POS- Week 1 Flashcards
Toxicity associated with HRT/Oral contraceptives
Low toxicity along with powder flower food, silica gel, zinc oxide cremes
Why is Paracetamol toxic?
Toxicity occurs via saturation of metabolic pathways. Toxic metabolite conjugated by gluthione but this is promptly depleted. Leads to OXIDATION and the formation of NAPQI
CCWhy does NAPQI lead to cellular death
NAPQI is the result of oxidation of paracetamol and binds to essential amino acids and results in cellular death
Clinical manifestation of paracetamol toxicity a) <24 hrs c) days after
a) <4 hrs: Progressive cyanosis, brown/blue MM, weakness and lethargy
b) Facial/Paw Oedema, vomiting, depression, methhaemaglobin
c) Severe methaemaglobinaema, hepatic necrosis
Cyanosis DOES NOT RESPOND TO OXYGEN THERAPY
What colour is Methaemaglobin? Significance in toxicity
Methaemaglobin is brown (apparent from 4-24 hrs) and days ahead post paracetamol toxicity.
Toxic metabolite NAPQI
At what dose should ingestion of paracetamol be treated?
Cat: 20mg/kg (i.e. any ingestion)
DogL 150mg/kg
Treatment for Paracetamol toxicity
Emesis (within 2 hrs) Apomorphin or Xylazine
Antidote: Acetylcystiene (precursor of glutathione)
Also SAMe
Ascorbic acid
Antidote for Paracetamol; how does it work?
Acetylcystiene which is a precursor of gluthione (try to prevent pathway being saturated so oxidation pathway doesn’t happen = NAPQI)
Continue treatment until clinically well
How to induce emesis in a) cat b) dog
a) Cat: Xyazine
b) Dog: Apomorphine
NSAID’s toxicity is largely due to ___ inhibition
NSAIDs toxicity is largely due to COX-1 inhibition
Carprofen and meloxicam are examples of
COX-2 inhibitors. (Flunixn and Phenylbutazone are non-selective)
Early and Late clinical manifestations of NSAIDs toxicity
Early: Gastrointestinal erosion, ulceration and potentially perforation. Vomiting/Diarrhoea (bloody), rarely CNS signs
Late: Renal/ Hepatic failure
NSAIDs treatment
No specific Antidote.
Emesis (optimal within 3 hrs, apomorphine/xyalizine)
Activated charcoal
Prevention of gastric ulceration: H2 receptor antagonists, proton pump inhibitors. ulcer healing
Supplement prostaglandin, maintenance of renal function (fluid therapy)
Examples of a) H2 receptor antagonist b) proton pump inhibitor
a) h2 receptor antagonist: Cimetidine, Ranitidine
b) proton pump inhibitor: Omeprazole
Approx toxic dose of a) white chocolate b) milk chocolate
Theobromine is toxic component of chocolate
a) white chocolate: 2200g/kg!!!!!!
b) milk chocolate: 9g/kg
c) dark choc: 1.25 g/ kg
Clinical effects of Theobromine toxicity
Vomiting/Diarrhoea/ Polydipsea/ Salivation/ Dehydration
CNS / Myocardial stimulation - tremor convulsion/ tachycardia
Renal failure
Severe cases- severe convulsions/ circulatory failure
Management of Theobromine toxicity
Emesis- apomorphine/ activated charcoal/ adequate rehydration
ECG/ Benzodiazapine for CNS stim.
Treatment of arrthymia (lidocaine/ beta blocker)
Tremorgenic Mycotoxins
Mycotoxins are fungal metabolites produced by mould. Normally mouldy food waste. Penitrem A/ Roquefortine.
How does toxicity come about from Penitrem A
Penitrem A is a Tremorgenic Mycotoxin (mould).
Interfers with release of neutrotransmitters (glytamate, aspartic acid/ GABA)
- Within 3 hrs whole body muscle tremors, tachycardia, nystagmus, bleparospasm
Onset of effects of Penitrem A
Usually within 3 hours; vomiting/ataxia whole body muscle tremors, rigidity with hyperextension of exrememeties, tachycardia, tachypnoea, nystagmus
Management of Tremorgenic Mycotoxins
from mould e.g. Penitrem A.
Decontaimination (emesis/ apomorphine./ activated charcoal)
Anticonvulsants (benzodiapine, barbiturate)
Allium species includes…
Which part is toxic
Large group of plants (>600), mostly pereenial bulbous herbs inc LEEKS, ONIONS, SHALLOTS, SPRING ONIONS, GARLIC/ CHIVE.
Contain organosulphoxides
Toxic dose of Allium species
e.g. onions/leeks/shallots.
>0.5% of body weight (therefore 5 g/kg)
Leads to Heinz body formation and anaemia
Clinical effects of Allium species
Due to organosulphoxides, forms mixed sulphide bond between haemaglobin and gluthione resulting in formation of Heniz bodies = damaged erythrocytes removed from circulation
Onset of Allium species
Onset is variable (toxic dose = 0.5% of body weight)
Signs of haemolysis can be delayed for 1-5 days.
Heinz bodies can appear within 24 hrs.
Vomiting/ inappetance (onion breath..)
Heniz body anaemia (pale MM, tachycardia)
Haematuria/Haemaglobinurea are common
Urine smells of onions
Why would icterus be a (less common) effect of Allium species ingestion
Allium species = Heinz body formation and anaemia (Organosulphoxide)
More serve cases, icterus due to haemosiderin (high iron stores) in the liver.
Management of Allium poisoning
No antidote, supportive.
Emesis/ activated charcoal/ IV fluids
High protein diet may promote rsotration of gluthioone stores.
Anticoagulant poisoning halflife for a) warfarin and b) brodifacoum
a) Warfarin half life is 14 hrs
b) Brodifacum half life is 6 days.
Vit K essential for production of clotting factors (2, 7, 9 and 10)
Which coagulation test would be increased first in acute rodenticide poisoning
Factor VII has the shortest half life = Prolonged PT. (pro thrombin time)
Then will affect extrinsic and instrinsic pathway as factor 2, 7, 9 and 10 are all vit K dependent
Onset of effects for Rodenticide toxicity
Depends on half life of clotting factors.
VII 6.2 hors IX 13 hours
Onset of effects = 27-72 hours.
Bleeding from gums, nose, Gi tract and wounds
Treatment for Rodenticide toxicity
Not always required, monitor elevations in PT.
Vit K1 therapy if prolonged. Administer until PT normalises MULTIPLE INJECTION SITES.
Once PT is normalsed then oral K1 for 2-3 weeks gradually reduced dose.
What compound causes the most fatalities (as reported to VPIS)
Mollusicides. Contain Metaldehyde. Death normally due to respiratory depression. Common signs: Hypersalivation/ V&D/ Ataxia/ Convulsions
Mechanism of toxicity for Vipera berus?
Hypovolemia and local oedema result from increased vascular permeability due to released of mediated histamine.
Renal impairment possible due to Hypovolemic shock.
Over the phone advice for suspected adder bite
reassure. high morbidity low mortality.
No tourniquets or ligatures (ischemia)
AVOID INTERFERENCE OF WOUND
Immobilise the affected limb. i.e. carry dog not walk)
Clip area and Look for puncture marks 5-10mm apart.
Necrosis is rare.
Systemic effects of adder bite
shock, collapse and hypotension.
Pain, panting and hypersalivation, pale mm, tachypnoea.
Coagulopathy: anaemia, thrombocytopnea, leucocytosis, DIC, and haematuria.
Monitoring and Treatment for adder bite
Observation IV fluids Antivenom (zagreb) BP, RR, HR, Temp ECH (arrival, 12 hrs, 24 hrs) BT (coagulopathy) Renal/hepatic parameters
Indications for use of antivenom *ZACREB)
Any animal with bite to facial region/ severe swelling.
Swelling beyound next major joint prox to bite
Hypotension unresponsive to IV fluid
Evidence of coagulopathy
Any ECG abnormality.
EXCESSIVE USE OF A/V = SEVERE REACTION. Previous use is not a contraindication.
Still indicated if systemic signs days after bite. If ONLY local signs NO value a/v after 24hrs.
What analgesics are recommended for adder bite?
Opiods preferrerd over NSAIDs due to renal perfusion concern if hypovolemic.
Antibiotics routine use NOT recommended.
NO role for steroids unless anaphaylactic reactions to anti venom.
Antidotes for a) Antifreze b) Benzodiapemine c) 5-HT
A) Anti-freeze: Ethanol
b) Benzodiazapine: Fluamezil
c) 5-HT - Cryptohepatidine
Antidote for Organophosphate poisoning
Pralidoxime for OP poisoning
Naloxone for Opiod poisoning
Lipid rescue therapy is useful for poisonings with____
Lipophillic drugs e.g. Moxidectin, Avermectin, Ivermectin
Thought that lipid component binds them so they cannot act as a toxin at their target receptor.
Xylitol containing products and management (inc monitoring)
Some protein bars and CHEWING GUM (Wrigleys)
Nicorette gum, Strepsils,
AGGRESSIVE THERAPY - GASTRIC DECONTAIMINATION.
Rapid and potent stimulator of insulin release in dogs/ induces liver damage by unknown mechanisms.
Monitor glucose concentrations,. potassiu, phosphrous, total bilirubin, clotting tests
Treatment of Xylitol
Hypoglycemia (ECG monitoring- hypokalamia-induced arrthymias)
Hepatotoxicty (consider immediate dextrose therapy)
Treat with IV saline, glucose and potassium supplements, and essential fatty acids
Which breeds are more susceptible to Onion toxicity in dogs
Japanese (akitas) and Korean breeds.
Inhertied trait characterised by erythrocytes with high conc of gluthione.
Once an idea of the likely therapeutic dose has been decided, safety studies will be undertaken at ))) times the therapeutic dose
3 to 5 times the therapeutic dose for up to 3 x the recommended dosing period. Up to 6 months if chronic dosing intended
If a drug is for use in food producing animals how long is it tested
Life time safety studies in lab animals and 2 year safety studies in dogs. Carcinogenicity, embrotoxicicity and foetoxicity studies are also required.
Example of Type A ADR
Augmented. PREDICTABLE e.g. beta blockers causing bradycardia. ACE inhibitors causing renal failure.
In Neonates
a) gut motility
b) total body water
c) glomerular filtration
In Neonates, gut motility is decreased, neonates also have increased total body water (polar drugs have larger volume of distribution i.e. lower plasma concentration),
Neonates also have decreased glomerular filtration.
Effect of decreased muscle mass on drug metabolism
Decreased lean muscle mass and decreased total bodt water in eldery lead to higher plasma drug concentrations (for polar drugs) e.g. Gentamycin.
Endotoxin is only found in
Endotoxin is a lipopolysaccharide that is part of the outer membrane of gram NEGATIVES and never found in gram +ve.
Endotoxin effects are thought to result from interaction of the _____ with a receptor on the macrophage membrane
Lipid A. This binding (Pattern regognition receptors) - this stimulates production and release of tumour necrosis factor, then interleukin (IL-1)
IL-1 acts on the hypothalamus to modulate temp.
Exotins are produced by
gram positives and many gram negatives (cholera, e coli, pseudomonas, bordetella)
Pathogenesis of Ergotism
Black ergots (fungal sclerotium) claviceps purpurea
Constriction of the arterioles in extremitis –> gangrene and lameness. Also convulsions.
Detection in food is relatively easy.
Nociception pathway
Can have nociception without pain.
- Tranduction
- Transmission
- Modulation
- Projection
- Perception
Define Allodynia
Non painful stimuli that is actually painful.
Which spinal tract sends pain signals
Spinothalamic tract (transduction of nociception)
Which fibres are involved in the Transmission phase of Nociception
Transmission phase
First order syndrome in dorsal horn
myelinated Aδ fibers$–first pain
unmyelinated fibres = visceral phase
What happens in modulation
Peripheral sensory nerve impulses are amplified or surpressed in the spinal cord
Visceral pain is
Unmyelinated fibres in transmission phase
Projection occurs
Spinal cord/ white matter (NSAIDs work here)
Which analgesics can be used as local anaesthetics?
Local anaesthetics, opiods and a2 agonists
What is the difference between Buprenorphine and Butorphanol
buprenorphine is a partial u-agonist and butorphanol is a mixed agonist-antagonist.
Buprenorphine: Does not produce maximal effect, analgesia but not as profound as full agonistm mild to moderate pain
Mechanism of action for NSAIDs
Phospholipids–>Arachidonic acid then cyclooxygenase pathway (COX1 and COX2) and Lipoxygenase Pathway
COX-1 function
Production of prostaglandins important in the physiological modulation of function (gut mucosal barrier, intra rernal perfusion when reduced blood flow)
Aside from the suppression of inflammation, pain and fever, what other benefits does COX-2 inhibition have?
Alzheimers disease? Some cancers (colon, pancreas, lung, transitional cell carcinoma, melanoma)
Coxibs=
(100 x greater) inhibition of COX-2 receptors (inflamm, pain and fever)
COX-1 Inhibition of clot induced___-
COX-1 inhibition of clot-induced thromboxane B2 production.
c.f. COX-2 activity = inhibition of lipopolysaccharide (LPS) induced prostaglandin E2.
Therapeutic aim for NSAIDs (in terms of % inhibition)
> 80% Inhibition of COX-2
COX-1 Inhibition should be <10% (to avoid side effects of inhibiting clot induced thromboxane b2)
Phenylbutazone and Asprin are examples of
Non selective COX inhibitors (Asprin, Phenybutzaone, Ketoprofen, Tolfenamic acid)
Examples of some preferential inhibitors of COX-2 in the dog/cat
Meloxicam/ Carprofen.
Carprofen inhibits COX-1 receptors less than Meloxicam (i.e. should be less side effects?)
Selective COX-2 inhibitors
Firocoxib/ Robenocoxib
Tepoxalin
Inhibit LOX for short periods during day.
Non-selective inhibitor of COX-1 and COX-2
Carprofen (dog, cat, horse)
Dog: COX-2 preferential
Cat: COX-2 preferential (LONGER HALF LIFE= NOT DAILY DOSING!)
Horse: Non-selective
How do the pharmackinetics of Carprofen help
Readily absorbed from Stomach/ Small intestine after sc or im injec
Weak acid so readily penetrate inflammed tissue. Highly protein bound (accumulation of drug in protein rich exudate) therefore Duration may exceed apparent systemic half life
In cat much longer half life than dog!
Licence of Carprofen in cats
Once only use (+++ half life in cats)
COX-2 preferential in cat (and dog) non selective in HORSE
In general NSAIDs have a ____ half life in cats vs dogs
Generally NSAIDs have a longer half life in cats vs dogs i.e. asprin, carprofen (only licenced for one use in cats)
How do PGE/ PGI2 normally protect the gastric mucosa
Inhibiting gastric acid secretion, maintaining mucosal blood flow, being involved in secretion/composition of healthy mucous, act as intracellular messengers for stiulus of mucosal cell turnover and migration
Cells that express COX-2 include - macrophages, neutrophils, myofibroblasts, endothelial cells
Contraindications for use of NSAIDs
COX-2 rapidly expressed in response to GI injury and contributes to mucosal defense/repair.
Avoid NSAID use in patients with confirmed, presumed or potential GI inflammation (INC Pancreatitis)
Even highly selective COX-2 inhibitors GI ulceration reported occasionally.
Normal renal tissue has COX-1 and COX-2 receptors therefore CONTRAINDICATED in RENAL DISEASE
Current opinion on the use of NSAIDs in the management of a patient in hypovolemic shock secondary to trauma
No rational basis and clinically insupportable, particularly when such drugs are used concurrently with corticosteroids.
Which NSAIDs are given in renal disease
NO NSAIDS is completely renally safe when renal perfusion is reduced (e.g. retaining sodium in congestive heart failure). Preferential (carprofen/meloxiccam) have a LOWER RISK than non selective (ketoprofen, phenylbutazone, asprin)
Why might animals on phenylbutzazone have increased risk of bleeding
Phenylbutzaone (asprin, ketoprofen) are non selective NSAIDs. Thromboxane is a potent vasoconstrictor and activator of platelet aggregation.
Inhibition of thromboxane can lead to increased risk of bleeding. Use with care if in breed with risk of VonWillebrand disease
Why do you need to take care when using Diuretics and NSAIDs
COX-2 inhibition may attenuate effect of diuretc.
Also when using NSAIDs avoid high dose ACP as premed (and don’t use a2 as premed??)
