmacokinetic – Related to interactions within ADME (Absorbtion, Distribution, Metabolism and Excretion)
Describe Pharmacodynamic interactions
o Pharmacodynamic – Related to interactions within receptor signalling
Describe summation
Summation – Effect of multiple drugs = sum of individual effects of each drug (eg 1+1=2)
Describe potentiation
o Potentiation – Drug increases the effect of another drug but has no effect when administered alone (1+0=2)
Describe synergism
o Synergism – when two drugs are administered produce effect that are greater than would be produced with summative of individual admin effects (1+1=3)
Describe the link between Km and affinity
- Low Km = High affinity
* High Km = Low affinity
Define Km
The concentration of substrate that allows the enzyme to reach half of Vmax
Define Vmax
Vmax- The reaction rate when the enzyme is totally saturated by substrate
Describe a competitive inhibitor (incl effect on Km, VMax aetc)
Competitive inhibitor - • Increases Km
• No effect on Vmax
• Amount of inhibition depends on Ki
• Example: Captopril-angiotensin converting enzyme inhibitor (treatment of hypertension)
Describe a non competitive inhibitor (incl effect on Km, VMax aetc)
- No effect on Km
- Decreases Vmax
- Example:Aspirin-cyclo-oxygenase (anti-inflammatory, analgesic, antipyretic)
Define Ki
• Ki- (dissociation constant for inhibitor binding) = Indicator of enzyme affinity for inhibitor
Define Pharmacology
Pharmacology is the study of how drugs interact with living systems.
A drug is a substance which alters the chemical and biological processes occurring in the body.
Define pharmacodynamics
Study of the effects that drugs have on the body
Define pharmacokinetics
Pharmacokinetics - the branch of pharmacology concerned with the movement of drugs within the body.
Describe antagonist drug receptor interactions (competitive, irreversible, non competitive)
As the name suggests, competitive antagonists compete with the agonist for binding sites at the receptor. Competitive antagonism is surmountable – that is, may be overcome/reversed with increased concentrations of the agonist.
Irreversible antagonists dissociates from the receptor only very slowly or not at all. This sort of antagonism is non-surmountable – that means that additional agonist cannot overcome the receptor blockade. Irreversible antagonists that act at receptors are not widely used clinically.
Non-competitive antagonists block the chain of events “post” receptor binding, this sort of antagonism is not related to receptor binding. This type of antagonism could be described as acting “downstream” of the receptor.
Describe the 4 main stages of pharmacokinetics
Absorption
Distribution
Metabolism
Excretion
Describe how drugs are absorbed post oral administration
Site of absorption depends on the drugs properties and conditions in each area of the tract.
Rapidly absorbed compounds tend to have:
- Low degree of ionisation
- High lipid/water partition
- Relatively low molecular weight
Describe the effect of the drugs acid /base properties on absorption mechanism
• Drugs must be neutral to cross a membrane
o Many drugs are weak acids/weak bases
Weak acids donate H+ to form anions (no charge in protonated form)
Weak bases accept proton H+ to form cations (protonated has positive charge)
Describe the involvement of the Henderson Hasselbalch Equation in the absorbtion of drugs
pH=pKa+log[nonprotonated/protonated]
pH=pKa: protonated form equal to nonprotonated concentration
pHpKa: vice versa
Describe First Pass Metabolism
- Oxidation and conjugation, make compounds water soluble (common method of inactivation and excretion (of drugs)
- Lipophillic converted to become hydrophilic, often inactive and then excreted
- Enzymes in the Smooth Endoplasmic Reticulum of liver cells
- Entero- hepatic circulation Parent drug/metabolites may recycle several times before entering systemic circulation (follows bile salts)
Define and explain Cmax
• Cmax – Peak level of drug in the plasma
Define and explain Tmax
• Tmax – Time taken for drug to reach peak level in plasma from administration
Define and explain Area Under the Curve in drug effect/time
Area under the Curve - Represents the bodies exposure to the drug
Describe Absorption rate
• Absorbtion rate – Amount of drug absorbed from the admin site to measurement site per unit time (in mass or moles per time)
o From bolus intravenous = instant
o From infusion admin e.g. IV infusion follow Zero order kinetics (rate is independent to the amount of drug)
o From diffusion type admin e.g. oral, IM follow first order kinetics (proportional to amount of drug)
Describe Elimination rate
• Elimination rate – Amount of parent drug eliminated from the body per unit time (mass or moles per time)
o Defined with respect to irreversible removal
o = plasma clearance x plasma concentration
Describe volume of distribution
• Volume of Distribution
o The volume into which a drug appears to be distributed with a concentration equal to that of plasma OR
o A proportionality constant relating the Blood/plasma conc to the amount of drug in the body
o Amount of drug in the body at time (t) = Volume of distribution (t)x Blood/plasma concentration at time(t)
Usually given in L/Kg
Describe total body clearance
• Total Body Clearance
o The volume of blood/plasma cleared of parent drug per unit time
OR
o A constant relating to the elimination to the blood/plasma concentration
o Rate of Elimination = Blood/Plasma Clearance x Blood/Plasma Concentration
o Is the sum of all organ clearances (hepatic, renal and pulmonary)
o Measured in volume per time (moles /hours)
o Can be determined by the area under the curve after an IV administration
CL=Dose/AUC
Describe the process and stages in drug discovery
- Identification of need
- selection of target protein
- Proof of concept - small group of animals confirm drugs potential
- Exploratory development - formulation of dose regimen etc
- Full development - evidence of efficacy and safety full clinical/field studies
Describe Bioavailability
• Bioavailability
o Measure of extent of absorption from the administration site to the measurement site
o Separate IV and oral studies required
Describe elimination constant K
• Elimination rate constant (K)
o F
Describe First Order Kinetics
Distribution rate is directly proportional to the concentration of substrate
Describe Zero Order Kinetics
No correlation between the distribution rate and the concentration of substrate
Describe Steady State
The rate of distribution remains steady despite changes in average concentration.
What is a loading dose and when is it most useful ?
Loading dose - initial higher dose of a drug that may be given at the beginning of a course of treatment before dropping down to a maintenance dose. Useful when drugs are eliminated from the body relatively slowly.
Describe allometric scaling and its importance in veterinary medicine (also the considerations that must be made)
Kleibers Law - Metabolic rate/gram needed to sustain an animal decreases with body weight by 1/4 power.
MassSpecificMetabolicRate=Xonstant xBW(To the power -0.25)
Links to blood flow (but to the 1/5 law) which in turn is required for clearance.
Therefore clearance is greater in smaller animals. .
(does not relate so well with metabolism)
Describe what is meant by in vitro/in vivo scaling of metabolic clearance
Look this up when you have time
Describe the clinical relevance of changes in drug plasma protein binding
Total drug concentration is the sum of unbound and plasma protein bound drug - this is measured in a PK study.
Plasma protein binding levels change in response to increased dose.
Explain the usefulness of continuous release for drug delivery
- Issues with patient compliance with repeated doses has encouraged the development of oral drugs that slowly releases the drugs into the body
- Similar kinetics to IV infusion
- Reduced risk of breaching therapeutic window
- Drug delivery periods can be over several months from single administration
Describe the depot effect
Look into this
Define therapeutics
Therapeutics - the branch of medicine concerned with the treatment of disease and action of remedial agents
List the core components which inform the therapeutic decision process
o Welfare of animal: rapid resolution of disease, avoid adverse reactions/interactions
o Potential self resolution or preventative care
o Culling: notifiable diseases, diseases of farmed fish
What factors could influence the concentration of the drug reaching the therapeutic site
Liver/kidney disease
Blood supply
Drug composition
Method of administration
Outline considerations for the development of a therapeutic plan (6)
- Other concurrent diseases
- Patient (e.g. species toxicity etc)
- Client (education and training etc)
- Practice and Personal
- Financial
Define adverse events and describe the process of reporting such events
Adverse events - Unintended or noxious response to a drug that occurs within a reasonable time frame following admin.
Must be reported to DEFRA if novel
What are the considerations during therapeutic decision making for pregnant patients?
- Increased plasma volume
- increased Vd
- Fetal trapping (due to its acidic nature the foetus donates H+ to alkaline drugs ionising them and preventing them from crossing the placental membrane)
What are the considerations during therapeutic decision making for neonates/paediatric patients
Increased SA:V
Increased metabolic rate but decreased function
More rapid topical absorption
Lower adipose level - reduced control of drug level in the blood
Reduced hepatic function
What are the considerations during therapeutic decision making for geriatric patients
Slower gastric absorption
Increased adipose tissue (increased Vd of fat soluble drugs)
Decreased renal elimination
Reduced plasma protein binding (potential increased toxicity)
What are the considerations during therapeutic decision making for patients with Hepatic failure
Little effect on drug metabolism until 80% functional loss
Most antimicrobials well tolerated
What are the considerations during therapeutic decision making for patients with Renal disease
Most profound changes in PK
Reduced albumin binding of the drug
Define Therapeutic index
comparison between the quantity of a therapeutic agent that causes the therapeutic effect to the amount that causes a toxic effect
Describe what could be interpreted by a drug having a low Vd
Drug is mostly contained within the plasma either due to its high water solubility (higher water content in plasma than tissues) OR is ability to bind to proteins (unable to enter tissues)
Why is drug monitoring important?
Avert toxicity
Optimize dose /therapeutic responce
Detect changes in pharmacokinetics
Describe the process of monitoring drug therapeutics
Steady State monitoring - provides the best correlation between serum drug cons and clinical status
Usually achieved after 3-5 half lives
Give the calculation for Vd
Vd=Amount in the body (dose) / Plasma concentration
Define Clearance and explain how it can be determined
Clearance - A pharmacokinetc parameter that relates elimination rate to its plasma concentration (CP)
Elimination rate = Clearance x plasma conc
Can be measured with a continuous rate IV being determined by the point at which the drug reaches a steady state in the body.
Can also be measured by a single bolus IV dose CL= dose/AUC
Outline the importance of the Veterinary Medicines Regulation in the UK
- Control risks to human health and environment
- Provide assurance of efficacy
- Provide reliable info to users
List the processes by which regulation is achieved for a veterinary licensed product
- Data assessment and authorization
- Certification and qualification
- Prescribing, dispensing and supply
Testing inspection and investigation
Describe the key considerations of dispensing and prescribing POM-V drugs
POM-V drugs must only be prescribed by a veterinary surgeon following a clinical exam and then may only be supplied by registered premises
Describe the key considerations of dispensing and prescribing POM-VPS drugs
Must be both prescribed and supplied by a vet surgeon, pharmacistor SQP (suitably qualified person) - must be confident of the competence of the administrator
Describe the key considerations of dispensing and prescribing NFA-VPS drugs
(Vet, Pharmacist, SQP)
o For companion animals only (expt horses) and may be prescribed by a Vet, Pharmacist etc
o Before prescription must be confident of competence of those administering drug, advise on safe admin
o Supply no more than the minimum required for treatment
Describe the key considerations of dispensing and prescribing SAES drugs
• SAES (small animal exemption scheme)
o For use withcertain pet species, birds, fish, ferrets, rodents etc
o Ecempt from the requirement for a marketing authorisation
Define an SQP
- Suitably qualified persons
- Can prescribe and supply POM-VPS and supply NFA-VPS and AVM-GSL medicines
- Works according to their Code of Practice
- Has to pass certain modular qualifications
Describe the process for post marketing pharmacoviligance (worth defining)
- Post authorisation monitoring residues testing, imported products from non EU countries
- Pharmacovigilance Range of activities to detect, assess and understand the adverse reactions and any problems with a medicine EU wide database, trend analysis
Describe the roll of the Cascade
• The cascade is a long-standing legal flexibility providing a rational balance between the legislative requirement for veterinary surgeons to prescribe and use authorized veterinary medicines where they are available, and the need for professional freedom to prescribe other medicines where they are not
• In the absence of a UK authorized drug for a condition, in order to avoid unnecessary suffering animal may be treated in accordance with:
o A veterinary medicine authorized in the UK for use in another animal species or for a different condition in the same species.
o If there is no such medicine, use either: (a) A medicine authorized in the UK for human use (b) A veterinary medicine from another Member State or country outside the EU in accordance with an import certificate from the Veterinary Medicines Directorate (VMD).
o If there is no such medicine, a medicine prepared extemporaneously by a veterinary surgeon, pharmacist or a person holding an appropriate manufacturer’s authorization.
Describe the Misuse of Drugs Regulations of 2001
o Under the Misuse of Drugs Regulations 2001, Controlled Drugs are classified into five Schedules according to their therapeutic usefulness, need for legitimate access and potential for misuse
Describe MDR Schedule 1 drugs
Vets have NO authority to possess.
Home office licence required.
Name 3 MDR Schedule 2 drugs
Morphine, Ketamine, amphetamines
Name 3 MDR Schedule 3 drugs
Buprenorphine, pentobarbital, benzodiazepine
Name 3 MDR Schedule 4 drugs
Anabolic and androgenic steroids benzodiazepines
Name 3 MDR Schedule 5 drugs
Codiene, Paracetamol (other low strength)
Describe lead optimisation
Chemical modification of lead compounds to increase potency, selectivity and metabolic stability (lock and key)
Give the timeline and cost of drug development
Pharmacological Testing - efficacy, interactions, adverse effects
Prelim Toxicological testing - max non toxic dose established
Pharmacokinetic testing - ADME and bioavailability
chemical and Pharmaceutical development - feasibility of large scale release
Describe the difference between locally and centrally licenced drugs
Locally
- authorised in a national basis only
- driven by market size/ production
- can jump to centrally licenced by mutual recognition between countries
Centrally
- Beneficial if Europe wide
- regulation by European agency for evaluation of medical products
What data is required for licensing of a drug and what does it aim to prove?
Aim - to prove that the drug is both efficacious and safe
- target species
- experimental design (dosing and efficacy with comparison to other drugs)
- Adverse effects (safety and economic benefit)
Give 5 key components of a clinical efficacy trial
Legal document for registration Selection of animals(and management supplies) Treatment details Effectiveness assessment Schedule of events
How does orally administered aluminium hydroxide reduce the oral bioavailability of tetracycline? (and how can this be avoided?)
Coadministration may impair the absorption of tetracycline and therefore reduce its efficacy.
To avoid this tetracycline and aluminium hydroxide administration should be 2-3 hours apart.
Define Oral Bioavailability
The fraction of an orally administered drug that reaches the systemic circulation.
- Why might propantheline increase the absorption of orally administered digoxin (in slow release formulation)?
Propantheline reduces stomach and intestinal motility, increasing the time that digoxin spends in the GI tract and therefore increasing the amount absorbed into the blood.
- Probenecid prolongs the action of penicillin but how?
Probencid acts at the kidney, interfering with the renal secretion of penicillin, decreasing its renal clearance and increasing its half life in the body.
How could chloramhenicol increase the plasma concentration of phenylbutazone?
Chloramphenicol inhibits the hepatic Mixed Function Oxidase (MFO) system which is important in the metabolism of phenylbutazone. This results in the increased half life of this drug in the body.
What is the likely effect of the administration of dibutamine and propanolol on the cardio respiratory system?
Increased risk of hypertension and bradycardia.
What could be the effect of coadministration of clomipramine and selegiline?
Both increase the risk of major bleeding and taken together have a major increase in effect and therefore also a risk factor.
