Medications Flashcards
Platinum compounds e.g. cisplatin, carboplatin
Activated within cell by displacement of chloride, leaving positively charged molecules that react with DNA
Inhibits replication/transcription/division, leading to apoptosis
Chemotherapeutic agent, e.g. neuroblastoma
Adverse effects: myelosuppression (cumulative and dose related, ~3 weeks after dose and recover within 6 weeks), nephrotoxic, ototoxic
Dinutuximab
Monoclonal antibody against disialoganglioside GD2 (ubiquitous expression on neuroblastoma cells)
Topotecan
Topoisomerase I inhibitor, inhibits nucleic acid synthesis
Indications: Cancers
A/E: myelosuppression (1 week and recover in 3)
Doxorubicin/danorubicin
AKA Hydroxydaunorubicin
Inhibits DNA/RNA synthesis by intercalation of DNA base pairs, prevents repair by inhibiting topisomerase II
Indications: Cancers
A/E: Infusion reactions, myelosuppression, cardiac toxicity, extravasation, secondary malignancy (AML)
AE: N/V, cardiomyopathy, red urine, tissue necrosis on extravasation, myelosuppression, conjunctivitis, radiation dermatitis, arrhythmia
Dexrazoxane reduces risk of cardiotoxicity
Etoposide
AKA VP-16
Inhibits topoisomerase II, therefore DNA strand breaks and inhibits cell division
I: Cancers
A/E: Myelosuppression (1-2 weeks, recover by 3), hypersensitivity, secondary malignancy (AML)
Cyclophosphamide
Immunosuppressant/chemotherapeutic due to cytotoxic effect of lymphocytes
Interferes with all replication by forming cross-linkages between DNA - alkylates guanine -> inhibits DNA synthesis
I: Cancers, autoimmune
A/E: Myelosuppression (1-2 weeks, 3-4 recovery), haemorrhagic cystitis (chemotherapy man), pulmonary fibrosis, SIADH, infertility
Eculizumab
Anti-C5 antibodiy
Inhibits complement activation
I: Atypical haemolytic uraemic syndrome, paroxysmal nocturnal haemoglobinuria
Diazoxide
Opens K-ATP channels (in beta-cells of pancreas this prevents depolarisation of the cell, thereby preventing insulin secretion
Used for some causes of hypoglycaemia
Octreotide
Somatostatin analogue (mimics somatostatin)
Inhibits release of growth hormone, insulin, others
Reduces splanchnic blood flow
I: Acromegaly, ?hyperinsulinaemic hypoglycaemia…
Sumatriptan
MOA: Constrict cranial vessels by acting selectively at 5HT1B/1D receptors; also thought to inhibit the abnormal activation of trigeminal nociceptors.
I: Migraine, cluster headache
S/E: Tightness in jaw, chest, fingers d/t vascular constriction, subsequent feeling of grogginess and fatigue from central serotonin effect, transient burning sensation in the nose or throat, taste disturbance (nasal spray); dyspnoea, dystonia (rare)
Prochlorperazine
MOA: Dopamine antagonist (D2)
I: Nausea, vomiting, vertigo, migraine
A/E: Common: constipation, dry mouth, drowsiness, akathisia, parkinsonism, blurred vision, EPSE (especially in children), hypotension, hyperprolactinaemia; Rare: prolonged QT interval, tardive dyskinesia
Amitriptyline
MOA: TCAs inhibit reuptake of noradrenaline and serotonin into presynaptic terminals. Although unrelated to the therapeutic effects of the TCAs, they also block cholinergic, histaminergic, alpha1-adrenergic and serotonergic receptors.
S/E: Drowsiness, anticholinergic effects, prolong QT
Indications Major depression Nocturnal enuresis, seek specialist advice Accepted Adjuvant in pain management Migraine prophylaxis
Sodium channel blockers
Class 1 anti-arrhythmic (NAB-KC)
Block sodium channel, inhibit depolarisation
Quinidine, lignocaine, flecainide
Beta blockers (anti-arrhythmic)
Class 2 (NAB-KC) Act at SA/AV node to inhibit sympathetic activity
Potassium channel blockers
Class3 antiarrhythmic (NAB-KC) Prolonged repolarisation Amiodarone, sotalol (also beta blocker action)
Calcium channel blockers
Class 4 anti-arrhythmic
Block L-type Ca channels, inhibit AV node conduction
Digoxin
Cardiac glycoside
Mechanism
Stimulate vagal activity, inhibit Na/K/ATPase
AMH: Slows heart rate and reduces AV nodal conduction by an increase in vagal tone and a reduction in sympathetic activity. Increases the force of myocardial contraction by increasing the release and availability of stored intracellular calcium.
I: AF, atrial flutter, heart failure
b. Side effects:
i. Risk of arrhythmias
ii. Not to be given in WPW
AMH: Narrow therapeutic window
Digoxin usually has an effect on the ECG and may result in prolonged PR interval, ST depression or T wave inversion (these changes do not necessarily indicate digoxin toxicity or myocardial ischaemia).
In children, arrhythmias (including sinus bradycardia) are the earliest and most frequent indicators that digoxin dosage is too high.
Atropine
a. Anticholinergic (a group of substances that blocks the action of the neurotransmitter called acetylcholine at synapses in the central and peripheral nervous system. These agents inhibit the parasympathetic nervous system by selectively blocking the binding of ACh to its receptor in nerve cells.)
b. Inhibits vagal stimulation
Indications Premedication for anaesthetic procedures Prevention of muscarinic effects of neostigmine when used to reverse neuromuscular blockade Bradycardia with haemodynamic compromise Organophosphate poisoning
Adenosine
a. Naturally occurring nucleotide (not adenine)
Mechanism (AMH)
Depresses sinus node activity and slows conduction through the atrioventricular node; also produces peripheral and coronary vasodilation.
Adenosine has a rapid onset and short duration of action.
c. Useful to terminate SVT
d. Very short half life (10 seconds)
e. Side effects: Headache, Dyspnoea, Bronchospasm, Can trigger atrial fibrillation
ACE inhibitor
- Action
a. Inhibit production of angiotensin II reduce afterload +/- have some effect on venodilation , reduction of preload
b. Decrease afterload by reducing peripheral vascular resistance
c. Increase myocardial contractility
d. Remodeling benefits likely - Side effects
a. Hypotension
b. Hyperkalemia
c. Rash (often disappears spontaneously)
d. Chronic cough - Contraindications
a. Stenotic lesions of LV outflow tract ( may compromise coronary perfusion)
AMH:
Mechanism:
ACE inhibitors block conversion of angiotensin I to angiotensin II and also inhibit the breakdown of bradykinin. They reduce the effects of angiotensin II-induced vasoconstriction, sodium retention and aldosterone release. They also reduce the effect of angiotensin II on sympathetic nervous activity and growth factors.
Indications
Hypertension
Chronic heart failure with reduced ejection fraction
Diabetic nephropathy
Prevention of progressive renal failure in patients with persistent proteinuria (>1 g daily)
Post MI
Cyclosporin
Calcineurin inhibitor. AMH: Ciclosporin and tacrolimus form complexes with cytoplasmic immunophilins (cyclophilin and FKBP‑12 respectively), which block the action of calcineurin in activated T cells. This prevents production of interleukin‑2 and other cytokines, which normally stimulate T cell proliferation and differentiation.
Indications Prevention of transplant rejection Nephrotic syndrome Severe rheumatoid arthritis unresponsive to other antirheumatics Atopic dermatitis, severe refractory Psoriasis, severe refractory
AE (Common): gingival hyperplasia, hirsuitism
Azathioprine
Purine antimetabolite. Azathioprine is metabolised, via mercaptopurine, to thioguanine nucleotides which interfere with purine synthesis, impairing lymphocyte proliferation, cellular immunity and antibody responses.
Indications Prevention of organ transplant rejection Used for its immunosuppressant effects in a number of immune and inflammatory diseases including: Severe rheumatoid arthritis Inflammatory bowel disease Autoimmune hepatitis Systemic lupus erythematosus Pemphigus
AE: dose dependent myelosuppression, pancreatitis
Thiopurine methyltransferase (TPMT) activity—where possible, determine TPMT phenotype (enzyme activity) or genotype before starting treatment. 1 in 300 people have low or no detectable TPMT activity and are at risk of severe myelosuppression; avoid use in these people if possible or reduce the dose (to one-tenth of normal or less). As TPMT testing does not identify all patients at risk of severe myelosuppression, regular blood count monitoring is still required.
Interaction with allopurinol or febuxostat
Both allopurinol and febuxostat reduce azathioprine metabolism, increasing the risk of severe bone marrow toxicity
Mycophenolate mofetil (MMF)
Depletes guanosine nucleotides.
Mycophenolate mofetil and mycophenolate sodium are both converted to mycophenolic acid, which selectively suppresses lymphocyte proliferation and antibody formation by inhibiting inosine monophosphate dehydrogenase. Depletion of guanosine nucleotides (required for de novo purine synthesis in lymphocytes) results.
Acts on the immune system at a similar level to azathioprine but by a distinct and more lymphocyte-selective mode of action.
i. Antimetabolite: affects denovo purine synthesis – noncompetitive inhibitor of de novo guanine nucleotide synthesis
ii. Selectively inhibits lymphocyte proliferation (with less myelosuppression than AZA)
iii. More potent than azathioprine
iv. Side effects
1. Opportunistic infections more common
2. Main side effects: GI – N+V+D
Prostaglandin E1 / Alprostadil
Alprostadil is a synthetic PG used to relax the ductus arteriosus in the early post-natal life. Preserves ductal patency if administered before anatomical closure occurs. Over time ductus arteriosus rapidly loses its responsiveness – MOST effective within 96 hours of birth
Actions
a. Maintain patency of ductus arteriosus
b. Vasodilation of all arterioles
c. Inhibition of platelet aggregation
d. Stimulation of intestinal and uterine smooth muscle
Metabolism
a. Rapidly cleared by metabolism in the lungs and excreted by kidneys – therefore given as continuous infusion
b. Maximal effect in 30 minutes
Dose
a. 5-100 nanongrams/kg/min
Side effects
a. Apnoea usually occurs in neonates <2kg within the first hour of administration
b. Fever
c. Irritability
d. Cutaneous flushing – secondary to vasodilation
e. Bradycardia or tachycardia
f. Hypotension
g. Seizures
h. Decreased platelet aggregation, thrombocytopaenia
i. Edema
j. May require ventilation for transport + caffeine
k. With-holding can kill patient
Palivizumab
a. Palivizumab = humanized monoclonal antibody against RSV
i. Provides passive immunity against RSV
ii. Decreases hospitalisation for RSV related illness
iii. Dose = 15 mg/kg IM any time from birth; dose 2 given 3 weeks after dose 1 and then 4 weekly for duration of RSV season
iv. Indications
- Preterm infants with or without chronic lung disease of prematurity or congenital heart disease
- Infants with haemodynamically significant congenital heart disease
- Children with anatomic pulmonary abnormalities or neuromuscular disorder
- Immunocompromised children assessed on an individual basis
v. Adverse effects
- Common: fever, rash, rhinitis, wheeze, cough, diarrhoea, injection site reaction
- Infrequent: anaemia, elevated liver enzymes
- Rare: hypersensitivity
Salbutamol
Mechanism of action
● Simulates beta 2 receptors 🡪 increased adenlylate cyclase 🡪 increase cAMP levels 🡪 diminishes Ca2+ available for contraction 🡪 bronchodilation
● B2 selective at lower doses
● In high doses, loses its selectivity 🡪 B1 agonist to heart 🡪 tachycardia
AE ● Tremor ● Palpitations ● Headache ● Hyperglycaemia (high dose) ● Tachycardia (high dose) ● Hyperactivity in children ● Lactic acidosis – with high doses
Ipratropium bromide
Mechanism
● Relax smooth muscles by inhibiting cholinergic bronchomotor tone
● Block muscarinic action of acetylcholine ●
AE
Headache, nausea, taste disturbance
● Anti-cholinergic AE = blurred vision, dizziness, urinary retention, constipation, palpitations
Magnesium sulphate
Mechanism
● Relaxation of bronchial smooth muscles
AE
● Related to hypermagnesaemia
Aminophylline
Mechanism
● Not entirely understood
● Possible effects include bronchial smooth muscle relaxation, anti-inflammatory effects, increase in diaphragm contractility and CNS stimulation
AE
● Nausea, vomiting, diarrhoea, GERD, headache, insomnia, irritability, anxiety, tremor plapitations
● Seizures
● Arrythmias (continue cardiac monitoring)
● Tachycardia
Montelukast
Mechanism
● Inhibits Cysteinyl leukotriene receptor
● Antagonises smooth muscle contraction and inflammation caused by leukotrienes
AE
● Headache, abdominal pain, diarrhoea
● Neuropsychiatric effects = nightmares, hallucinations, mood or behavior changes
Inhaled corticosteroid
Mechanism
● Reduce airway inflammation and bronchial hyper-reactivity
● Decreases activation of eosinophils, production of cytokines, generation of prostaglandins/leukotrienes, histamine release, production of IgE, and production of mast cells.
AE
● Local = dysphonia, oral candidiasis
● Systemic = adrenal suppression, loss of bone density, cataract, skin thinning and bruising, poor growth (contentious)
Omalizumab
Mechanism
● Humanised monoclonal Ab directed against IgE
● Reduces the immune system’s response to allergen exposure
AE ● Injection site reactions ● Rash, bleeding, headache, MSK pain ● Mild thrombocytopenia ● Anaphylaxis ● Angioedema, urticaria, serum sickness, Churg-Strauss
Loop diuretics
- Act in the thick ascending LOH
- Sodium entry primarily mediated by the Na-K-2Cl carrier in the luminal membrane
- Loop diuretics compete for the chloride site – therefore reducing net reabsorption
• Key AE o Hypokalaemia (due to tubal Na) o Hypercalciuria + hypocalcaemia o Alkalosis (due to tubal Cl) o Hypotension/hypovolemia o Hyponatremia o Hypochloraemia o Hypomagnesaemia
Thiazide diuretics
- Act in the distal tubule
- Sodium entry is mediated by Na-Cl co-transporter
- Thiazides inhibit NaCl reabsorption in these segments by competing for chloride site on the transporter
• Key AE
o Hypokalaemia (Na-K antiporter Na absorb distally)
o Hyponatremia
o Hypochloraemic alkalosis (Cl- lost, Na-H+ antiporter Na absorb distally)
o Hypercalcaemia + hypocalciuria
o Hyperuricaemia
Potassium sparing diuretics
• Act in the collecting duct
• Sodium entry mediated by aldosterone-sensitive sodium channels
o Reabsorption of cationic sodium without an anion creates a lumen-negative electrical gradient that favours the secretion of potassium (through selective potassium channels) and hydrogen ions
o Inhibition of sodium reabsorption results in hyperkalaemia + metabolic acidosis due to the reduction in potassium and hydrogen ion excretion
• Two classes
o Amiloride
Act on principle cells (ENaC)
Inhibits Na+ reabsorption – therefore inhibiting K+ secretion
o Aldosterone inhibitors = spironolactone
Act on intercalated cells
Aldosterone normally stimulates Na/K/ATPase pump on basolateral side of cortical collecting tubule AND increases sodium permeability on luminal side of the membrane (activates ENAC)
Blocks BOTH these actions - reducing resorption of Na+ and excretion of K+
• Key AE
o Hyperkalaemia
Calcineurin inhibitors
Ciclosporin, tacrolimus
Mode of action
Ciclosporin and tacrolimus form complexes with cytoplasmic immunophilins (cyclophilin and FKBP‑12 respectively), which block the action of calcineurin in activated T cells. This prevents production of interleukin‑2 and other cytokines, which normally stimulate T cell proliferation and differentiation.
Indications
Prevention and treatment of transplant rejection
Prevention and treatment of graft-versus-host disease in stem cell transplants
Induction or maintenance of remission in immune and inflammatory diseases
Adverse effects
Commonly dose-related. Major dose-limiting toxicity is acute nephrotoxicity.
Common (>1%)
nephrotoxicity (below), hypertension, hypercholesterolaemia, neurotoxicity (below), raised bilirubin, raised aminotransferases, hypomagnesaemia, hyperkalaemia, opportunistic infection, diarrhoea, hyperglycaemia, diabetes
Nephrotoxicity
Acute nephrotoxicity is dose-related and reversible with dose reduction or withdrawal. Chronic nephrotoxicity occurs with long-term use, is unrelated to dosage, potentially irreversible and involves permanent renal structural changes (eg interstitial fibrosis).
Neurotoxicity
Tremor and headache are most frequent; other effects include paraesthesia, confusion, seizures, coma, psychosis. Reversible posterior leucoencephalopathy syndrome has also been reported.
Basiliximab
Mode of action
Chimeric monoclonal antibody against interleukin‑2 receptors expressed on activated human T lymphocytes; blocks binding of interleukin‑2, inhibiting T lymphocyte proliferation.
Indications
Prevention of acute kidney transplant rejection
Adverse effects
Studies indicate a possible increase in surgical wound complications but otherwise no increase in adverse effects, incidence of opportunistic infection or lymphoproliferative disease, compared with baseline immunosuppression.
Rare (<0.1%) hypersensitivity reactions (below), cytokine release syndrome
Rituximab
Mode of action
Chimeric monoclonal antibody that binds to CD20 on B lymphocytes.
In cancer, it starts an immune response that lyses normal and malignant B cells. In chronic inflammatory diseases (eg rheumatoid arthritis), it suppresses immune response and inflammation by reducing T cell activation and resulting cytokine production.
Adverse effects
Generally the frequency and severity of adverse effects are greater with rituximab for antineoplastic indications than when used for other conditions.
Common (>1%)
infusion-related reactions (below), SC injection site reactions (eg erythema, pain, swelling), infections, neutropenia (may be delayed onset), lymphopenia (see below), decreased immunoglobulin levels, arrhythmias, musculoskeletal pain
Infusion-related reactions
Most common with first infusion and may be indistinguishable from hypersensitivity reactions, cytokine release syndrome or tumour lysis syndrome. Reactions usually occur 30–120 minutes after starting infusion and include fever, chills and/or rigors, nausea, vomiting, urticaria, itch, headache, bronchospasm, dyspnoea, angioedema, rhinitis, hypotension.
Stop the infusion if symptoms occur and treat symptomatically. If appropriate, restart the infusion at half the previous rate when symptoms resolve.
Lymphopenia
Rituximab induces a rapid loss of B lymphocytes. In patients with cancer, recovery usually begins about 6 months after stopping treatment; full recovery often occurs within 12 months but may take longer. In rheumatoid arthritis, time to recovery is variable (>2 years after last dose in about 8% of patients).
Sirolimus
Also known as rapamycin.
Mode of action
(Mode of action from mTOR inhibitors)
Bind to the same intracellular protein (FKBP‑12) as tacrolimus; however, the protein-drug complex blocks the activity of mTOR kinase, preventing cell cycle progression and cytokine-induced T and B cell proliferation.
Indications
Prevention of kidney transplant rejection
Alkylating agents (oncology)
Disrupt double helix of DNA by adding alkyl groups DNA breakage and cell death
Most active in resting phase of cell cycle
Can cause infertility and secondary cancers
Examples: cyclophosphamide, ifosfamide
Ifosfamide
Alkylating agent. Alkylates guanine -> inhibits DNA synthesis.
I: NHL, Wilms, soft tissue sarcoma
AE: N/V, myelosuppression, haemorrhagic cystitis (less common), pulmonary fibrosis, SIADH, Renal tubular acidosis, Ifosfamide encephalitis, infertility
Mesna
Mode of action
Contains free sulfhydryl (thiol) groups that interact with urotoxic metabolites, including acrolein, of ifosfamide and cyclophosphamide and reduce the incidence of haemorrhagic cystitis and haematuria. Enhances urinary excretion of cysteine, which may increase uroprotective effect.
Indications
Reduction and prevention of haemorrhagic cystitis and haematuria caused by cyclophosphamide or ifosfamide
Antimetabolites (oncology)
Folic acid, pyrimidine and purine analogues
Similar structure to naturally occurring molecules in DNA/ RNA synthesis but interfere with normal cellular function
Cause cell death during S phase of cell growth or inhibit enzymes needed for nucleic acid production
Examples: methotrexate, 6-MP, cytarabine (Ara-C), 5-flurouracil (5-FU)
Methotrexate
Folate antagonist; inhibits dihydrofolate reductase. Inhibits DNA synthesis and cell replication by competitively inhibiting the conversion of folic acid to folinic acid.
AE: Common: N+V, hepatitis, dermatitis (photosensitive)
Less common: Myelosuppression
Long term: osteopenia and bone fractures
High dose: renal and CNS toxicity (lowers IQ slightly)
IT: arachnoiditis, leukoencephalopathy, leukomyelopathy
If toxic – carboxypeptidase given (highly expensive)
Can’t give with penicillin, PPIs or Bactrim
6-mercaptopurine / 6-thioguanine
Purine analogue
I: ALL
AE: Myelosupression
Less common: N+V, hepatic necrosis, mucositis
6MP – hypoglycaemia
6TG – VOD
Note: allopurinol inhibits metabolism and increases toxicity
Cytarabine (Ara-C)
Pyrimidine analog; inhibits DNA polymerase.
Pyrimidine nucleoside analogue of cytidine. Cytarabine is converted intracellularly to a nucleotide that inhibits DNA synthesis.
I: ALL, AML, NHL, HL
AE: N+V, myelosuppression, conjunctivitis, mucositis, CNS dysfunction
Intrathecal: arachnoiditis, leukoencephalopathy, leukomyelopathy
Cytarabine fevers / flu like symptoms
5-flurouracil (5-FU)
Pyrimidine antimetabolite which, following intracellular conversion to active metabolites, interferes with DNA and RNA synthesis.
I: Multiple solid tumours
AE: Myelosuppression, diarrhoea, cardiotoxicity
Vinca alkaloids
Cytotoxics; halt division of cells and cause cell death – bind to tubulin and inhibit formation of spindle fibres (microtubules) – during MITOSIS
EG: vincristine, vinblastine
Vincristine
Vinca alkaloid
Inhibits microtubule formation
Antineoplastic
AE: Local cellulitis, alopecia, constipation, abdo pain
Neuropathy (peripheral sensorimotor, autonomic), jaw pain, ileus, SIADH, seizures, ptosis, minimal myelosuppression
IV only, must not be allowed to extravasate – central lines
Vesicant – severe extravasation injury
Incompatible with azoles – increases risk of neuropathy
NOT EMETOGENIC
MINIMAL BM SUPPRESSION
Can result in ALL types of neuropathy – peripheral, autonomic, cranial nerve
Vinblastine
Vinca alkaloid
Inhibits microtubule formation
Antineoplastic
AE: local cellulitis, leukopenia
IV only - must not be allowed to extravasate
Topisomerase inhibitors
Disrupts topoisomerase I and II, which play biggest role in uncoiling DNA for replication
Antineoplastic
EG etoposide
Anthracyclines
Increase oxygen free radicals
Risk of cardiotoxicity
Antineoplastic
Cell cycle nonspecific. Inhibit DNA and RNA synthesis by intercalation of DNA base pairs and prevent DNA repair by inhibiting topoisomerase II. Free radical production may also contribute to cytotoxicity. Mitozantrone, an anthracenedione, is structurally related to anthracyclines.
EG doxorubicin, danorubicin
Carboplatin
Platinum compound
Inhibit DNA synthesis, antineoplastic
Platinum compounds are activated within the cell by displacement of chloride ions, leaving positively charged molecules that react with DNA. DNA replication, transcription and cell division are inhibited, ultimately inducing apoptosis. Platinum compounds are cell cycle nonspecific.
AE: N/V, myelosuppression, electrolyte imbalance
Rare: ototoxicity, renal dysfunction, tetany, neurotoxicity, HUS, anaphylaxis
Aminoglycosides may increase nephrotoxicity
Cisplatin
Platinum compound
Inhibit DNA synthesis, antineoplastic
Platinum compounds are activated within the cell by displacement of chloride ions, leaving positively charged molecules that react with DNA. DNA replication, transcription and cell division are inhibited, ultimately inducing apoptosis. Platinum compounds are cell cycle nonspecific.
AE: N/V +++, diarrhoea, ototoxicity, renal impairment, anorexia, hypomagnesaemia, myelosuppression
Uncommon: metallic taste, tetany, neurotoxicity, HUS, anaphylaxis
Aminoglycosides may increase nephrotoxicity
Amifostine – given as otoprotection; AE profound nausea, hypocalcemia
Sodium thiosulfate – also protective
Asparginase (L-asparginase, PEG-asparginase)
L-asparginase
Depletion of L-asparagine; specific to leukaemia cells (ALL, AML)
AE: Allergic reaction (anaphylaxis), pancreatitis, coagulopathy (thrombosis, bleeding DIC), hyperglycaemia, Cerebral sinus thrombosis, platelet dysfunction and encephalopathy
PEG-asparaginase now preferred to L-asparaginase (Erwinia)
Usually given multiple (6) times
PEG asparginase
Polyethylene glycol conjugate of L-asparagine
Indicated for prolonged asparagine depletion and if allergies to L-asparaginase
Usually given once
Bleomycin
An anti tumour antibiotic. Binds to DNA, cleaves DNA strands
Antineoplastic (HD, NHL, germ cell tumours)
AE: N/V, pneumonitis, stomatitis, Raynaud, pulmonary fibrosis, dermatitis, Mucocutaneous reactions (often affects palms), Hyperpyrexia
No myelosuppression (arrest at G2)
Major limitation to the use of this drug is the potential for life limiting pulmonary fibrosis (fibrosing alveolitis) which occurs in up to 10% of patients receiving the drug
Onset of symptoms usually 1-6 months after bleomycin treatment, but may occur > 6 months following administration of bleomycin
Injury can occur at any dose (but dose relationship)
Treat with pred
Dactinomycin
Binds to DNA, inhibits transcription
I: Wilms, rhabdomyosarcoma, Ewing
AE: N/V, tissue necrosis on extravasation, myelosuppression, radiosensitiser, mucosal ulceration
Tretinoin
Enhances normal differentiation
I: Acute promyelocytic leukaemia, neuroblastoma
AE: Dry mouth, hair loss, pseudotumour cerebri, premature epipheseal closure, birth defects
Prednisolone and dexamethasone (as antineoplastic)
Lymphatic cell lysis. Unclear mechanism.
I: ALL, HL, NHL
AE: Cushing, cataracts, diabetes, HT, myopathy, OP, AVN, infection, PUD, psychosis
Can suppress fever; avoid dex in brain tumours – inc BBB to chemo
Leflunomide
Inidcations:
RA
Psoriatic arthritis
Mechanism:
Inhibits dihydro-orotate dehydrogenase 🡪 inhibiting pyrimidine synthesis
Side effects: GI side effects Elevated LFTS Hepatic failure Paresthesias Peripheral neuropathy Cytopenias Teratogenic
Hydroxychloroquine
Indications: RA SLE JIA Malaria
Mechanism:
Anti-inflammatory agent + immunosuppressive effects
Side effects: GI side effects Retinal toxicity Ototoxicity Bone marrow suppression Myositis, weakness Allergy
Sulfasalazine
Indications:
IBD
Enthesitis related JIA
Mechanism:
Exact mechanism unknown
Anti-inflammatory effect
Side effects: Vomiting , diarrhoea Nausea, rash headache (poorly tolerated) Allergy Rare: blood dyscrasias, pancreatitis, hepatitis
Adalimumab
Etanercept
Infliximab
Indications: Psoriatic arthritis Ank spond JIA IBD
Mechanism:
Etanercept = TNFα receptor blocker
Adalimumab = humanised Ab against TNFα
Infliximab = chimeric MAb against TNFα
Side effects: Infection Lupus like syndromes Cytopenias Demyelination ILD
Abatacept
Indications:
Severe JIA
Mechanism:
Fusion protein of IgG1 to CTLA-4
Binds to CD80/CD86 to prevent T cell activation
Side effect: Infection Headache, dizziness Paraesthesia Liver enzymes Injection site reactions Malignancies Depression Thrombocytopenia
Anakinra
Indications:
RA
Familial fever syndromes
JIA
Mechanism:
IL -1 receptor antagonist
Side effects: Injection site reactions Headache Infections Neutropenia
Tocilizumab
Indications:
RA
JIA
Mechanism:
IIL-6 receptor antagonist
Side effects: Infection Neutropenia Deranged LFTs Increased lipids HT S/C injection site reactions Antibodies GI perforations
Biguanides
Metformin
First choice oral agent in T2DM
Does not cause hypoglycaemia
Action:
• ↓ hepatic glucose production
• ↓ glucose uptake in GI tract (stomach)
• ↑ insulin sensitivity = ↑ peripheral glucose uptake
• Has antilipolytic effect, lowers free fatty acids
• Promotes weight loss, NOT weight gain
SE: • GI = diarrhoea, anorexia, nausea, abdominal discomfort o Common (5-20%) usually transient o Minimise by starting with low dose, and taken after meals • Lactic acidosis – care if renal impairment (GFR < 50mls/minute) or dose reduce if some GFR impairment
Sulphonylureas
EG: Gliclazide, Glipizide, Glibenclamide, Glimepiride
Action:
Increase pancreatic insulin secretion; may decrease insulin resistance
SE:
• Hypoglycaemia = rapidly effective, start cautiously
o Can use in mild renal impairment, but commonly renally excreted so they may be present for longer and cause overnight hypoglycaemia
• Weight gain (2-3kg)
• GI upset, rash
Thiazolidinediones
Eg: Rosiglitazone, Pioglitazone
Action:
• ↑ insulin sensitivity = ↑ peripheral glucose uptake
• ↓ hepatic glucose production
• ↓ lipolysis in adipose tissue
SE:
• Weight gain
• Fluid retention
• Cardiac failure due to fluid
• Fractures (women)
• Rosiglitazone was assoc with ↑CV events – fluid retaining properties, ↑circulation fluid; NOT with pioglitazone
• Pioglitazone may ↑bladder cancer risk
- Not commonly used due to AE of weight gain + fluid retention
- Limited use, unusual to start in new patient
- Action via stimulating nuclear PPAR-gamma receptor
Acarbose
Action:
• ↓glucose absorption from GI tract
• Blocking enzyme which breaks down starch (reduces GI of food)
SE: • Flatulence • Diarrhoea • GI pain • Abnormal LFTs
Other: • Have w/ first mouthfuls of food • Does NOT cause hypoglycaemia or weight gain • Not used with insulin • Treat hypoglycaemia with glucose
GLP-1 Analogues (glucagon like peptide)
Eg: Exenatide, Liraglutide
Action:
• Improve pancreatic islet glucose sensing
• Slow gastric emptying
• Improve satiety
Analogues of glucagon-like peptide‑1 (an incretin); increase glucose-dependent insulin secretion and suppress inappropriate glucagon secretion. They also delay gastric emptying, which slows glucose absorption, and decrease appetite.
SE: • Nausea, vomiting • Hypoglycaemia (only if with sulphonylureas) • Headache • Reports of acute pancreatitis
Other:
• Given as s/c injection before meals
• WEIGHT LOSS
DPP4 Inhibitors (Dipeptidyl peptidase‑4)
Eg: Sitagliptin, Vidagliptin, Saxagliptin, Linagliptin
Action:
• Inhibit breakdown of GLP1
• Prolong GLP1 action, leading to improved beta-cell sensing
• Increase insulin secretion
• Decease glucagon secretion
Inhibit DPP4 -> increase incretins/GLP1 -> glucose-dependent insulin secretion is increased and glucagon production reduced
SE: • Nasopharyngitis • Nausea • Headache • Hypersensitivity
Usually well tolerated
SGLT2 Inhibitor (sodium glucose cotransporter)
Eg: Dapagliflozin, Empagliflozin
Action:
• Promote glycosuria, thus lowering blood glucose
• Associated with mild weight loss
SE:
• Thrush
• Balanitis
Growth Hormone
- Key points
a. Given as subcutaneous injection 6 or 7 divided doses
b. Maximal response to GH occurs in the first year of treatment
i. Speed at growing GREATER when started later – no benefit in starting early
c. Growth velocity during first year is typically >95th centile for age – with each successive year it decreases
d. If growth rate drops below the 25th centile evaluate compliance then increase dose
e. Note also used in non-GH deficient children (eg. Turner, Prada Willi)
f. Remember testosterone and oestrogen replacement in those with pubertal delay - Complications and adverse effects
a. Risk of primary or central hypothyroidism while on treatment with GH
b. Increased risk of T2DM
c. Possible risk with leukaemia, brain tumours (UNCLEAR, conflicting studies/data)
d. Pseudotumour cerebri
e. SUFE
f. Gynaecomastia
g. Worsening of scoliosis - Limitations
a. May not improve overall outcome (def won’t if prev epiphyseal fusion)
b. Can develop GH antibodies (less risk now using recombinant Rx)
c. Need to treat other conditions – subclinical hypothyroidism, chronic disease - RCH HANBOOK
a. Qualification
i. Growth hormone deficiency - Short stature with low height velocity, OR
- Biochemically proven GH deficiency with growth failure
- GH deficiency and precocious puberty
ii. Intracranial lesion or cranial irradiation – 12 months in remission
iii. Neonates with GH deficiency and hypoglycaemia
iv. Turner syndrome or SHOX gene disorder
v. Chronic renal disease
vi. Short and slow growth – defined as below the 1st centile and GV below the 25th centile for bone age
vii. Bone age <13.5 years for girls, <15.5 years for boys
viii. ?? Prader-Willi – improves body composition
ix. ?? Skeletal dysplasia
x. ?? Other conditions eg. Russel-Silver
b. Exclusion criteria
i. Diabetes mellitus
ii. Known risk of malignancy (eg. Down or Bloom syndrome)
iii. Active malignancy - Failure to grow with GH
a. Technical problems
i. Measurement errors
ii. Poor compliance
iii. Improper preparation/ handling/ storage
iv. Incorrect injection technique
v. Incorrect GH dosage
b. Other conditions
i. Subclinical hypothyroidism
ii. Chronic disease or poor nutritional status
iii. Glucocorticoid therapy for any reason
iv. Hx of irradiation of the spine
v. Previous epiphyseal fusion
c. Failure of GH effect
i. Anti GH antibodies
ii. GH resistance syndromes
iii. Incorrect diagnosis and child not actually GH deficient
leuprolide, histrelin, goserelin
GnRH agonists = mainstay of treatment central precocious puberty
i. Physiolgical GnRH is pulsatile in manner continuous administration results in ‘desensitization’/ negative feedback on the gonadotropic cells of the pituitary inhibit endogenous GnRH production
iii. Decision to treat based on chronological age at presentation + height preservation
iv. Treatment results in decrease of growth rate, decrease in the rate of osseous maturation – results in enhancement of predicted height
v. Protocol = 11.25 mg IM dose 3 monthly
1. Review at 3/12 with LH level 1-hour post
2. Adequate suppression = LH <2
3. If not suppressed, consider increasing dose
4. Annual GnRH test and bone age
vi. Length of treatment
1. Normal age of onset of puberty (<14 years)
2. Patient/parent preference
3. Anticipated time of menarche = mean time from end of treatment to menses 16 months
4. Chronological age
5. Bone age
b. Effect of treatment
i. Girls
1. Breast develop may regress if Tanner stages II-III (or unchanged in III-V)
2. Pubic hair remains stable or may progress slowly during treatment
3. Menses if present cease
4. Greatest height gain seen in girls with onset age <6 months (average gain 9-10cm)
ii. Boys
1. Decrease of testicular size
2. Variable regression of pubic hair
3. Decrease in frequency of erections
iii. If treatment effective, sex hormones decrease to pre-pubertal levels
1. Testosterone <10-20 ng/dL
2. Estradiol <5-10 pg/mL
3. LH and FSH decrease to <1 IU/L in most patients
c. Adverse effects = nil serious (apart from reversible decrease in bone density)
Antithyroid medications
i. Anti-thyroid medication = carbimazole/methimazole (preferred in children), propylthiouracil (PTU)
1. Most studies report remission of 25% after 2 years
2. Can either add T4 or ↓ dose if become hypothyroid
3. Usually trial cessation of therapy after 1-2years
a. Remission = euthyroidism after stopping Rx
b. Recurrence can occur months to years after stopping treatment
- Mechanism of action
a. Actively transported into the thyroid gland
b. Inhibit the organification (blocks thyroid peroxidase) of iodine to tyrosine residues in thyroglobulin
c. PTU also inhibits the 5’-monodeiodinase that converts T4 to T3
d. Reduces stores in 2-6 weeks - Comparison
a. Methimazole (carbimazole methimazole) has a longer half-life (4-6 hours) vs PTU (75 minutes) therefore can be given daily rather than TDS
b. Methimazole 10x more potent than PTU
c. PTU is heavily protein bound and less likely to cross the placenta and pass into breast milk - Monitoring
a. Monitor TFT every 2-3 months - TSH levels suppressed for several months after starting treatment; hence T3 and T4 better initial markers of euthyroid state
b. Recheck minimum 4 weeks after starting, long T1/2 TSH - Adverse effects
a. Minor = 10-20%
i. Transient granulocytopenia – not a reason to discontinue
ii. Transient urticarial rashes
b. Severe = 2-5%
i. Agranulocytosis (0.1-0.5%) - Usually occurs in first 2-3 months – if febrile have FBE done
- Risk from methimazole but NOT PTU appears to be dose related
ii. ANCA vasculitis = associated with PTU
iii. Pancreatitis = associated with methimazole
iv. Hepatotoxicity - PTU = fulminant hepatic necrosis, particularly in children
- Methimazole = reversible cholestatic jaundice
v. Teratogenicity - More severe with methimazole than PTU
- Aplasia cutis, tracheo-esophageal fistula, patent vitellointestinal duct, choanal atresia, omphalocele
vi. Lupus like polyarthritis syndrome
vii. Glomerulonephritis - PTU
a. Not used in children due to rare but significant risk of liver failure (1-2/4000)
i. Days to years after initiation of treatment
b. Indications
i. Pregnancy (methimazole associated with risk choanal atresia and aplasia cutis)
ii. Severe reaction to carbimazole (E.g. SJS) and radiotherapy or surgery unfit
iii. T3 toxicosis
Carbamazepine
Actions
• Blocks voltage gated Na+ channels
Indications
• Partial epilepsy
• Generalised TCS
Efficacy
• Partial seizures
• Primary and secondarily generalised TCS
Dosing (start low go slow)
• Start 5 mg/kg/day
• Increase weekly over 2-3 weeks to 15-20 mg/kg/day
• Takes 2-4 weeks to reach steady-state due to autoinduction of metabolism
Levels (rarely - neuro lecturer anecdotally could remember checking one patient per year roughly)
• Target = 4-12 mcg/ml
Interactions
• Liver enzyme induction and lower AED levels (also interacts with OCP)
• PD interactions with other Na+ channel blockers (PHT, PB)
AE • Rash 3-5% • GIT – nausea, vomiting, diarrhoea • CNS side effects • Hyponatraemia (SIAHD) • Leukopenia (non-dose related, occurs in first 3-4 months) • SJS and DRESS (esp HLA-B*15:02) • Exacerbates absence seizures and myoclonus in IGE • Teratogenic – spina bifida • First sign of toxicity is diplopia
Valproate
Actions
• Blocks Na+ channels +/- GABAergic action
Indications (nearly everything - neuro lecture “if you could take one AED to a desert island it would be valproate)
• Partial and generalised epilepsy – including absence
Efficacy • GTCS • Absence • Myoclonic • Tonic + partial seizures • Drug of choice for idiopathic epilepsies
Dosing
• Start with 10 mg/kg/day
• Increase over 2-3 weeks to 20-30 mg/kg/day
• Give BD, no need for levels, take with food
Interactions
• Blocks liver enzymes and raises AED levels
• Competes for protein binding
AE (teratogenicity was main one in lecture - do not prescribe to women of childbearing age)
• CNS side effects + tremor in toxicity
• Weight gain, obesity, insulin resistance
• Thrombocytopaenia – dose related
• Hair loss (alopecia), GIT disturbance
• Pancreatitis
• Risk of liver failure (infant, multiple AEDs, mitochondrial disorders)
• Teratogenic – NTD, other midline defects (cardiac, GU, hypospadias, cleft)
• Avoid in suspected mitochondrial disorders
Benzodiazepines
Actions
• Enhance GABA action at synapse
Indications
• Partial and generalised epilepsy
Efficacy • Partial • GTCS • Myoclonic • Tonic +/- absence
Dosing
• Depends on drug eg. clonazepam, diazepam etc
• Generally start low
Interactions
• Minimal PK interactions
AE (lecture: secretions) • Drowsiness, sedation (esp PB, other BZPs) • Increased secretions eg. drooling • Behavioural change, mood disturbance • Tolerance and tachyphylaxis
Phenobarbitone
Actions
• Blocks Na+ channels
• Enhances GABA
Indications (mostly neonatal seizures) • Partial seizures • GTCs • Neonatal seizures • Status epilepticus
Efficacy
• Partial and GTC seizures
Dosing
• Load 15-20 mg/kg
• Maintenance 5 mg/kg/day (monitor levels)
Interactions
• VPA, BZP
AE
• Behaviour and cognitive disturbance
• Rash
Lamotrigine
Actions
• Blocks Na+ channels and ? other actions
Indications
• Partial and generalised seizures
Efficacy • Partial • Absence • Myoclonic • TCS • Tonic
Dosing
• Start <0.5, max 5-15 mg/kg/day without VPA
• Start <0.2, max 1-5 mg/kg/day with VPA
• Very slow titration
Interactions
• VPA increases levels ++++ (half life increases from ~1 day to 60 hours)
• Beneficial PD when used with VPA
• Potentiates CBZ side effects
AE
• Rash 2-5%
• Severe hypersensitivity 0.3-1% (SJS)
• CNS side effects including tremor in toxicity exacerbates seizures in SMEI
Oxcarbazepine
Actions
• Blocks Na+ channels
Indications
• Partial epilepsy
• Generalised TCS
Efficacy
• Partial seizures
• Primary and secondary generalised TCS
Dosing
• Start 5 mg/kgday
• Increase over 2-3 weeks to 15-25 mg/kg/day
Interactions
• Liver enzyme induction
AE
• Low Na+
• Exacerbates absence seizures and myoclonus in IGE
Levetiracetam
Actions
• Novel – binds to synaptic vesicle protein
Indications
• Partial seizures
Efficacy
• Partial and generalised seizures
Dosing
• Start 10 mg/kgday, target 25-50 mg/kg/day
Interactions
• Nil significant
Adverse (behavioural - suicidality)
• Behaviour disorder, psychosis, sleep disturbance
Topiramate
Actions
• Blocks Na+ channels
• Blocks kainate/AMPA
• Enhances GABA
Indications
• Partial and generalised seizures
- LGS
Efficacy
• Atrial, GTCS, tonic ? spasms ? absence
Dosing
• Start 1, max 5-10 mg/g/day
• Slow titration
Interactions
• Nil significant
AE (nephrolithiasis, weight LOSS) • Weight loss • Metabolic acidosis • Cognitive, speech • Nephrolithiasis (inhibit renal carbonic anhydrase -> serum metabolic acidosis), weight loss • Anhydrosis and hyperthermia • Mood disturbance • Glaucoma contraindication
Vigabatrin
Actions
• Non-competitive inhibitor of GABA transaminase
Indications
• Partial seizures
• Infantile spasms (second line to prednisolone, unless TS/TSC)
Efficacy
• Partial and tonic seizures, especially if lesions eg. TS
Dosing
• 50-150 mg/kgday/day
• 0.5-4 g/day
• Rapid titration if possible
Interactions
• Nil significant
AE
• Behavioural disorder, psychosis, weight gain
• Retinopathy -30% of adults ? children
• Exacerbate myoclonic seizures
Phenytoin
Actions
• Blocks Na channel
Indications
• Partial generalised status
Efficacy
• Partial generalised status
Metabolism
• Liver
Interactions
• Zero order kinetics
• Narrow therapeutic index (measure levels)
• Induces CYP450
• Reduces VPA levels as displaces protein binding
• Reduces effect of OCP and steroids
• Plasma levels increased by macrolides, isoniazid, diltiazem and amiodarone, acute alcohol
• Plasma levels reduced by rifampicin, theophyllines
AE • Rash • Hirsutism • Gum hypertrophy • Ataxia, dizziness, nystagmus • Osteoporosis • Megaloblastic anaemia (reduces folate absorption) • Peripheral neuropathy • Hepatic dysfunction + fulminant hepatic failure • Worsens absence seizures • Seizures worse at toxic levels
Levels
• Target 10-20 mg/L
• Check within 5-7 days of dose change
• PRIMARILY guided by clinical effect
Zonisamide
Actions
• Blocks voltage gated Na+ channels
• Inhibits T type Ca2+ channels
• Carbonic anhydrase inhibition
Indications
• Partial seizures
Efficacy
• Partial and generalised seizures
Dosing
• Start 2-4 mg/kg/day, target 4- mg/kg/day
• Daily or divided dose
Interactions
• Nil significant
AE
• Dizziness, drowsiness, headaches, hyperoxia
• N+V, weight loss
• Renal calculi (inhibitor renal carbonic anhydrase -> serum metabolic acidosis)
• Rash
Lacosamide
Actions
• Enhances slow inactivation of voltage gated Na+ channels
Indications
• Focal seizures
Efficacy
• Focal seizures
Dosing
• 4-8 mg/kg/day in divided doses (oral IV)
Interactions
• Compound blocks side effects from other Na channel blockers
AE
• Diplopia, dizziness, headache
• PR prolongation – usually asymptomatic
Thiopentone
• Mechanism of action
o Barbiturate derivative that increases the duration of GABA-dependent Cl channel opening in the CNS
o This results in hyperpolarization and inhibition of neuronal activity
o The effects appear to be mediated through their interaction with the beta subunit within GABA(A) receptors
• Indications
o Induction of GA
o Status epilepticus
• SEs o Hypotension o Arrhythmias o Laryngeal spasm o Hypothermia o Anaphylaxis
Desferrioxamine
Iron chelator
Administration Subcut infusion
Mechanism Urinary excretion of Fe+ and faecal
Uses 1st line therapy in Europe
Monitoring LFTs, UEC monthly
SE Impaired linear growth, bony changes, ocular toxicity, hearing loss (worse if started early)
** Titrate dose to reduce toxicity, skin reaction, infection (Yersinia, Klebsiella)
Deferasirox
Iron chelator
Administer: Oral
Mechanism: GI removal of Fe+
- Removes liver iron more rapidly than cardiac
USe: 1/3 poor responders, give BD can increase Fe excretion
Monitor: LFTs/UECs monthly
- Urine protein/creat clearance
AE: 20% transaminitis ( 5 x ALT), renal effects/low GFR (reversible), GI intolerance, rash, no effect on growth, GI bleeding
Deferiprome
Iron chelator
Administer: Oral
Mechanism: Urinary and faecal
- ? removal of cardiac iron with greater reduction in T2
Use: 2nd line if poor response or non-adherence or combined salvage in severe iron toxicity
Monitor: Weekly FBE, LFTs
AE: Arthropathy, thrombocytopaenia, abnormal LFTs, agranulocytosis, GI intolerance
Unfractionated Heparin
a. Action = large MW polysaccharide chains interact with AT -> inhibits factor Xa AND thrombin
b. Indications = acute or chronic thrombus, prophylaxis
c. Administration = IV continuous infusion; half live 60 minutes in adults, 30 minutes newborn
d. Monitoring = APTT
i. Maintaining APTT can be difficult in children
1. Bioavailability of heparin difficult to predict, may be influenced by plasma proteins
2. Requires frequent monitoring and dose adjustments
ii. Note in patients with a lupus anticoagulant, elevated factor VIII, or neonates anti-Xa level should be used (more accurate) target 0.35-0.7 units/mL
e. Complications
i. Bleeding
ii. Osteoporosis
iii. Heparin-induced thrombocytopaenia (HIT) = rare in children
1. Prothrombotic, immune-mediated complication in which antibodies develop to a complex of heparin and platelet factor 4 -> platelet activation, stimulation of coagulation, thrombocytopenia, and in some cases, life-threatening thrombosis
2. If suspected – discontinue heparin immediately
f. Advantages
i. Rapid onset and offset – can be discontinued rapidly
ii. Monitoring with APTT or FXa
iii. Lack of substantial renal elimination – can be used in renal failure
iv. Reversal agent available - protamine sulfate
Low molecular weight heparin
a. Mechanism = smaller molecular weight polysaccharide chains interact with AT-III -> primary inhibition of Xa, with less effect on thrombin
b. Available products = enoxaparin
c. Indications = acute or chronic thrombus, prophylaxis
d. Administration = S/cut BD dosing
e. Monitoring = anti factor Xa
i. Peak levels achieved 2-6 hours post injection - taken 4 hr after the 2nd or 3rd dose
ii. Therapeutic anti–factor Xa level – 0.5 and 1.0 IU/mL
f. Advantages
i. Longer duration of anticoagulant effect
ii. Lower risk of HIT + osteoporosis
g. Disadvantages
i. Delayed onset of action
ii. Longer duration of action – therefore difficult to stop rapidly
iii. Less easily reversed with protamine sulfate
iv. Prolonged half-life in patients with renal failure – especially with enoxaparin
Warfarin
a. Indications = subacute or chronic thrombosis, thromboprophylaxis for cardiac valves
b. Mechanism
i. Decreases reduction of vitamin K to activated form (by inhibition of enzyme VCOR C1) – decreases production of factors II/VII/IX/X, protein C and protein S
c. Monitoring = INR
i. Takes 5-7 days for INR to become therapeutic
1. Note FVII and protein C are reduced first – reduced protein C gives slightly Thrombophilic state
ii. LMWH or UFH should be continued until INR therapeutic for 2 days
iii. Standard target 2-3, may be higher if mechanical heart valve, APS, recurrent thrombosis
d. Considerations = heavily influence by diet and medications (alter clearance or rate of absorption)
e. Complications
i. Bleeding
ii. Teratogenic – particularly first trimester, chondrodysplasia punctate – nasal hypoplasia, excessive calcifications in epiphyses and vertebrae
f. Reversal = vitamin K, FFP, prothrombinex
g. Factors affecting levels
i. Prolonged PT/INR
1. Alter intestinal flora reduced intestinal Vit K synthesis – bactrim, metronidazole, macrolides (erythromycin), fluoroquinolones
2. Inhibition of CYP2C9 reduced warfarin metabolism – azoles, metronidazole, amiodarone
3. Interruption of Vit K recycling – paracetamol
ii. Reduced PT/INR
1. CYP2C9 inducers – carbamazepine, phenytoin
Direct thrombin or Factor Xa inhibitors (NOACs)
a. Direct thrombin inhibitors = dabigatran
b. Inhibitors of factor Xa = apixaban, rivaroxaban
c. Benefits = fixed dosing, oral administration, no dietary interference with Vi K, no need for regular monitoring
d. Paucity of data for use in children
Thrombolytic therapy
a. Indication
i. Rapid clot resolution necessary
ii. Due to high risk of bleeding – reserved for patients with life or limb threatening thrombosis
b. Mechanism = activate fibrinolytic system – conversion of endogenous plasminogen to plasmin -> plasmin can degrade several plasma proteins including fibrin and fibrinogen
c. Available product = tissue plasminogen activator (TPA is the primary agent used in children)
d. Administration = IV continuous infusion
e. Monitoring
i. No specific laboratory test to document a “therapeutic range” for thrombolytic therapy.
ii. Maintain the fibrinogen >100 mg/dL and the platelet count >75,000/mm3 during treatment.
iii. The clinical and radiologic response to thrombolysis should be closely monitored
iv. The duration of therapy depends on the clinical response
f. Absolute contraindications
i. Significant bleeding (intracranial, pulmonary or gastrointestinal)
ii. Peripartum asphyxia with brain damage
iii. Uncontrolled hypertension and severe thrombocytopenia
Anti-platelet therapy
a. Agents = aspirin
b. More likely protective against arterial VTEs then VTEs
c. Mechanism = irreversibly inhibiting cyclooxygenase, preventing platelet thromboxane A2 production
d. Indications = Kawasaki disease, stroke, VADs, single ventricle cardiac defects
TB meds and side effects
Rifampicin = rifamycin = Inhibit bacterial RNA polymerase, bactericidal • Inducer of liver enzymes • Orange secretions • Hepatitis • Influenza-like reaction • Thrombocytopaenia • Pruritis
Isoniazid = May involve inhibiting synthesis of mycolic acids, constituents of the mycobacterial cell wall. It is bactericidal against actively dividing M. tuberculosis and bacteriostatic against resting bacteria; it is active against intra‑ and extracellular organisms.
• Hepatitis – particularly if >35 years, comorbid alcohol intake – check LFTs prior to starting treatment
o Asymptomatic mild elevation of serum liver enzymes < 5 x normal do not stop treatment
• Immediate hypersensitivity reaction
• Peripheral neuritis – prevented by B6, increased risk with poor nutrition
• Haematological problems
Pyrazinamide = Bactericidal against M. tuberculosis in acid pH (inactive against non-tuberculous mycobacteria); active against bacteria within macrophage; activity declines with time (pH increases as inflammation decreases). • Hepatotoxic • Arthralgia • GIT upset • Pruritis • Rash
Ethambutol = May inhibit incorporation of mycolic acid into the mycobacterial cell wall. It is slowly bacteriostatic against M. tuberculosis.
• Optic neuritis – particularly colour + acuity
• GIT disturbance
• Hypersensitivity
Aciclovir/Valaciclovir
- Inhibits viral DNA polymerase
- Can cause reversible obstructive uropathy (crystallizes in renal tubules) , neurotoxicity , neutropenia with prolonged use
- Valaciclovir: Prodrug of acyclovir, Greater bioavailability of acyclovir
I: HSV/VZV
Ganciclovir/Valganciclovir
- Inhibits viral DNA polymerase
- Better for CMV than acyclovir
- Causes myelosuppression – potential side effects of carcinogenicity and gonadal toxicity
I: CMV
Lamivudine
• Inhibits viral DNA polymerase and reverse transcriptase
I: HIV/Hep B
Oseltamivir
- Neuraminidase inhibitor: interefers with de-aggregation and release of viral progeny
- Active against influenza A and B
- Renal excretion, causes N+V
- Needs to be started within 2 days of symptoms
I: influenza
Ribavirin
- Interferes with viral messenger RNA
- Can be given via aerosol to sick children with RSV
- Generally safe – may cause conjunctivitis + bronchospasm
I: RSV
Palivizumab
Monoclonal antibody against RSV
I: RSV prophylaxis (chronic lung disease, congenital heart disease)
Famciclovir
• Inhibits viral DNA polymerase
I: VZV
