Warfarin reversal guideline

Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis. MJA 2004

Antidotes

Agent	Indication
Activated charcoal with sorbital	used for many oral toxins
Adenosine	Theophylline antidote for adenosine poisoning
Atropine	organophosphate and carbamate insecticides,nerve agents, some mushrooms
Beta blocker	theophylline
Calcium chloride	calcium channel blockers, black widow spider bites
Calcium gluconate	hydrofluoric acid
Chelators such as EDTA, dimercaprol (BAL), penicillamine, and 2,3-dimercaptosuccinic acid (DMSA, succimer)	heavy metal poisoning
Cyanide antidote (amyl nitrite, sodium nitrite, or thiosulfate)	cyanide poisoning
Cyproheptadine	serotonin syndrome
Deferoxamine mesylate	Iron poisoning
Digoxin Immune Fab antibody (Digibind and Digifab)	digoxin poisoning
Diphenhydramine hydrochloride and benztropine mesylate	Extrapyramidal reactions associated withantipsychotic
Ethanol or fomepizole	ethylene glycol poisoning and methanol poisoning
Flumazenil	benzodiazepine poisoning
Glucagon	beta blocker poisoning and calcium channel blockerpoisoning
100% oxygen or hyperbaric oxygen therapy (HBOT)	carbon monoxide poisoning and cyanide poisoning
Insulin	beta blocker poisoning and calcium channel blockerpoisoning
Leucovorin	methotrexate and trimethoprim
Methylene blue	treatment of conditions that cause methemoglobinemia
Naloxone hydrochloride	opioid poisoning
N-acetylcysteine	Paracetamol (acetaminophen) poisoning
Octreotide	oral hypoglycemic agents
Pralidoxime chloride (2-PAM)	organophosphate insecticides, followed after atropine
Protamine sulfate	Heparin poisoning
Prussian blue	Thallium poisoning
Physostigmine sulfate	anticholinergic poisoning
Pyridoxine	Isoniazid poisoning, ethylene glycol
Phytomenadione (vitamin K) and fresh frozen plasma	warfarin poisoning and indanedione
Sodium bicarbonate	ASA, TCAs with a wide QRS

Neuroleptic malignant syndrome

- rare but life threatening, idiosyncratic reaction to a neuroleptic medication
- characterised by fever, muscular rigidity, dysautonomia (sweating, tachypnea, tachycardia and labile blood pressure) and altered mental status
- thought to be secondary to decreased dopamine activity in CNS either from blockade of dopamine D2 receptor or decrease availability of dopamine itself
- blockade of dopamine neurotransmission in nigrostriatum and hypothalamus results in muscular rigidity and altered thermoregulation
- most common cause are haloperidol, fluphenazine depot preparation and chlorpromazine
- high creatinine kinase and high white cell counts are seen
- complications include rhabdomyolysis and subsequent renal failure
- stop all neuroleptic, correct volume depletion and hypotension with IV fluid
- bromocriptine 5mg tds is the treatment of choice (dantrolene was formerly recommended as initial treatment of choice although recent studies suggest that it is associated with increased mortality when used without bromocriptine)

Immunosuppressive for transplantation

Ciclosporin and Tacrolimus
- Both are calcineurin inhibitors, inhibit T cell activation
- ciclosporin forms complexes with cyclophilin whereas tacrolimus binds with immunophilin FK binding protein-12
- both used as rescue agent for treating rejection and  as maintenance agent
- levels of both drugs need to be monitored carefully
- both metabolised by cytochrome P450 3A enzyme
- DO NOT cause myelosuppression

Azathioprine
- purine analogue metabolised to mercaptopurine
- prevent cell mediated rejection by blocking purine synthesis
- converted to inactive metabolite by xanthine oxidase (thus, CANNOT give allopurinol!)
- check TPMT (thiopurine methyltransferase) level before initiate treament
- side effects: bone marrow suppression, pancreatitis

Mycophenolate mofetil
- nucleotide inhibitor
- inhibits IMPD (inositol monophosphate dehydrogenase)
- specific for lymphocytes because unlike other cells, an alternative purine synthetic salvage pathway is absent in lymphocytes
- side effects: mostly GI upset, also pancytopenia

Antibodies
- polyclonal : anti-thymocytic globulin (ATG) and anti-lymphocytic globulin (ALG)
- monoclonal : OKT3

Clinical drug trials

Phase I
- to establish the human toxicity of a new drug by delivering carefully selected increase doses to fit patients with incurable diseases

Phase II
- to establish the antitumor activity of a drug against a particular tumor in fit patients with incurable diseases

Phase III
- to compare new drug with the best conventional therapy usually by a prospective randomised controlled trials

Phase IV
- to establish the drug efficiency in the adjuvant setting and are use to determine the long term side effects

side effects of HAART

NRTI (eg: zidovudine, stavudine, abacavir and didanosine)
- lactic acidosis (mitochondrial dysfunction) and peripheral neuropathy
- abacavir is associated with potentially fatal hypersensitivity reaction (HLAB5701)
- associated with fat metabolism abnormalities (treatment = pravastatin)

NNRTI 
- efavirenz: nightmares, hallucination
- nevirapine: liver dysfunction, severe rash with eosinophilia

protease inhibitor (eg: indinavir, ritonavir)
- hyperlipidemia, lipodystrophy
- indinavir crystallises in renal tract causing renal stone

Methaemoglobinaemia

- caused by either genetic defect in red cell metabolism or haemoglobin structure or acquired by a variety of drugs and toxins
- results from oxidation of ferrous iron in haemoglobin to ferric form
- oxygen-hemoglobin dissociation curve shifts to left
- causing precipitation as Heinz bodies and eventually leads to hemolytic anemia
- common drugs: dapsone, nitrates, antimalarials, sulphonamides and dyes
- presents with cyanosis, SOB, mental status change, headache, dizziness, arrhythmias, seizures
- chocolate brown blood
- low SaO2 (on oximeter) but good PO2 (ABG)
- treatment: methylene blue 1-2mg/kg and oxygen, ascorbic acid as second line drug

DMARDs side effects

Methotrexate

- marrow suppression, hepatic fibrosis, pneumonitis

Sulfasalazine

- leukopenia & thrombocytopenia, rash and macrocytosis

Hydroxychloroquine

- retinopathy

Gold 

- given by IM

- pancytopenia, lung fibrosis, cholestatic jaundice, glomerulonephritis, angioneurotic edema, exfoliative dermatitis

Penicillamine

- drug-induced lupus, proteinuria, loss of taste, pancytopenia

Leflunomide

- diarrhea, nausea, alopecia, rash

Ciclosporin

- calcineurin inhibitor
- inhibit calcium dependent second messenger signals in T cells following activation via TCR
- inhibits IL-2 production by T-lymphocytes
- adverse effects (4HRT)
  H - hyperkalemia, hypertension, hypertrichosis, hypertrophy of gum
  R - renal toxicity (chronic interstitial nephritis)
  T - tremor

Serotonin syndrome

- toxic hyperserotonergic state can be caused by ingestion of 2 or more drugs that increase serotonin levels (eg: SSRI with MAOI, dopaminergic drug or TCA)
- presents with agitation, confusion, tremor, diarrhea, tachycardia, hypertension and hyperthermia
- treatment: supportive,removal of causative agent, drugs with serotonin antagonist activity (cyproheptadine, methysergide)

Adverse drug reaction (ADR)

Types
A (Augmented) : dose dependent and predictable, can occur to anyone
B (Bizarre) : dose independent and unpredictable
C (continuous or chronic) : prolonged drug use (eg: analgesic nephropathy)
D (delayed) : teratogenic or carcinogenic
E (end of use) : withdrawal phenomena after drug is stopped

activated charcoal

- mechanism of action
  i) binding of toxin to prevent stomach or intestinal absorption.
  ii) interrupt enterohepatic or enteroenteric circulation of some drugs/toxins and their metabolites


Contraindications "CHEMICAL"

C: Cyanide
H: Hydrocarbon
E: Ehtanol
M: Metals
I: Iron
C: Caustic/corrisives (acid/alkali)
A: Airway unprotected
L: Lithium

Drugs causing gynaecomastia

" DISCO"

D: Digoxin
I: Isoniazide
S: Spirinolactone
C: Cimetidine
O: Omeprazole / Oestrogen

Drugs removed by hemodialysis / hemoperfusion

Hemodialysis "BLAMES"

B: barbiturates
L: lithium
A: alcohol
M: methanol
E: ethylene glycol
S: salicylate

Charcoal hemoperfusion
- paracetamol
- theophylline

SIADH inducing drugs

"ABCD"

A: analgesia (opioids, NSAIDs)
B: barbiturates
C: carbamazepine, cyclophosphamide, chlorpromazine
D: diuretics (thiazide)

other medications: vincristine, vinblastine, etc

- democlocycline can induce nephrogenic DI and thus can be used to treat SIADH

- criteria for diagnosis of SIADH includes normal renal, adrenal and thyroid function with hyponatraemia and hypotonic plasma (<270mOsmol/kg)

Drug induced lupus

- more common in caucasian
- typically presents with myalgia and arthralgia
- risk factors: HLA-DR4, slow acetylator status (autosomal recessive), large total daily dose of precipitating drug
- common drugs: hydralazine, isoniazide, procainamide (highest risk), penicillamine, chlorpromazine, minocycline, simvastatin, captopril
- pulmonary and skin involvement is common, renal and CNS rarely affected
- positive antihistone antibodies
- treatment: discontinue the medication

Valproate (side effects)

VALPROATE

V: Vomiting
A: Alopecia
L: Liver toxicity
P: Pancreatitis/Pancytopenia
R: Retention of fat (weight gain)
O: Oedema
A: Appetite increase
T: Tremor
E: Enzyme inducer (liver)

Amiodarone

- Amiodarone has high iodine content (40% of its weight)
- can directly cause both sinus bradycardia and AV block due to its calcium channel blocking activity
- prolonged QT interval due to blockage of potassium channels

Side effects of Amiodarone : BITCH

• B - Bradycardia
• I  - Interstitial pulmonary fibrosis
• T - Thyroid disorder (hyper/hypo)
• C - Corneal microdeposits (visual haloes & photophobia)
• H - Hepatitis / Hypersensitive skin (slate grey)

Amiodarone-induced hyperthyrodism

- Type 1 : high iodine content cause release of thyroid hormones (Jod Basedow effect). Positive antithyroid antibodies,normal IL-6

- Type 2 : amiodarone cause destructive thyroiditis, raised IL-6
- colour flow doppler ultrasound can differentiate (increase in type 1 and reduced in type 2)

- treatment: antithyroid in type 1, steroid + antithyroid for type 2
                  consider stop amiodarone if possible

Amiodarone also can cause hypothyroidism by inhibiting the peripheral conversion of T4 to T3 (thus elevated T4, low T3 and raised TSH)