Week 2 Summary.pdf

THE USE OF DRUGS TO TREAT PATIENTS Therapeutics: Interacting Considerations 1. Disease Factors 2. Drug Importance of diagnosis Efficacy and safety Specific therapeutic goals Licensed — for condition and species? Can be cases for symptomatic Off-label therapy Formulation—long or short acting? 4. Pat...

THE USE OF DRUGS TO TREAT PATIENTS Therapeutics: Interacting Considerations 1. Disease Factors 2. Drug Importance of diagnosis Efficacy and safety Specific therapeutic goals Licensed — for condition and species? Can be cases for symptomatic Off-label therapy Formulation—long or short acting? 4. Patient Temperament to allow administration Underlying physiology e.g. young, old, pregnant 3. Owner Financials Physical ability to administer treatments Should be involved in the decision making 5. Practice Corporate practices—specific disease protocol Drug buying power/deal e.g. deals with particular brands Shelf stock and turnover 6. Compliance Training and education—does the owner need training Therapeutic options—consider LA Drug Targets Dose Response Curves: Agonist 1. Receptors e.g. benzodiazepines—GABA receptor agonist, adrenoceptor agonists and antagonists 2. Ion Channels 3. Structural Proteins e.g. verapamil—L-type e.g. Taxol—Tubulin calcium channel antago- ‘agonist’ nist 4. Enzymes e.g. ACE inhibitors, aspirin, neostigmine 5. Carrier Molecules e.g. flaconoid—PGP antagonist, digoxin 6. DNA e.g. anti-cancer agents like Doxorubicin Definitions/Concepts Partial vs Full Agonist Potency (ED50) Amount of drug required to produce 50% of its maximal effects Potent drug = we can use less of it—not always the best choice Efficacy The maximum therapeutic response that a drug can produce Specificity Capacity of a drug to cause a particular action in a population Selectivity Relates to a drugs ability to target only a selective population i.e. cell/ tissue/signalling pathway/protein etc. in preference to others If activation is 100% = full agonist If activation is <100% = partial agonist Partial agonist = lower efficacy even with maximal occupancy of receptors This doesn't mean they shouldn't be used Therapeu- Effect of the drug as we increase the amount in the blood—reaches a tic Index threshold where it becomes effective, then another threshold where it becomes toxic. Wide therapeutic index is more beneficial with more room for dose increases. Tachyphylaxis—loss of target sensitivity The effect of a drug can decrease when given continuously or repeatedly due to: Change in or loss of receptors; exhaustion of mediators; increase metabolic degradation; physiological adaptation; drug transporters—need to monitor effectiveness and adapt THE PRESCRIBING CASCADE G R E A T N O R T H E R N I R E L A N D B R I T A I N WRITING A PRESCRIPTION Dx Diagnosis AR Adverse Reaction VMD Veterinary Medicine Directorate POM-V Prescription Only Medicine— Veterinarian Px Prescription SAR Suspected Adverse Reaction NOAH National Office of Ani- POM-VPS Prescription Only Medicine— mal Health Veterinarian/Pharmacist/SQP Tx Treatment SQP Suitable Qualified Person COPC RCVS Code of Professional Conduct NFA-VPS AE Adverse Event RQP Registered Qualified Person CD Controlled drugs AVM-GSL Authorised Veterniary Medicine—General Sale List How to Write a Prescription 1. Print or write legibly in ink. Sign with normal signature. Include the date 2. Product or approved generic name for drugs in CAPITAL LETTERS—no abbreviations; Include pharmaceutical form and strength 3. State duration of treatment and total quantity to be supplied 4. Write out microgram/nanogram—no abbreviations 5. Put 0 before decimal (e.g. 0.3); but not after decimal (e.g. 3.0) 6. Precise instructions concerning route/dose/formulation 7. Any alterations invalidate the prescription—must rewrite 8. Preparations for Schedule 2 and Schedule 3 controlled drugs must be entirely handwritten 9. Prescription shouldn't be repeated more than 3 times without a re-check 10. Include prescribers and clients names and addresses 11. Include directions such as ‘for animal treatment only’ is good practice 12. Include a declaration e.g., ‘this prescription is for an animal under my care’ 13. Clear declaration and justification if prescribing under the cascade Non-food animals—VPS Controlled Drugs Schedule 1—possession requires a Home Office Licence Schedule 2—drugs obtained and supplied must be recorded in a register for each drug Schedule 2 and 3—prescriptions are subject to additional requirements Schedule 4 and 5—drugs are subject to fewer controls Health and Safety Aspects of Prescribing - Must be satisfied that the person who will use the product is competent to use it safely and intends to use it for a use for which it is authorised - Must advise on the safe administration of the product - Must advise as necessary on any warnings or contraindications on the label or package leaflet - Must not prescribe more that the minimum quantity required for the treatment Definition: Any observation in animals whether or not considered to be product-related, that is unfavourable and unintended and that occurs after any use of a veterinary medicine Includes events related to a suspected lack of expected efficacy or noxious reaction in humans after exposure to veterinary medicine Adverse Reaction Reaction which is harmful and unintended and which occurs at doses normally used in animals for prophylaxis, diagnosis or treatment of disease Adverse Events Lack of expected efficacy = if during use the intended beneficial effects have not been observed this is suspected lack of expected efficacy (SLEE) Unexpected AE = if the nature, severity or outcome of an observed AE is not described in the SPC that event is unexpected Serious AE = AE results in death or increased rates of death in a species for which there is an expected death rate; life-threatening clinical signs; significant disability or incapacity; congenital anomalies or birth defects, or permanent or prolonged signs Non-serious AE = all other adverse reactions or lack of efficacy following treatment with a veterinary medicine are non-serious Any suspected AE involving animal or human you must: - record what happened in as much detail as possible - report the event electronically to the VMD within 15 calendar days USE OF CONTROLLED DRUGS AND SPECIAL CONSIDERATIONS Schedule 1 No current therapeutic use (possession and supply required Home Office permission) Schedule 2 Have therapeutic use but are highly addictive (subject to restrictions—prescription, storage, destruction and record keeping E.g., Methadone, morphine, fentanyl, pethidine, quinalbarbitone, ketamine, etorphine Schedule 3 Have therapeutic use, but misuse may leaf to moderate or low or high physical dependence (subject to restrictions—prescriptions and sometimes storage) E.g. buprenorphine, tramadol, gabapentin, pregabalin, midazolam, pentobarbitone Schedule 4 Therapeutic use but misuse may lead to limited physical dependence or psychological dependence (no additional control) E.g. alprazolam, diazepam, nandrolone, clenbuterol, somatotropin Schedule 5 Contain such small quantities of substance which may cause dependence that the potential for abuse is considered extremely low (no additional controls) E.g. paracetamol with codeine Procurement Producers and suppliers of controlled drugs are licensed by the Secretary of State Procurement of Schedule 2 and 3 drugs required a requisition form: - details of drugs requested and supplied - RCVS number - Copy retained by the supplier Storage Schedule 2: Kept in locked cabinet; recorded in register Schedule 3: Buprenorphine, Diethylpropion, flunitrazepam and temazepam must be kept in a locked cabinet Both schedule 2 and 3 should be in a locked box if being kept in a vehicle Prescribing and Dispensing Only an MRCVS can prescribe a controlled drug Disposal Written prescriptions for schedules 2 and 3 are valid for 28 days and must contain the MRCVS number Controlled drugs must be made irretrievable before disposal: The prescription must be kept by the supplier for 5 years, and the use recorded in the CDR - denaturing kits - soap for tablet - cat litter Destruction of schedule 2 drugs must be: - witnessed by: - VMR (veterinary medicines regulations) inspector - CLDO (controlled drugs liaison officer) - Independent MRCVS - recorded in CDR PRESCRIBING DRUGS Drug Distribution Classification POM-V (Veterinary Surgeon) POM-VPS (Vet, Pharmacist, SPQ) NFA-VPS (Vet, Pharmacist, SQP) Non-food animal AVM-GSL (General Sales List) SQP (Suitably Qualified Person) Works according to a VMD Code of Practice Training covers, legislation, basic anatomy and physiology, basic disease challenges plus species modules leading to a different qualification (R-SQP = all species; E-SPQ = equine and companion only; C-SQP—companion only) To supply medicines, the SQP must have passed the relevant species module and base exam POM-V POM-VPS NFA-VPS - Only prescribed by a vet following clinical assessment of animal(s) under their care - may be supplied by that vet or in accordance with a written prescription by another vet or pharmacist - Must be supplied from registered premises - No definition of ‘clinical assessment’ - client may request a written prescription - must be supplied from a registered premises - may supply in accordance with a written prescription from any authorised prescriber - client may request a written prescription - clinical assessment of the animal not required - clinical assessment not required - supplier must be satisfied that the medicine administrator is competent to do so safely - advise on safe administration and any warnings or contraindications - supply no more than the minimum amount required for treatment Medicine classification - requires strict limitation on use for safety reasons - required secialised knowledge of a vet for its use/application - it has a narrow safety margin requiring above average care in its use - government policy to demand a high level of professional control Medicine classification: Before prescribing: - indicated for use only in non-food ani- person administrating medicine must mals with no requirement for a prescripbe competent to do so safely and use for tion-only status authorised purpose - used routinely to limit the effects of - must advise on safe administration endemic disease in NFAs - risks to the user, animal or environment that can be explained and given Classified as POM-VPS when used to suitable countermeasures through simtreat endemic diseases e.g. antiparasitics ple oral or written advice Any risks to safety can be explained suitably through oral or written advice Small Animal Exemption Scheme (SAES) Medicines for use in certain pet species (aquarium fish, cage birds, homing pigeons, rabbits, small rodents, and terrarium animals) - the active ingredient of which has been declared by the Secretary of State as not requiring veterinary control Controlled Drugs All controlled drugs are listed in one of five Schedules in the Misuse of Drugs Regulations 2001 (MDR) and the Misuse of Drugs Regulations (Northern Ireland)(MDR (NI)) 2002. These are exempt from the requirement for a marketing authorisation and not required to prove safety, quality or efficacy, but must be manufactures to the same standards as authorised medicines and are subject to pharmacovigilance reporting Specified Feed Additive Authorised under Regulation EU 1831/2003 belonging to the functional groups; coccidiostats, histomonostats and certain other zootechnical additives ie non-antibiotic growth promoters These medicines may be considered for sale and supply purposes to be equivalent to AVM-GSL Prescribing take into account: Circumstances of the animal, available authorised veterinary medicinal products, the responsible use of medicines and the competence of the person administrating the product The supply process Access by staff/public; stock control and out of date medicines; labelling; authorisation for prescribing; safety and contraindications; hand over SOPs; prescription has all necessary details on it Records, Storage, Disposal Checked and must be kept for 5 years: Receipts and supply of prescription meds; date of supply/receipt, name, batch, quantity, address; copies of prescriptions; records of recent audits; imported drugs IMPORTANCE OF PHARMACOKINETICS TO THE PATIENT Drug Absorption Absorption from IV can be considered instant Absorption from infusion is independent of the amount of drug Drug Elimination Rate The amount of parent drug eliminated from the body per unit time Unit: mass or moles per time Elimination rate is defined with respect to irreversible removal of the parent drug and does not include metabolites (metabolites are a different chemical entity to the drug) Absorption from oral/IM is proportional to the amount of drug (first order kinetics). Need to define parameters that relate the amount of parent drug in the body to blood/plasma As the amount of drug at the administration site decreases with time, therefore the rate of absorption decreases Drug Metabolism Majority of drug metabolised in the liver—undergo enzymatic metabol-isation into new metabolites Phase 1 = drug made more water soluble Phase = attach an endogenous water soluble molecule CYP450—major family of enzymes that metabolise drugs— gives a hydroxy functional group = more water soluble Drug Clearance measure of the efficiency of drug elimination The volume of blood/plasma cleared of parent drug per unit time OR a constant relating to the rate of elimination to the blood/plasma concentration The sum of all organ clearances: CLtotal = CLheptaic + CLrenal + CLpulmonary (units—volume/time/kg) Blood plasma clearance determined for the area under the blood/plasma concentration versus time curve (AUC = area under curve) for IV administration Volume of Distribution (Vd) The volume into which a drug appears to be distributed with a concentration equal to that of plasma OR a proportionality constant relating the blood/plasma concentration to the amount of drug in the body A drug’s reversible affinity for tissue proteins versus plasma proteins determines magnitude of Vd usually expressed in units of volume/kg Drug Excretion Drug Renal Excretion Filtered at the glomerulus drugs are bound to proteins only the free drug can be filtered into the nephron PCT—transporters that move weak acid and basic drugs into the lumen DCT—lipophilic —> blood; less lipophilic = excreted with urine Bioavailability Measure of the extent of absorption from administration site to measurement site Separate IV and oral studies required Fraction or percentage of administered dose that reaches the plasma Often used with oral route administration Not about how fast it is absorbed, but how much is ultimately absorbed Half-Life The time for the concentration of the drug to halve Half-life is dependent on volume of distribution (reversible) and the clearance (irreversible) POLYPHARMACY AND MULTIPLE DRUG ADMINISTRATION Drug-drug Interactions—altered pharmacological response to one drug caused by the presence of a second drug Pharmaceutical: interaction prior to administration Pharmacokinetic: tissue/plasma levels of one drug altered by another one Effects: Action of one or more drugs is enhanced, inhibited or has completely no effects or no change Mechanisms of interactions: Pharmaceutical Physical—Incompatibility/interaction: binding to plastic e.g. diazepam; insolubility in certain solutions e.g. amphotericin B precipitates in electrolyte solutions Chemical—Stability of drugs is often pH dependent e.g. penicillin G inactivated by alkaline sulphonamide; Oxidation/reduction reactions e.g. tetracyclines are oxidised by riboflavin; Complex formation e.g. chelation of drugs; Inactivated by certain vehicles e.g. fluoroquinolones can be inactivated in calcium-containing solutions Mechanisms of Interactions: Pharmacokinetic Absorption Change in gastric pH and bacteria flora Chelation of drug in stomach Altered gastric emptying—can increase or decrease absorption Interference with intestinal efflux protein Metabolism Inhibition of liver enzymes –CYP450) Excretion Urinary pH will alter clearance of renally excreted drugs e.g. sodium bicarbonate makes urine more alkaline Distribution Competition plasma protein binding e.g. warfarin and phenylbutazone Some drugs reduce circulation and blood flow to tissue, leading to reduced clearance and reduced absorption from intra-muscular or subcutaneous administration e.g. injectable and inhalant anaesthetics Mechanism of Interactions: Pharmacodynamic Additive (could be beneficial or detrimental) - could enable reduced doses to be administered e.g. barbiturates + benzodiazepines for sedation; opioids and NSAIDS analgesia - increased toxicity e.g. NSAIDs + steroids = increased risk of GI ulceration; NSAIDs + aminoglycosides = nephrotoxicity Synergistic (combination leads to a greater than the sum of each drugs action produce an enhanced therapeutic effect or increased toxicity e.g. B-lactam antibiotics + aminoglycosides = enhanced; aminoglycosides + furosemide = toxicity Negation (Opposing action leading to reduced effect) the basis of antidote/reversal agents—atipamezole and medetomidine, and opioids and naloxone Adverse Events (ADE) Unintended or noxious response to a drug that occurs within a reasonable time frame following administration Use patterns associated with increased ADE—use of human-label drugs, drugs with low therapeutic indices, inappropriate/ trivial use, lack of therapeutic goals, multiple drugs, young, old, altered PK (pharmacokinetic potential) Types of ADE: Lack of efficacy, exaggerated normal response (often dose related), hypersensitivity (non-predictable, can be immediate; non-dose related), toxic effects (unrelated to pharmacological action), idiosyncratic (unknown cause, genetic?) Considerations: Recognition—may be a challenge especially with lack of efficacy; Reporting—if in doubt, report! FUNDAMENTALS BEHIND DRUG REGIMES Determinants of a dose regimen Pharmaceutical company will give you the regime for the condition in the species The information comes from the pharmacokinetics of the drug Ultimately, want concentrations to rise rapidly, maintain within the therapeutic range for the required duration, and then to be eliminated from the body Dosage (the giving of medicine in prescribed amounts over time) 1. How much is needed to illicit a response. Ideally higher potency = less drug needed 2. Need to cross a plasma membrane (except IV) need to be lipophilic, uncharged and small 3. Oral—go directly to liver from gut—first pass = less if any will reach the systemic circulation Bioavailability = amount that’ll reach the circulation 4. Protein bound in the plasma vs free—higher affinity for tissue proteins— moves out of blood Onset of action (related to Tmax) 1. IV enters circulation immediately; oral = slower effect; gut contents can speed up or slow it down 2. Freely cross plasma membrane = absorbed quicker = earlier onset of action Higher effect for shorter vs lower effect for longer 3. State of shock (among other things) can greatly reduce absorption Loading and Maintenance Dose Drug with a long half life will take a while before reaching high levles—could take several days to reach steady state concentrations—may or may not be clinically appropriate Loading dose = can reach the steady stable doses at an earlier time Maintenance dose = after reaching the required level with loading dose—lower doses to maintain the same level Multiple dosing and Frequency Ideally constant infusion Increasing frequency of dosing reduces peaks and troughs Multiple Dosing and Saturation CHANGING DRUG THERAPEUTIC REGIMES Related to Drugs Related to the Body Factors Affecting Drug Absorption - High for lipid soluble drugs - Low for Molecular size >1000 - Increases for small particle size - Decreases for high degree of ionisation - Formulation can improve absorption - Increases with surface area of absorptive surface - pH will affect extent of ionisation - GI motility (slow increases absorption, fast decreases) - Integrity of absorptive surface - Diseases Factors affecting Drug Distribution (Vd) - High for lipid soluble drugs - High for weak base drugs - Low for water soluble drugs - Low for weak acid drugs - Increases with high body fat content for lipid soluble drugs - Increases with high body water content for water soluble drugs - Low for drugs highly bound to plasma proteins Factors Affecting Drug Metabolism Clearance - Generally high for lipid soluble drugs - Generally low for water soluble drugs - Protective chemical groups for lipid soluble drugs can reduce metabolism (eg F, CN) - Drug – drug interactions: > Inhibition reduces > Induction increases - Quantity of drug metabolising enzymes—more enzymes = greater metabolism - Enzyme polymorphisms - Clearance of drug decreases with decreasing blood flow to metabolising organ - Drug plasma protein binding – low binding increases clearance - Diseases Factors Affecting Drug Excretion Clearance - High for water soluble drugs - High for ionisable drugs - Low for lipid soluble drugs - Inhibitory drug – drug interactions - Quantity of drug transporters - Clearance of drug decreases with decreasing blood flow to excreting organ and GFR for the kidney - Drug plasma protein binding – low binding increases clearance - Diseases Altered Pharmacokinetics in the Neonate Absorption Distribution Difference from average Adult Absorption is variable Increased for non-lipid drugs Outcome Variable bioavailability Affects plasma level •Dose •Dosing frequency Metabolism Excretion Reduced hepatic function GFR normal within a few days •altered gastric emptying •Very species specific •Irregular peristalsis •Greater water content •Biotransformation of Drug Tubular secretion in •Increased permeability •Decreased plasma pro- drugs normal within a few nephron takes longer of mucosa tein binding days in foals •for many weak acid or •Rapid topical absorption Decreased for lipid drugs •3-6 weeks in other dobasic drugs may take 3-4 due to immature percuta- •Lower adipose content - mestic species weeks neous barrier less fat uptake Possible lower metabolic clearance Possible lower excretion clearance Changes to dosing regimen in the Neonate - rarely dose needs increasing - Usually dose needs reduction—adult doses may result in accumulation due to differences in distribution—more likely to produce toxicity, adverse reactions; blood brain barrier not fully complete—risk of undesired CNS penetration - sometimes—absolute contraindication—fluroquinolones and tetracyclines CHANGING DRUG THERAPEUTIC REGIMES Altered Pharmacokinetics in the Geriatric Absorption Distribution Metabolism Excretion Difference from average Adult Absorption reduced Body mass decreases •Gastric pH increased altered drug ionisation •Less microvilli •Less mixing and dissolution •Delayed disintegration of tablets •Less water content •Increased adipose tissue •Increased Vd for fat soluble drugs-increases half life •Lower Vd for water soluble drugs - decreases half life Effects on metabolism minimal Decreased renal elimination •Decreased plasma albumin •less binding may lead to more free drug for metabolism but also increases Vd resulting in no change in half-life •Decreased renal mass, GFR and tubular secretion •Very similar to animal with chronic renal disease Outcome Reduced bioavailability Lower Cmax Later Tmax Affects plasma level •Dose •Dosing frequency Little change in metabolic Lower excretion clearclearance ance Changes to dosing regimen in the Geriatric - For drugs mainly eliminated by the kidneys: reduce dose or dosing frequency; use alternative drug that is liver metabolised - For fat soluble drugs: average adult dosing regimens may result in accumulation due to increased fat distribution—more likely to produce ‘hang-over effect’ and toxicity - For water soluble drugs: rarely need to change dosing regimen as reduction in Vd and therefore half-life tends to be small Disease Altered Pharmacokinetics Changes to regimen Chronic cardiovascular disease Respiratory disease Liver disease Renal disease •Decreased mentation - increased effects of sedatives etc •Decreased blood flow – lower clearance for highly cleared drugs (eg anesthetics) Altered serum pH and protein binding Content and activity of phase I/II reactions is decreased Little effect on drug metabolism until 80% functional loss No adequate functional tests—bile acids closest Most antimicrobials are well tolerated Associated with the most profound changes in PK A gradual loss of urine concentrating ability and ability to acidify Also altered drug distribution patterns Change in acid base balance Uraemia: chronic acidosis, reduced albumin binding of drug, less hepatic metabolism Mainly an issue for IV anesthetics Avoid drugs with high Adjust dose clearance or reduce down for intradose venous anesthetics Rarely an issue but reduce Avoid renally cleared drugs? dose if necessary for seAdjust dose down for changes in vere cases or use a drug GFR? that is primarily renally cleared Drug Therapeutic Indexes High Therapeutic Index— rarely require therapeutic monitoring NSAIDs: Aspirin, Tylenol, Ibuprofen Sedative/hypnotics: Most antibiotics Benzodiazepines Low Therapeutic Index—may require the measurement of drugs plasma concentrations Neuroleptics: Phenytoin, Phenobarbital Lithium Betablockers Some antibiotics: Digoxin Gent/Vanco/ Amikacin Immunosuppressives ANTI-VIRALS AND ANTI-FUNGALS Anti–Virals Medications that help the body fight off certain viruses A preventative measure Large cost associated Better to develop effective vaccines, but this isn't always possible Not typically used in first opinion practice 1. 2. - Limited safety and efficacy in animals - Widespread use not common - Drugs that negatively impact a virus are also likely to negatively impact the host - Anti-virals have a narrow therapeutic margin - Anti-virals that inhibit singular steps are only temporary - Adequate immune response required Acyclovir—Herpesvirus family e.g. Pacheco’s disease (parrots/cockatoos) - relatively safe, resistance increasing Famciclovir—Herpesvirus family (cats) - longer duration of action Treatment Approach 1. Viral enzyme inhibition—blocks the ability of a virus to attach/ enter host cells 2. Immune response enhancement—block the ability of a virus to attach/enter host cells Example: Interferon: Inhibits viral synthesis in infected cells—FeLV and parvovirus uses Ribavirin—Broad Spectrum - Adenoviruses, Herpesviruses, Rotaviruses and Retroviruses— resistance rare; greater complications 3. Trifluridine—ocular Herpes Anti-Viral vs Viricide Viricide destroy external to host e.g. Virkon (disinfection) 4. Zidovudine—Retroviruses—FeLV and FIV— useful in acute stages (prevents replication) Additional options—increased use Supplements (L-lysine) blocks viral enzymes Antifungals Class Examples Mechanism Azoles Itraconazole, Ketoconazole Inhibit cytochrome P450-dependent synthesis of ergosterol in fungal cells Allylamines Terbinafine Inhibits synthesis of ergosterol in fungal cells but via inhibiting an enzyme (squalene epoxidase) Polyenes Amphotericin B, Nystatin Binds to sterols (ergosterol) in fungal cell membrane Pyrimidine Analogues 5-fluorocytosine Converted by the fungal cells to 5-fluorouracil—antimetabolite chemical—results in inhibition of DNA and RNA synthesis Cellular toxin—not 1. Silver sulfadiazine specific to fungi, but 2. Chlorhexidine (hibiscrub) have antifungal 3.. Virkon—disinfectant activity 1. Releases silver in concentrations that are toxic to bacteria and yeasts 2. Binds to the skin and forms a protective layer 3. Per-oxygen compound that oxidises sulphur bonds in proteins and enzymes disrupting the function of the cell membrane Cats and Dogs (Off licence in cats) (Off licence in dogs) (Off licence in both) Otitis Externa (Malassezia) Malassezia Skin Infections Ringworm (Dermatophytosis) Nystatin Miconazole Clotrimazole Terbinafine Posaconazole Silver sulfadiazine All (apart from silver sulfadiazine) also contain steroid and antibiotics Miconazole shampoo Climbazole wipes Itraconazole—oral Ketoconazole shampoo or skin spray Terbinafine—oral/gel/cream/spray Itraconazole—systemic treatment Itraconazole—oral Ketoconazole—oral Enilconazole—skin rinse Miconazole—shampoo Chlorhexidine—shampoo/foam/spray/otic solution/ wipes Clotrimazole Terbinafine—oral/gel/cream/spray Fluconazole—oral/injectable Itraconazole most commonly used in cats Systemic/Deep Mycoses, Amphotericin B—injectable Cryptococcosis, Urinary Can- Fluconazole—oral/injectable didiasis Flucytosine—oral/injectable Silver sulfadiazine useful for Malassezia/ Pseudomonas resistant infections DO NOT USE ketoconazole in cats Terbinafine rarely used Ketoconazole most commonly used in dogs—DO NOT USE in cats Chlorhexidine synergistic with miconazole— ineffective alone Terbinafine and Fluconazole rarely used Not used very often as these diseases are rare in the UK Rabbits and Small Mammals—**all are off licence** Ringworm (Dermatophytosis) Itraconazole—oral Enilconazole—skin rinse Miconazole—shampoo Chlorhexidine—shampoo/foam/spray/otic solution/wipes Clotrimazole—cream Itraconazole—systemic treatment Chlorhexidine synergistic with miconazole— ineffective alone Guinea pigs can be subclinical carriers of ringworm—only treat if showing sings or infection in in contact animals Horses—**all are off licence** Ringworm (Dermatophytosis) Enilconazole—skin rinse Miconazole—shampoo Griseofulvin Griseofulvin—systemic treatment Fungal Keratitis (Keratomycosis) Clotrimazole Human canestan cream Enilconazole—skin rinse Ringworm is normally self-limiting in cows Enilconazole—only on licence treatment is in the form of the imaverol rinse Cattle Ringworm (Dermatophytosis) Non-food producing birds (red = off licence) Candidiasis Aspergillosis Itraconazole Voriconazole Nystatin Amphotericin B Aspergillosis affecting commercial birds cannot be treated—culled Itraconazole F10 products—disinfectant Itraconazole off licence Voriconazole—very expensive Reptiles Fungal dermatitis (dermatomycosis) NSAIDS Small Animal Equine Farm Animal Meloxicam Carprofen Robenacoxib Firocoxib Phyenylbutazone Meloxicam (suxibuzone) Ketoprofen Flunixin megluime Meloxicam Gapiprant Pharmacokinetics Weak acids well absorbed after PO administration Food can impair absorption Several NSAIDs have formulations for IV, IM and SC Very high plasma protein binding—potential for drug displacement but limited affect on free drug concentrations—proteins concentrate in areas of inflammation—therefore NSAIDs tend to collect here Biotransformed in the liver to inactive metabolites, with some limited direct excretion via the kidney Mavacoxib is not metabolised and excreted via bile Action Inhibit COX enzymes and therefore prostanoid synthesis in inflammatory cells. Anti-inflammatory: decrease in PGE2 and PGI reduces vasodilation and indirectly oedema Analgesic effect: decreased PG generation means reduced sensation of nociceptive nerve ending to inflammatory mediators such as bradykinin Anti-pyretic effect: Interleukin 1 releases PG in the CNS, where they elevate the hypothalamic set point for temperature control = causing fever. NSAIDs prevent this General Notes: Do not administer with other NSAIDs concurrently or within 24 hours of each other; do not use/minimise use in animals with cardiac, hepatic or renal disease Classes of NSAIDs Salicylates Phenylbutazone Carprofen Ketoprofen Flunixin Oxicam Derivative Coxib - Non-selective - Irreversible interaction with COX - Mild to moderate pain - Aspirin - No licensed product - Non-selective - Management of mildmoderate pain and inflammation - Main metabolite has similar properties - Therapeutic index of phenylbutazone is low - Half-life: 3-6h DO NO USE IN CATS - Non-selective - Acute pain and chronic pain from osteoarthritis - Alleviation of inflammation and pain associated with MSK and GI disorders - Not licenced for perioperative indication - Alleviation of inflammation and pain associated with MSK, respiratory and GI disorders - COX2 selective - Alleviation of inflammation and pain in chronic MSK disorders and post-operative pain Meloxicam, Piroxicam - Highly COX2 selective - >100 fold selectivity for COX over COX1 - Pain and inflammation associated with osteoarthritis and peroperative - Robenacoxib, Firocoxib, mavacoxib, cimicoxib - COX2 preferential - Post-operative pain and inflammation - Reduction of chronic inflammation - Adjunct to reduce pain associated with acute infectious respiratory disease and mastitis Contra-indications: Stem from inhibition of COX1 constitutive housekeeping GI disturbances—gastric and intestinal damage may occur with chronic use—risk of ulceration and bleeding. Due to suppression of gastroprotective PGs in gastric mucosa Adverse Cardiovascular Effects—can occur with many NSAIDs including coxib. May be related to COX2 inhibition in the kidney —> hypertension Reversible renal insufficiency—mainly in patients with compromised renal function when the compensatory PHI2/PGE2-mediated vasodilation is inhibited Bronchospasm—seen in aspirin-sensitive asthmatics Grapiprant (brand name galliprant) New class of priprant NSAID Selective antagonist of the EP4 receptor EP4 receptor mediates PGE2-induced nociception Rapid absorption after oral treatment Gapiprant is primarily excreted via faeces (largely unchanged) but also direct renal excretion Use with caution in dogs suffering from pre-existing liver, cardiovascular, renal or GI disease ANTIBBIOTIC DECISION MAKING Antimicrobial Stewardship—coordinated interventions designed to improve and measure the appropriate use of antimicrobials by promoting the selection of the optimal antimicrobial drug regimen, dose, duration of therapy and route of administation Critically Important Antibiotics (CIAs) ANTIBIOTIC DRUG CLASSES AND MECHANISMS Spectrum of Activity Narrow Spectrum: Targets narrow group of bacteria i.e. either Gram positive or Gram negative Broad Spectrum: Targets the Gram positive and Gram negative bacteria - can have a bigger impact on the other bacteria in the host—bad idea in management and reduction in risk of bacterial resistance Killing Activity Bactericidal: kills the organism e.g. penicillin’s, cephalosporins—useful in critical care where the host won’t be able to manage the infection Bacteriostatic: drugs that temporarily inhibit the growth of an organism e.g. reversible if removed e.g. tetracycline’s, chloramphenicol; rely on host to remove the organism Context and Concentration Distributions of an antibiotic will depend on its chemistry To be effective, the drug needs to reach the MIC at the site of infection MIC = minimum inhibitory concentration MBC = minimum bacterial concentration Values for MIC/MBC for each class of antibiotic will vary be type of bacteria Cell Wall Targeting - Peptidoglycan is unique to bacteria—good target - Peptidoglycan is a polymer of sugars and amino acids that form a mesh-like cell wall - Polysaccharide chains cross linked by interlinking peptides Antimicrobials targeting the wall: Lysozyme produced by host—breaks bond in sugar polysaccharide Beta-lactam antibiotic—inhibit the transpeptidase (PBP) so peptide cross links cannot be formed Glycopeptides—these cap the peptide chains so peptide cross-links form Results: weakened cell walls rupture due to positive osmotic pressure Inhibition of protein synthesis—ribosome targeting Work by binding specific points in the ribosomal complex—either bind to either 30S or 50S units Modifications of these sites can lead to poor binding increasing the MIC required and therefore resistance All inhibit translation of RNA through the ribosome to a protein—selective for 70S bacterial ribosomes rather than 80S in eukaryotic cells Cationic Antimicrobial Peptides Topical application Interact with membranes to disrupt Product licenced for dermatology (ears) Lipids/charge properties of host vs. bacterial membrane allow for distinction Considerations for success: Time: time that the serum concentration exceeds the MIC Concentration: killing increases with concentration; requires high concentrations at drug binding site to be effective—not always beneficial to maintain this level between doses However… The longer the antibiotics is present, the higher the risk of selection for resistance Need to consider if the site I likely to be aerobic or anaerobic ANTIBIOTIC DRUG CLASSES AND MECHANISMS Cell Wall Targeting Beta-Lactams Ribosome Binding Antibiotics ANTIBIOTIC DRUG CLASSES AND MECHANISMS Other Groups and Targets Groups of Antibiotics and Relative Activities COMMON COMBINATIONS OF ANTIBIOTICS PRINCIPLES OF ANTI-MICROBIAL RESISTANCE Resistance and MIC Determination Disk Diffusion—relative diameter of inhibition is related to the concentration right at the fringe of the zone MIC—liquid cultures—can take a direct reading— higher MIC = more resistant Breakpoints: e.g. if MIC less than X = sensitive; more than X = resistant OR if diameter <X = resistant; if >X = sensitive Intrinsic Resistance an innate ability to resist activity of a particular antimicrobial agent through which an inherent structural or functional characteristics which allow tolerance of the drug i.e. lacks target or has an altered target Poor Permeability due to outer membrane Non-veterinary Gram negative bacteria are generally resistant to Vancomycin which cannot penetrate the outer membrane of the bacteria Target different to other Genera Enterococci are generally resistant to cephalosporins which have a low affinity for enterococcal PBPs (penicillin binding proteins) Lack target Mycoplasmas lack cell wall, so cell wall targeting antibiotic will not work on them Acquired Resistance when a microorganism obtains the ability to resist the activity drug. Can be mutation or new gene acquisition—allows alteration of the drug, alteration of the target, bypass mechanism, efflux systems Gene Mutations Gene Acquisition Co-resistance Lead to change in a target Mechanisms transfer—conjugations of Genes physical linked on the same mobile element so binding site plasmids or other rounds found together once established Risks transfer between potential patho- Binds the same or very close sites. One change affects Efflux systems gens and commensals binding of multiples or modification of site Pump the drug out and keep it at a low level inside ← 1. Acquired resistance by mutation and modification of the cell where it would target normally have an effect 1. Normal structure of target—AB binds and inhibits 2. → 2. Mutated site missense—reduces binding reduce AB activity ← 3. 3. Modification site i.e. methylation reduces AB binding and function Efflux Common for Tetracycline but also other AB’s Degradation—of antibiotic most common you will experience are Beta Lactamases Factors that increase risk of selection Underdosing, length of selective level, presence of resistant bacteria to select Drugs with a long half life stay at a therapeutic range for a long time, but also have a long lag below the MIC but above the MSC line = high risk for increasing resistance Modification of antibiotics i.e. acetylation of aminoglycosides DISINFECTIONS Relative Resistance to Disinfection Some disinfectant don’t work on fungal spores, non-enveloped viruses or mycobacterium Only removal method for Prions is disposal and incineration Faecal Oral Route Thorough cleaning guidelines for all animal contact items and surfaces Food rotated first in first out basis (i.e. not constantly topped up) Food stored where pest can not get in (i.e. rodents on farms) Waste and Food streams kept separate Isolation units for patients with suspected/diagnosed infectious disease Routine to clean areas of exercise / general areas Prompt cleaning of bodily fluids where patient traffic may occur Fomites Hands are a source of transmission; wash frequently/wear disposable gloves Where possible have hands free sinks and towel dispensers Have routine checks on dispensers Avoid ‘topping off’ of dispensers (policy of total refills) Change PPE where soiled or dirty Ensure adequate washing of PPE Clean and disinfect shoes/boots routinely Have dedicated footwear for work purposes Equipment: Clean all equipment that is used on patient before reuse Contacts Limit number of staff with direct contact with infectious patients Reduce congestion in waiting areas to reduce contact time Cleaning protocols for stalls, pens, carriers are vital Use barrier controls to prevent inadvertent contamination between patients. Ensure all wounds / draining tracks covered Promptly clean up bodily excretions Use disposable items where possible Sequence rounds: i.e. Where have mix of boarding and hospitalized patients – tend to boarded animals first Farm Facilities Never use manure buckets to move feed Pest control, insect repellents House different ages groups separately Minimise manure run-off/have adequate storage Drain areas with standing water Advise clients to isolate incoming animals / returning patients Have foot bath/protective clothing available for visitors (spray down vehicles) Have a routine protocol for biosecurity Put in step-over barriers On top of this husbandry space, aeration of areas and isolation etc. STERILISATION Pasteurisation Passing heat over an item—more commonly used in food production—items placed without covering or packaging and heated to 150-180o for 30 minutes to perform any killing of microorganisms. Not effective against spore creating bacteria Sterilisation Using steam and high temperature—more effective destruction of all microorganisms including spores Most effective method is to combine heat and pressure = autoclave Vacuum associated autoclave—most commonly used—has multiple temperature settings, a vacuum pump to assist with maintenance of the correct pressures for the correct time and also have drying cycles to ensure the equipment is dry and suitable for storage 1.Surgical pack placed in the chamber (media flask) – need to ensure there is space around all items when on the rack for air flow around everything 2.Steam enters from the pipes within the system (water feed) – circulated around the surgical packs 3.Any air inside is pushed out by the steam through the air outlet – in most systems this is assisted by a vacuum mechanism 4.Steam condensates as it hits the cooler surfaces of the surgical kits 5.As it condensates, steam produces heat, higher pressure = hotter stem 6.Penetrates right to the centre of the kits = maximum sterilisation 7.Temperature drops after correct time, steam evacuated, pressure returns to normal 8.Activates a dry heat drying methods – pack should come out dry and ready to story 9.Security feature to ensure the pack cant be removed until the cycle is complete – safety Chemical Sterilisation Also known as cold sterilisation Not very effective Mainly liquid forms and would be considered more of a disinfectant Some liquids can cause a problem when placed in the body Gas Sterilisation Ethylene oxide, inactivates the DNA of the cells—very effective Has strict COSHH controls, highly toxic Requires training and specific equipment Cycles are either 12 or 24 hours and cannot be interrupted All gas must be evacuated prior to use of the equipment Excellent for sterilisation of non autoclavable products such as endoscopes Preparation of Surgical Instruments - Cleaning and checking of surgical instruments—thoroughly cleaned, checked for damage and lubricated prior to sterilisation - Packing surgical instruments—should be ready to use and storable - Method of sterilisation—depends on the kit that needs sterilising - Monitoring sterilisation—Bowie Dick tape -temperature only; TST strips—time, steam, temperature; Browns tubes—not common - Checking and out of date supplies—all sterile supplies should be labelled, date, initials and what is within the pack—storage is recommended 1 year for autoclaved items, 2 year for gas Any damage to packs or with visible moisture shouldn't be used and the material should be re-sterilised before use