Pharmacology 3 Flashcards
List some altered physiology in pregnancy that can affect drug kinetics
- Increased plasma volume
- Chronic metabolic alkalosis
- Increased volume of distribution
- Altered protein binding (increased free fraction)
- Increased gastric pH
- Decreased GI motility
- Altered cytochrome function (increased metabolism due to increased energy requirements)
Give some special pharmacokinetic considerations in pregnancy directly relating to the foetus
- Foetal trapping can occur
- Foetus more acidic than maternal side, so will trap weak bases due to becoming ionised
Give some potential detrimental effects of drugs on a foetus
- Teratogenic effects (e.g. nitrous oxide)
- Prevention of implantation
- Early termination
- Mutagenesis
Give some practical considerations of therapy during pregnancy
- Difficult to predict pharmacokinetics
- Avoid drugs where possible, use those with marketing authorisation
- Many are “off-label” in pregnancy
List some pharmacokinetic effects of neonates
- Increased surface area to volume ratio in neonate (allometric scaling)
- Increased metabolic rate but decreased metabolic function
- GI absorption variable
- More rapid topical absorption
- Increased Vd for on-lipophilic drugs
- BBB not complete first few days postpartum
- Lower adipose content
- Reduced hepatic function (species specific)
- GFR takes time to become normal
- Tubular secretion takes longer
Explain the GI absorption in neonates
- Variable
- Altered gastric emptying
- Irregular peristalsis
- Increased permeability of mucosa so absorption easier
Explain why neonates have an increased metabolic rate but decreased metabolic function
Lower amount of CYP enzymes but higher general metabolic rate
Why do neonates have more rapid topical absorption?
Immature percutaneous barrier
Why do neonates have an increased volume of distribution for non-lipophilic drugs?
- Greater water content
- Decreased plasma protein binding
Explain how the lower adipose content of neonates affects pharmacokinetics
- Less fat uptake and sequestration of drug
- May affect maintenance of plasma level
- Dosing, dosing frequency needs to be considered
Explain why neonates have slower tubular secretion
Immature expression or formation of transporters in tubules in kidney
What is the effect of neonatal status on drug dose?
Usually decrease dose as increased risk for toxicity
- Sometimes complete contraindication
Outline some pharmacokinetic effects of old age
- Gastric pH increased
- Less microvilli
- Reduced gastric motility and emptying
- Lower expression of enzymes
- Decreased body mass
- Less water content
- Increased adipose tissue
- Increased Vd for fat soluble drugs
- Less Vd for water soluble drugs
- Decreased plasma albumin
- Minimal effects on metabolism!
- Decreased renal elimination
- Concurrent disease likely
How does altered gastric function in elderly patients have an effect on pharmacokinetics?
- Delayed disintegration of tablets
- Altered ionisation
- Less mixing and dissolution
- Slower absorption
How does plasma albumin in elderly patients affect pharmacokinetics?
- Lower plasma albumin, more free drug
- Increased potential for toxicity
- Only a concern in IV administration
What factor has the greatest effect on pharmacokinetics in elderly patients?
- Reduced renal elimination
- Decreased renal mass, GFR and tubular secretion
- Similar to animal with chronic disease
Give examples of concurrent disease in elderly patients and how this may affect pharmacokinetics
- Chronic cardiovascular disease: decreased mentation, increased effects of sedatives when used, decreased cardiac output
- Respiratory disease: altered serum pH and protein binding
Outline how hepatic failure affects pharmacokinetics
- Content and activity of Phase I and II reactions decreased
- Little effect on drug metabolism until 80% functional loss
- Most antimicrobials well tolerated, but not licosamide, macrolides, sulphonamides and chloramphenicol
Outline how renal failure affects pharmacokinetics
- Most profound changes in PK
- Gradual loss of urine concentrating ability and ability to acidify
- Altered drug distribution patterns
- Loss ofability to acidify iincreases retention of basic drugs and excretion of acidiic drugs
How does uraemia affect pharmacokinetics?
- Chronic acidosis, reduced albumin binding of drug as less albumin present
- Leads to less hepatic metabolism
Define the term therapeutic index
A comparison of the amount of therapeutic agent that causes the therapeutic effect to the amount that causes toxic effects
Give examples of drugs with a high therapeutic index
- NSAIDs
- Sedative/hypnotics (e.g. benzodiazepines)
- Most antibiotics
- Beta-blockers
Give examples of drugs with low therapeutic indices
- Lithium
- Anaesthetics
- Neuroleptics (e.g. phenytoin, phenobarbital)
- Some antibiotics (e.g. gentamycin, vancomycin, amikacin)
- Digoxin
- Immunosuppressives
- Alcohol
Give examples of factors affecting the margin of drug safety
- Receptor saturation (e.g. medetomidine, alpha-2 agonsit at presynaptic cleft)
- Ability to bind to multiple targets
- Volume of distribution
Explain the effect of volume of distribution on drug safety margins
- More dangerous with high Vd
- Lots of distribution into tissues
- Tend to be lipophilic so binds to many targets in body, poor selectivity
- Small changes in plasma concentration reflect large changes in tissue
What is the importance of drug monitoring?
- Avert toxicity
- Optimise dose/therapeutic response
- Detect changes in pharmacokinetics
- Monitor compliance
When is drug monitoring particularly important?
- Low therapeutic index
- Chronic therapy
- Combination of both
- Polypharmacy
What is the importance of sampling at steady state when monitoring drug therapy?
- Provides best correlation between serum drug concentrations and clinical status
- Amount of drug eliminated is equal to amount administered
How is drug toxicity assessed for monitoring drug therapy?
- Sample at peak concentration
- Difficult to determine as may be individual variability
How is drug efficacy assessed for monitoring drug therapy?
Sample at concentration trough, just before next dose is administered, thus easier to time correctly
In drug clearance, what factors determine the time for the concentration in the plasma to fall to a set level?
- Rate of elimination
- Dose given
- Volume of distribution
- Method of elimination
- Blood flow
- Properties of the drug
Which of theese factors determine the peak plasma concentration after a bolus: dosage, volume of distribution, clearance?
- Dosage
- Volume of distribution
What would be the effect on drug distribution in an emaciated/starved animal with poor body condition?
Reduced adipose and muscle tissue for drug to distribute into, plasma volume also reduced. Phase I rate would be reduced (rate constant reduced), leading to faster phase II concentration drop
What is the clinical significance of K12 and K21 rate in race horses or dairy cows?
High K12 or low K21 would extend the withdrawal period of a drug
What is the importance of Veterinary medicines regulation in the UK?
- Control risks to human health, animal health and environment
- Provide assurance on efficacy
- Provide reliable information to users
When did the Veterinary Medicines Regulations come into force and what is covered?
2013
- Medicines as well as medicated feeds and some feed additives
List the processes by which regulation is achieved for a veterinary licensed medicinal product
- Data assessment and authorisation
- Certification and qualification
- Prescribing, dispensing and supply
- Testing, inspection and investigation
- Post authorisation
List the categories of veterinary medicines in the EU
- POM-V
- POM-VPS
- NFA-VPS
- AVM-GSL
- Schedule 6 exemption products
Who can prescribe POM-V medications?
Vets only
Who can prescribe POM-VPS medications?
Vets, pharmacists and suitably qualified persons
Who can prescribe NFA-VPS?
Vets, pharmacists and suitably qualified persons
Who can prescribe AVM-GSL medications?
General sales list (i.e. anyone)
When can POM-V drugs be prescribed?
Only by vet after clinical assessment of animal or group of animals under their care
Who can supply a POM-V medication?
- Vet giving prescription
- Another vet or pharmacist in accordance with written prescription
- Client may request written prescription if do not want prescribing vet to supply medication
Where can POM_V medications be supplied from?
Only from registered premises
When is a drug classified as POM-V?
- Requires strict limitation on use for specific safety reasons
- requires specialised knowledge of vet surgeon for its use/application
- Has narrow safety margin requiring above average care in use
- Government policy to demand professional control at high level e.g. antimicrobials and controlled drugs
What are the prescription and supply rules for POM-VPS medications?
- Prescribed and supplied by vet, pharmacist or SQP
- Any authorised supplier with written prescription from authorised prescriber
- Supply from registered premises only
What must occur before prescription of a POM-VPS?
- Prescriber satisfied that person administering drug is competent and will use for intended use
- Advise on safe use and administration, warnings and contraindications
- User made aware of suitable counter measures to minimise risk to animal, owner or environment through simple oral or written advice and given training
What does NFA-VPS mean?
Non-farm animals, prescribed by vet, pharmacist or SQP
What must occur before supply of an NFA-VPS?
- NO clinical exam required
- must be satisfied administrator is competent and will use for authorised purpose
- advise on safe administration, warnings and contraindications
- supply no more than minimum required for treatment
When is a medicine classed as NFA-VPS?
- Indicated for use only in non-food animals
- No statutory requirement for prescription only status
- Used routinely to prevent or limit effects of endemic disease
- Use implies risk for user, animal and environment but user can be made aware of suitable countermeasures through simple oral or written advice
- Can give sufficient practical advice to permit effective and safe use
What are drugs that come under the Small Animal Exception Scheme (SAES)?
- Medicines for use in certain pet species (exotics mainly), the active ingredient of which has been declared by Secretary of State as not requiring veterinary control, may be marketed under SAES
What are the regulations for drugs under the SAES?
- Not required to prove safety, quality or efficacy
- Must be manufactured to same standard as authorised medicines
- Subject to pharmacovigilance reporting
What legislations outline the Controlled Drugs?
All listed under one of 5 schedules in Misuse of Drugs Regulations (MDR) 2001 and Misuse of Drugs Regulations (Northern Ireland)(MDR)(NI))2002
What are the guidelines for internet/postal supply of drugs?
- Prescription available where necessary (e.g. POM-V products)
- Advice on safe administration
- Advise on warnings or contraindications
- Satisfied person is competent to use product safely and will use for intended purpose
- Keep adequate records of supply
Give examples of specified feed additives
- Coccidiostats
- Histomonostats
- Certain other zootechnical additives i.e. non-antibiotic growth promoters
- Less common in UK
What should be taken into account when prescribing drugs?
- Circumstance of animal being treated
- Available authorised veterinary medicine products
- Need for responsible use of medicines
- Requirement to prescribe minimum amount of product necessary for treatment
- Abilities and competence of the person who will administer the product and any available animal health plan
What are the requirements for drug VMP supply premises?
- Required to be listed as Veterinary Practice Premises
- Permanent and secure building, no entrance for birds or vermin
- Medicine storage areas designed to store at correct temperatures, monitored by thermometers
- Appropriate staff amenities
Outline the supply of a POM-V/POM-VPS without a vet present
- Must be authorised by vet surgeon
- Can meet requirement to authorise each transaction by making note on client’s records for repeat prescriptions
- phone call to vet to authorise supply
- Vet satisfied by SOP that person handling medicine to client is competent to do so
- Only minimum amount required supplied
- Vet must ensure client intends to use medicine for authorised use and is competent to do so safely
What are the regulations for records of drugs?
- Must be kept for 5 years
- Receipt and supply of prescription medicines
- Date of supply/receipt, name, batch, quantity, address
- Copies of all written prescriptions
- Records of recent audit
- Imported drugs must have special import certificate and special treatment certificate maintained
Define an SQP
Suitably qualified person
What regulations do SQPs work according to?
- Code of Practice issued by veterinary Medicines Directoratee, distributed by Animal Medicines Training Regulatory Authority
- Covers legislation, basic anatomy, physiology and basic disease challenges
- Must pass relevant species modules and base exam
What is an R-SQP, E-SQP and C-SQP?
- R: One that can work in all species groups
- E: equine and companion animal only
- C: companion animal only
What are the 2 major processes for post-marketing pharmacovigilance?
- Residues testing
- Pharmacovigilance
What is pharmacovigilance?
Range of activities that detect, assess, try to understand and ultimately prevent an adverse reaction or other sort of problems with a medicine including lack of efficacy
How is pharmacovigilance carried out?
- Monitor use of medicines in every day practice
- Monitor changes in patterns of adverse effects
- Assess risks and benefits of medicines
- Provide information to healthcare professionals and patients on safe and effective use
- Monitor impact of action taken
What is an adverse reaction
Any adverse effect that occurs within a reasonable time frame, including lack of efficacy
What are some consequences of pharmacovigilance?
- Changes to warnings on labelling/promotional material
- Information and advice in specialist press
- New benefit:risk assessment by VMD
- Recall of defective batch
- Change to legal category to ensure correct advice is given
- Suspension of marketing authorisation to allow resolution of a problem
- revocation of Marketing Authorisation in extreme cases
What is the purpose of the drug cascade?
If no medicine authorised in UK for specific condition, treat animals according to set out sequence to avoid unacceptable suffering
Outline the steps in the cascade
- If there is a medication authorised for the same condition in another species
- If there is no such medicine then a medicine for human use
- Veterinary medicine from another Member state or country outside EU in accordance with import certificate
- If nothing available, vet, pharmacist or person with manufacturers authorisation can prepare a emdicine extemporaneously
When can the cascade not be used?
Where cost is the main concern
What are the guidelines when using the drug cascade in food producing animals?
- Treatment restricted to animals on a single holding
- If imported, must be used in food producing animals in Member State
- Must have maximum residual limits
- Prescribing vet must specify appropriate withdrawal period
- Prescribing vet must keep specific records
When are import certificates for drugs required?
- When drug from another EU Member State is needed to be used if there is no suitable authorised medicine in UK
- Require Special Import Certificate
When are special treatment certificates (STCs) required?
When a veterinary medicine without a full marketing authorisation, or an authorised veterinary medicine from outside the EU or human medicine from outside the UK are to be used
Give examples of situations where the cascade may be used
- Dosage requirements that are not on the label of a medicine
- Individual characteristics of the patient
- Chronic infections
- Build up of resistance
- Unavailability of medicines
- Formulation of medicines (e.g. difficulty opening pill bottles with arthritis)
How does the cascade relate to SAES?
- Can use an SAES at any time in accordance with recommended use, not affected by cascade
- But if want to use in a way different to that describe on the bottle then this falls under the last of the cascade options
What is the minimum withdrawal period for meat from poultry and mammals including offal?
28 days
What is the minimum withdrawal period for milk and eggs?
7 days
What is the minimum withdrawal period for meat from fish?
500 degree days
What are the regulations for Schedule 1 controlled drugs?
- Vets have no authority to possess
- home office licence required to possess
- No recognised medicinal use
- E.g. cannabis, coca leaf, lysergic acid, diethylamide, LSD and mescaline
Give examples of Schedule 2 drugs
- Morphine (not licensed in veterinary but used for epidurals)
- Pethidine (rarely used, short action, IM)
- Fentanyl (anaesthesia)
- Alfentanil (not licensed, rare)
- Methadone
- Ketamine
- Amphetamines, secobarbital/quinalbarbitone
Give examples of Schedule 3 drugs
- Buprenorphine (no register, partial agonist)
- Pentobarbital, phenobarbital
- Benzodiazepine
- Some minor stimulants incl benzphetamine
- Tramadol
Give examples of Schedule 4 drugs
- Part 1: benzodiazepines
- Part 2: anabolic and androgenic steroids
Give examples of Schedule 5 drugs
- Low strength e.g. pardale V (codeine/paracetamol)
Which of the Schedule 2 rugs are excluded from safe custody?
Secobarbital and quinalbarbitone
What is meant by safe custody for drugs?
Stored in a suitable locked cabinet secured to the fabric of the building at all times
What are the rules for the prescription of Schedule 2 drugs?
- Written prescriptions valid for 28 days
- Special requirements for extra information on written prescriptions
- Repeat prescriptions not permitted and cannot be faxed or sent electronically
What are the rules on the obtaining of Schedule 2 drugs?
- Receipt and supply recorded in Controlled Drugs Register
- Written requisitions made to wholesalers
What is the procedure for the destruction of Schedule 2 drugs?
Must not be destroyed except in presence of person authorised by Secretary of State
What are the storage requirements for Schedule 3 drugs?
Subject to safe custody requirements
What are the prescription requirements for Schedule 3 drugs?
- Written prescription valid for 28 days
- Special requirements for extra information on written prescriptions
- Repeat prescriptions not permitted and cannot be faxed or sent electronically
What are the requirements for the destruction of Schedule 3 drugs?
Witnessed destruction requirements apply only to importers, exporters and manufacturers
What are the requirements for the obtaining of Schedule 3 drugs?
- Do not have to be recorded in Controlled Drugs Register
- Written Requisitions to wholesaler
What are the storage requirements for Schedule 4 drugs?
Not subject to safe custody requirements
What are the prescription requirements for Schedule 4 drugs?
Written prescriptions are valid for 28 days
What are the destruction requirements for Schedule 4 drugs?
Witnessed destruction requirements apply only to importers, exporters and manufacturers
What are the recording requirements for all controlled drugs?
- Date, name, address of person to whom supplied, name and signature of vet, amount and in which form supplied
- If schedule 2 also record person collecting and if ID requested
- Bound in books not loose pages
- Regular tallies to make sure all adds up
Outline the requirements for the destruction of Controlled Drugs
- Awaiting destruction stored separately from current stock but within CD cabinet
- Destruction witnessed by member of Animal Medicines Inspectorate, inspector of RCVS Practice Standards Scheme, Veterinary surgeon independent of practice or police officer
- Entry made into Controlled Drugs register and signed by authorised witness
Outline the method of destruction of controlled drugs
- Rendered irretrievable before destruction
- Denaturing kit used where possible
- Wear gloves
- Crush solid dosages with pestle and mortar, add to kit, pour in liquids
- Add parenteral preparations, open ampoules and empty into kit
- Fold transfermal patches in on selves and add
- Fill with water and store in CD cabinet for 24 hours until process complete
- Tablets can also be crushed and mixed with soapy water, injectables mixed with sawdust/cat litter
- Incinerate with other pharmaceutical waste labelling waste to show contains CDs
Give the stages in drug discovery and development
- Target identification and validation
- Hit finding
- Lead optimisation
- Proof of concept
- Exploratory
- Full development, clinical trials
- Registration
- Post-launch activities
What is meant by “hit/lead finding” in drug development?
Screen large bank of chemicals to see if one hits target and has an effect of choice
What is meant by “lead optimisation” in drug development?
Potential chemical but doesn’t yet have the right action, need optimising
How is lead optimisation carried out?
- Chemical modification of lead compounds to increase potency, selectivity and metabolic stability
- Beginning of in vivo/animal study including first pharmacokinetic and pharmacodynamic studies
What is proof of concept in drug development?
- Small group of target animals used to confirm drug’s potential
- Initial pharmacokinetic testing
What is exploratory development?
- Potential product characterisation
- formulation/dose regimen
- Safety testing and efficacy
- Secondary effects, interactions and adverse effects assessed
What are the requirements of exploratory development?
- Preliminary toxicological testing
- Pharmacokinetic testing
- Chemical and pharmaceutical development
What is full development in drug development?
- Evidence of efficacy and safety
- Full clinical/field studies
- product file defined and registered
How is preliminary toxicological testing carried out?
- Often lab animals
- Maximum non-toxic dose and therapeutic index
- Post-mortem histological examination of tissue damage
What is included in pharmacokinetic testing in drug development?
- Required for registration
- Absorption, distribution, metabolism and elimination assessed
- Bioavailability assessed
What is included in chemical and pharmaceutical development of a drug?
- Feasibility of large scale synthesis
- Purification, chemical stability (shelf life), formulation
Outline the general timescale and cost of drug development
- Humans: 12-15 years, £500-700 million
- Veterinary: 5-11 years, £5-50 million (as many are based on human drugs)
- Large animal products more expensive, takes longer to carry out radio-labelled metabolism studies and residue studies
- Patent lasts 20 years
What is a locally licensed product?
- Authorisation on national basis only
- Driven by market size/production zone
- Can jump to centrally licensed by mutual recognition between countries
What is the authorising body in the UK for locally licensed products?
VMD
What is a centrally licensed product?
- One that is licensed in the EU
- EU harmonisation of local requirements
What is the authorising body for centrally licensed products?
- In EU: European Agency for the Evaluation of Medicinal Products (EMEA)
- FDA in USA
What are the key components of a clinical efficacy trial?
- Legal document for registration (title and study number etc)
- Study design (selection of animals, animal management, treatment, assessment, schedule of events, data analysis, disposal of animals)
- The unexpected (monitoring of adverse reactions/events, deviation and amendments to plan)
