Pharmacology Flashcards
What is TIVA
Form of anaesthesia utilising only intravenous drugs, commonly a combination of a hypnotic agent such as propofol and a synergistic agent such as remifentanil
Indications of TIVA
Patient factors
- History of malignant hyperthermia
- Severe PONV
Surgical factors
- Shared airway surgery
- Smooth emergence required e.g. neurosurgery
- Use of neurophysiological monitoring
Practical
- Non-theatre
- Transfer
Safety considerations
General
- Vigilant anaesthetist e.g. drug errors
- pEEG monitoring (particularly if NMBD)
Equipment
- Visible free flowing drip
- Pumps - low / high pressure alarms, near end of syringe alarm
- Anti-syphon and anti-reflux valves
Organisational
- single strength of propofol stocked
Target controlled infusion
- Computer generated relevant pharmcokinetic model
- Set target concentration (e.g. in effect site) by anaesthetist
- Uses demographic data to manipulate infusion rate to achieve desired concentration
- increasing target - pump delivers bolus and increases rate
- reducing target - pump interrupts delivery then re-starts at lower rate
- Significant inter-patient variability
User interface
- patient demographic details etc
computer / microprocessor
- implements / calculates the model
infusion device
- up to 1200ml/hr, precision 0.1ml/hr
Three compartment model
- Body in 3 compartment
- central compartment is plasma where drug is administered and removed from (V1)
- drug redistributes initially to highly vascular tissue (V2) with rate constant for redistribution between central and V2
- Also redistributes to less vascular tissue via different rate constants (V3)
- Eventually all 3 compartments will be in equilibrium
- Models how infusions of drugs such as propofol behave within the body
Differences between three compartment models
Marsh - compartment sizes depend n weight, rate constants are fixed. Plasma target generally
Schnider - V1/V3 fixed, V2 depends on age, some rate constants variable. calculates lean body mass for dosing
Paedfusor / Kataria - paediatrics
Eleveld - new paeds / adults
Marsh vs Schnider
- size of central compartment
- Schneider uses fixed central compartment (smaller than marsh) - estimated concentrations will vary - age
- Schneider better for elderly, allows reduced rate of clearance - dose of propofol
- differences in infusion rates decreases with time. Schneider uses less - body weight
- marsh = TBW and can overdose obese unless using IBW
TIVA and obestiy
SOBA - recommend adjusted body weight (actual body weight may result in excessive boluses and infusion rates. ABW = IBW + 40%
Propofol and TIVA
Physical properties
- cheap
- safe
-stable
- long shelf life
Pharmacokinetic
- Rapid onset and offset
- small Vd
- rapid metabolism
- no excitation or emergence phenomenon
Pharmacodynamic
- antiemetic
- minimal toxicity
Clearance / Vd
Clearance = volume of plasma cleared of drug per unit time - accounts for elimination from body. elimination x Vp
Vd = apparent volume that drug is disributed. dose / plasma concentration
Important equations:
1. Loading dose can be calculated from desired plasma concentration and initial Vd (Pc x Vd)
2. Bolus dose to rapidly increase plasma concentration (Cnew - Cactual) x Vd
3. Rate to maintain steady state = Cp x clearance
Context sensitive half time
Time for plasma concentration to half when infusion stopped after reaching steady state
comparison between distribution and elimination clearances. drug with high distribution clearance and low elimination clearance will have half a long CSHT
Fentanyl has distribution : elimination ratio of 5:1 propofol 1:1 remifentanil <1 :1
Rate constant
coefficient of proportionality relating to rate of chemical reaction and concentration of reactants
half life - time taken to reduce plasma concentration to half it’s original value
time constant - time taken for plasm concentration to reach zero if initial rate of decline continues
Neuropathic pain definition
Pain caused by lesion or disease of somatosensory nervous system
Clinical features of neuropathic pain
Unprovoked pain - shooting, burning, electric shock, tingling, numbness, painful parasthesia
Allodynia and hyperalgesia
Neuropathic pain syndromes
Peripheral nervous system:
Trigeminal neuralgia
Post-herpetic neuralgia
Phantom limb pain
Diabetic neuropathy
Central nervous system:
Spinal cord injury
MS
Post stroke
Drug treatments
1st line (Non-TN) = amitriptyline, duloxetine, gabapentin or pregabalin
2nd line = another one
Tramadol rescue
Capsaicin cream for localised symptoms
Pharmacology of neuropathic agents
Amitriptyline = TCA, inhibits reuptake of serotonin and noradrenaline. 25-75mg at night
Duloxetine = SNRI. Diabetic neuropathy. 60mg ON
Gabapentin / Pregabalin = anticonvulsant. Inhibts a2d subunit of VGCa channels
What are Antidepressants
Drugs whilst alter neurochemistry in such a way as to improve mood. Depression felt to be due to deficiencies in NA, serotonin within CNS and most antidepressants increase their concentration
How are antidepressants classified?
SSRI e.g. fluoxetine. Prevent pre-synaptic reuptake of serotonin - increase levels. safer in overdose and more favourable SE profile
SNRI e.g. duloxetine. Prevent reuptake of both serotonin and NA with minimal effects on other NTs
TCA e.g. amitryptilline. prevent presynaptic reuptake of NA and serotonin. Have antimuscarninin, histamine, A1 effects. Sedation, dry mouth, toxic overdose, QTc prolongation
MAOI - Reduce breakdown of neurotransmitters e.g. phenelzine. risk of hypertensive crises, tyramine reaction (cheese, beer)
How do antidepressants interact with anaesthetic agents?
TCA - serotonin syndrome with tramadol, pethidine. potentate ephedrine. cholinergic syndromes if withdrawal
SSRIs - serotonin syndrome with tramadol, pethidine. Codeine interference CYP2D6
MAOI - hypertensive crisis indirect sympathomimetics (use direct)
Signs and symptoms of serotonin syndrome
Caused by excess serotonin levels, either recreationally or inadvertent overdose
Cognitic / autonomic / somatic
CVS
- Tachycardia, HTN, arrhythmias,
CNS
- Brisk reflexes, clonus, seizures, agitations, confusion, coma, mydriatic pupils
Hyperpyrexia, sweating
Uterotonics - what receptors are on the uterus
Contraction
- Oxytocin - Synthesised hypothalamus stored and released from post. pituitary. +ve feedback loop (stimulates uterine contraction, fetal head exerts pressure and causes more release)
- A adrenergic
- Prostaglandin E3
Relaxation
- Beta 2 adrenergic receptors
Drugs causing uterine contraction
- Syntocinon - 5 unit bolus IM/IV. stimulates oxytocin receptors. SE Tachycardia, vasodilation. ADH-effect (similar structure)
- Ergometrine - synthetic ergot derivative. IM. Binds to A adrenoceptors and D2 Can cause vasoconstriction, vomiting, headcache
- Haemobate (carboprost) - Prostaglandin agonist, 250mcg IM. cause bronchospasm
- Misoprostol - 800mcg PR. Prostaglandin E2 receptors. increase uterine tone. shivering diarrhoea
Drugs causing uterine relaxation
- Terbutaline - B2 agonist. 5ug/min infusion. Beta agonist SE..
- GTN - NO mediated uterine relaxation
- Atosiban - competitive oxytocin antagonist. Prevent premature labour
- Inhaled anaesthetic agents - direct dose related
Types of calcium channels
Voltage gated
- L-type - ventricular myocytes (refractory period)
- T-type - cardiac pacemakers
Ligand-gated
- Ryanodine receptor
Calcium channel blockers
Act on L-type Ca channels
Class 1 - (cardiac pacemaker cells) phenylalkylamines
- verapamil
- L-type - slow AP through SA and AV node
- Oral / IV preparation
Class 2 - (vascular smooth muscle) dihydropyridines
- amlodipine - PO only, HTN
- nifedipine - PO, SL. coronary and peripheral vasodilator. HTN, angina
- nimodipine - oral and IV, crosses BBB, SAH vasospasm
Class 3 - benzothiazepines
- diltiazem
- PO only, coronary and peripheral dilation. HTn and angina
Anticonvulsant drugs
Increase GABA activity
- Benzodiazepines - BDZ receptor , increase chloride channel opening
- Barbiturates - increase chloride channel opening
- Gabapentin - A2D subunit of calcium channels
Reduce excitatory transmission
- Phenytoin - Na channel blocker
- Carbamazepine - Na channel blocker
- Lamotrigine - Na channel blocker
Tell me about a drug
- Class
- Uses
- Mechanism of action
- Chemical properties
- Dose
- Pharmacokinetics ADME
- Pharmacodynamics by system
Suxamethonium
Deplarising muscle relaxant
Used in rapid sequence induction of anaesthesia to provide optimal intubating conditions
It’s MOA is related to structure - essentially 2 ACh molecules joined together. It binds to post-synaptic nACHR at NMJ causing depolarisation. Unlike ACH it does not move away from the receptor so there is sustained activation and influx of cations - uncoordinated muscle contraction (fasciiculations) followed by flaccid paralysis
It is presented as vial of clear colourless solution of 100mg/2ml, stored at 4oC
The dose is 1-2mg/kg
Kinetics - IV 100% bioavailability. Polar and low Vd. Metabolised by plasma cholinesterase’s and renal excretion - rapid offset of 5mins
Dynamics
- Neuro - flaccid paralysis, raised IOP
- CVS - binding to muscarinic receptors in heart - bradycardia
- raised intragastric pressure
- raised serum K+ due to K+ efflux
- myalgia
- Sux apnoea / MH / anaphylaxis
CI
- Known MH susceptibility
- Previous anaphylaxis
- burns or spinal cord injury 24hrs - 18 months
- hyperkalaemia
Sux apnoea
Autosomal recessive genetically acquired deficiency in plasma cholinesterase’s
Leads to reduced breakdown of suxamethonium at NMJ and prolonged block
4 alleles
- usual - 96% homozygous normal gene
- silent - homozygous for silent gene. no enzyme function
Dibucaine test - higher number better function
Acquired plasma cholinesterase deficiency
- pregnancy, liver disease, renal disease, malnutrition, cancer, plasmaphoresis
Sux - Phase 1 and 2 blockade
Phase 1 - initial depolarising block
- ToF - reduced height, no fade
- Tetany - reduced, no fade
Further doses –> Phase 2 - features of NDMR
- ToF - fade
- Tetany - fade
Dementia definition
progressive neurocognitive disorder characterised by memory impairment plus other cognitive deficits such as language, complex tasks, reasoning.
Types of dementia
Alzheimers - short term memory and word finding. amyloid plaques and neurofibrillary tangles
Vascular - 20% - series of minor strokes, stepwise decline
Lewy-Body - visual hallucinations and PD
Parkinsons dementia
Frontotemporal dementia - personality and language changes
Dementia drugs (minimal evidence)
Acetylcholinesterase inhibitors (some symptoms felt to be cholinergic deficit)
- donepezil - central acting
- rivastigmine
NMDA receptor blockers
- memantine
Delirium definition
acute reversible cognitive dysfunction with reduced awareness and inattention. may be associated with hallucinations delusions, memory impairment
Hyper/hypo
Management of delirium
Non-pharmacological
- Orientation
- Calm quiet environment
- Minimise staff changes, night time disturbances
- family
- access to hearing aids, glasses
- Removing wires and tubes
- Mobilisation
Pharmacological
- Typical antipsychotic e.g. haloperidol
- Atypical antipsychotic e.g. olanzapine
- Benzodiazepines if contraindicated
Vomiting centre
region of the medulla control of vomiting
many inputs including
- chemoreceptor trigger zone - vagal afferents from GI, outside BBB
- nucleus tracts solitarius - vestibular H1 and ACh, cerebral cortex, D2 receptors, muscarinic inputs
Classes of antiemetics
5-HT3 antagonists - ondansetron
D2 antagonists - Droperidol (act at CTZ) domperidone (act peripherally) metoclopramide (both)
H1 antagonists - cyclizine (some anticholinergic properties) works at CTZ
Phenothiazines e.g. prochlorperazine - D2 / musc / H1 antagonists in CTZ
anti-cholinergic - hyoscine central anti-cholinergic transdermal.
Dexamethasone - uncertain mechanism
Aprepitant - neurokinin 1 antagonist in GI tract
Antiemetic strategy
Risk factors (Apfel score)
Risk mitigation (minimise N20, volatile, consider RA, opiate sparing)
Risk stratification - 1-2 risks - give 2 antiemetics. 3-4 risks - give 3-4
Rescue antiemesis
Neuroleptic malignant syndrome
Idiosyncratic reaction to antipsychotic drugs
- fever, rigidity, confusion, autonomic dysfunction
- Stop drug, cool, dantrolene, fluid (CK)
Principles of chemotherapy
Chemotherapy targets replicating cells and ultimately trigger apoptosis in cancer cells. usually administered in combination to achieve synergy.
Regimes
Neoadjuvant - prior to surgical resection, aim to improve chance of curative resection, reduce extent of surgery
Adjuvant - given after resection with aim of reducing recurrence
Palliative - aim to prolong survival
Mechanisms of action of common chemotherapy agents
Alkylating agents - cisplatin, cyclophosphamide - prevent cell replication by cross linking DNA
Anti-metabolites - 5-FU, methotrexate. disrupt DNA repair
Anti-microtubule agents - paclitaxel - interfere with mitotic processes
Cytotoxic antibiotics - bleomycin, doxorubicin - damage DNA
Side effects by system
RESP
- infection, PE risk
- Pneumonitis - methotrexate
- Pulmonary fibrosis - bleomycin (aggravated by O2, minimise O2, titrate to 88-92%)
CVS
- toxicity may cause MI, cardiomyopathy, myopericarditis, cardiac failure
- doxorubicin - cardiomyopathy
RENAL
- platinum based e.g. cisplatin may cause tubular damage
HEPATIC
- hepatic metabolism, abnormal enzymes common.
- methotrexate - fibrosis
CNS
- peripheral neuropathy, autonomic dysfunction e.g. vincristine
GI
- vomiting, electrolyte abnormalities
HAEM
- myelosuppression, neutropenia
Radiotherapy
Use of ionising radiation which is toxic to dividing cells, administered directly at cancer cells
Generalised side effects - fever, nausea, vomiting
Localised fibrosis
- head and neck - difficultt airway
- thoracic - lung fibrosis
Antibiotic classification
mechanism of action
- inhibition of nucleic acid synthesis - quinolones
- inhibition of cell wall synthesis
- inhibition of protein synthesis - aminoglycosides
Nucleic acid synthesis inhibitors
Quinolones - ciprofloxacin - inhibit DNA gyrase. Gram +ve and gram -ve
Trimethoprim - inhibit enzymes involved in folate synthesis
Imidazoles - metronidazole - inhibit DNA synthesis. anaerobic species
Cell wall synthesis inhbitors
Penicillins - B-lactam rings inhibit cross linking of peptidoglycan. Gram +ve
Cephalosporins - similar mechanism of action
Glycopeptides - Teicoplanin, Vancomycin - inhibit peptidoglycan formation, Gram +ve
Protein synthesis inhibitors
Aminoglycosides - inhibit RNA binding. gentamicin, narrow therapeutic index
macroldies - clarithromycin - inhibit translocation of RNA. narrow spectrum
Antibiotics resistance
Innate - some bacteria naturally resistant to certain antibiotics
Acquired - genetic mutation by natural selection or horizontal transmission of gene in the form of plasmids
Mechanisms
- enzyme inhibition - B-lactamase
- binding site modification
- outer membrane protein channel changes
- upregulating cell wall pumps that actively remove antibiotics
Plasma proteins
Albumin (60%)
A1 globulins
A2 globulins
B globulins
Y globulins
Albumin
Large water soluble protein 67kDa, negatively charged at physiological pH
synthesised in the liver, 350-50mg/ml
hydrophobic core hydrophilic exterior x3 binding sites
- responsible for 80% plasma oncotic pressure
- Number of substances bind to albumin and transport
- hormones -s steroid, thyroxine
- unconjugated bilirubin
- electrolytes - ca, mg
- free fatty acids
- drugs - NSAIDs, warfarin, digoxin (compete)
- negative acute phase protein (conserve AA for positive APPs)
- contributes to anion gap (unmeasured anions in plasma)
Human albumin solution
Indications
- Burns
- Plasma exchange
- Paracentesis of ascites
- (resuscitation)
Presentation
- solution of 4.5%, 5%, 20% in 100ml, 250ml, 500ml bottles
- Pooled from multiple doors and purified
- 3 yr shelf life
Kinetics
- IV only 100% bioavailability
- low Vd (0.07l/kg)
- metabolised reticulendothelial system
- minimal renal excretion (unless nephrotic)
Effects
- Increase plasma oncotic pressure
- may increase BP
- May cause fluid overload
- may worsen cerebral oedema following TBI
- anaphylactic reactionsA
Albumin evidence
Resuscitation
- not statistically superior to n/saline (SAFE)
- higher mortality in TBI
- otherwise safe
Septic shock
- no evidence of superiority to crystalloid
Liver
- less circulatory dysfunction with paracentesis
- 100ml 20% per 3L
expense / transfusion risks
Use in SBP
Don’t use in TBI
Don’t use to correct low albumin
Warfarin
- VKA - inhibits synthesis of II, VII, IX and X
- coumarin derivative
99% protein bound to albumin - 3-5d to peak effect
interacts with numerous drugs, particularly those that compete with albumin binding sites e.g. antibiotics, NSAIDs
teratogenic
monitoring
NOACs
Rivaroxaban / apixaban Xa inhibitors
- Rivaroxaban : 20mg once daily dosing, 3 hours to peak effect, hepatic metabolism
- apixaban : BD dosing 3 hours peak, lower dose in renal failure. 2.5 - 5mg BD
Dabigatran = thrombin inhibitor
BD Dosing, 2 hrs peak 110-150mg BD
Dabigatran reversal = idarucizumab
Apixaban reversal = Adexanet alpha
Heparins
Naturally occurring glycosaminoglycans
UFH - antithrombin 3 1000x - inactivates Xa and thrombin.
IV bolus infusion. APTTr. 4hrs offset
LMWH - antithrombin 3 - augments ability to inactivate Xa. caution renal failure. monitoring xa levels difficult. peak 4 hrs. invasive procedures 12hrs post prophylactic 24hrs post treatment
Neuraxial and NOACs
warfarin INR < 1.4
NOACS - 48hrs (apixaban 24-48) (dabigatran 48-96)
UFH 4hrs
LMWH prophylactic 12 treatment 24
Dopamine
Catecholamine neurotransmitter
Phenylalinae –> L-tyrosine –> L-DOPA –> DOPA –> NA –> Adr
Dopa decarboxylase LDOPA–>DOPA
Dopamine broken down by dopamine b hydroxylase to NA / Adr, broken down by COMT and MAO
Drugs used to treat parkinsons
- L-DOPA
+ Peripheral decarboxylase inhibitor (reduce S/E e.g. carbidopa) - Dopamine agonists e.g. ropinerole
- MAO-B Inhibitors e.g. selegiline - prevents dopamine breakdown
- COMT inhibitors e.g. entacapone - smooth out off effects
Drugs to avoid in parkinsons
- Antiemetics - metoclopramide, prochlorperazine. (domperidone safe)
- Antipsychotics - typicals e.g. haloperidol
- Antihypertensives - pronounced effect
- central anticholinergics e.g. atropine - cholinergic crisis
Blood gas solubility coefficient
The ratio of the amount of anaesthetic in blood and gas when the two phases are of equal volume and pressure at equilibrium at 37oC.
Low BGPC = higher partial pressure in blood, higher in brain, faster onset
Des 0.42 Sevo 0.68 Iso 1.4
Graph = wash in, time x axis, Fa/Fi y axis
Oil:gas partition coefficient
Measure of lipid solubility of anaesthetic agent, correlates to potency. Higher lipid solubility means more drug entering brain and therefore greater potency.
Inverse correlation to MAC
Meyer-Overton
MAC
Measure of potency
Concentration of anaesthetic agent at steady state which prevents reaction to surgical stimulus in 50% of subjects at one atmosphere
Factors altering MAC
Increase
- Hyperthermia
- Young age
- Chronic alcohol / drug use
- Catecholamine
Decrease
- Pregnancy
- Hypotension
- Hypothermia
- Acute opioid use
Ideal volatile
Physical
- Stable to heat and light
- Inert
- Not flammable or explosive
- Non-irritant
- Atomospherically friendly
Biochemical
- Low BGPC - quick onset and offset
- High OGPC - potent
- No toxic metabolites
- Only effects CNS
Cardiac output and onset of action of volatiles
High cardiac output maintains concentration gradient between alveolus and arterial pressures, slower equilibrium, slower onset of action
Serotonin production / metabolism
produced from hydroxylation and decarboxylation of tryptophan (essential amino acid)
reuptake and inactivation by MAO. products renally excreted
Serotonin found in brain
GI (enterochromaffin)
platelets
Serotonin receptors
5HT1-7
All GPCR apart from 5HT3 (ion channel)
5HT2 = platelet aggreggation
5HT3 = GI tract and area postrema = vomiting
5HT6-7 = limbic function
Serotonin syndrome
Excess serotonin in CNS. Triad
- autonomic activation –> diaphoresis, HTN, hyperthermia, tachycardia, dilated pupils, diarrhoea
- altered mental status –> agitation, delirium, disorientation seizures
- neuromuscular excitability –> tremors, rigidity, hypereflexia, nystagmus
Hunter criteria for serotonin syndrome
Serotoningeric agent and combination of
- spont / inducibe clonus
- agitation
- diaphoreiss
- tremor
- hypertonia
- hyperreflexia
- hyperpyrexia
Tricyclics mechanism of action
Complex
- H1/H2 blockade
- Anticholinergic
- Blockade of presynaptic NA / serotonin uptake
- Blockade of cardiac fast Na channel
TCA kinetics
A - well absorbed 2-4hr peak
D - high Vd, low free drug (albumin A1 glycoprotein)
M - liver hydroxylation and methylation
E - 10% renal excretion
TCA cardiac toxicity
Slow phase 0 by Na channel blockade
delay depolarisation AV node, prolong QRS, abnormal repolarisation
hypotension direct myocardial depression, alpha blockade vasodilation
Secondary prevention post MI
ACEi
Antiplatelet (DAPT)
Beta blocker 12months (indefinite if LVF)
Statin
(ca channel blocker if beta blocker contraindicated)
ACEi indications
secondary prevention post MI
Essential hypertension
CKD
Diabetic nephropathy
Heart failure
ACEi side effects
- cough
- hypotension
- electrolyte derangement - hypokalaemia
- renal impairment
- Angioedema
approach to hypotensive agents
BP = CO X SVR
Reduce HR
- beta blockers
Reduce venous return
- venodilators
- neuraxial blockade
Reduce contracility
- volatile
Reduce SVR
- anaesthetic
- vasodilators
- neuraxial
hypotensive drugs
beta blockers
- esmolol - selective B1
- labetalol - A1 and B1 (vasodilation, without reflex tachycardia
vasodilators
- GTN
- sodium nitroprusside (arterial and venous)
- hydralazine
A blocker
- phentolamine
Sodium nitroprusside
- arterial and venous dilator
- hypotensive anaesthesia, management of increased SVR with cross clamp
- dose 0.5 - 6mcg/kg/min
- presented as brown powder, reconstituted in glucose. covered in aluminium foil as exposure to sunlight cause cyanide ion formation
- MOA - prod NO - cGMP - reduce calcium
PD - CVS - reduces SVR, preload, causes tachycardia
- Resp - inhibit HPVC
- CNS - vasodilation and inc ICP
Tachypyhlaxis - thiocynaite toxicity (oxygen, chelating, sodium thiosulphate)
Three types of anticholinesterases
Easily reversible
- edrophonium
- tension test
- Binds anionic and esteratic sites
- ACh will compete
Formation of carbamylated-enzyme complex
- neostigmine, pyrodistigmine
- produced carbamylated enzyme with reacting with ACHE - slower rate of hydrolysis than ACH and ACHE complex - stops ACH hydrolysis
Irreversible inactivation
- organophosphates
- esteratic site of AChE phosphorylated - enzyme inhibition and very stable
Organophosphate poisoning
Parasympathetic overload SLUDGE
- lacrimation
- meiosis
- salivation
- bradycardia
- diarrhoea
- urination
- bronchospasm
- confusion agitatation coma
Treatment organophosphate poisoning
- remove clothes, PPE, shower, irrigate eyes, charcoal
- ABC
- avoid sux
- atropine ++ child 20mcg/kg repeat every 20mins
- pralidoximine
- diazepam
- toxbase
Warfarin reversal
- Stop warfarin - 2-4 days to reverse
- Vit K 4-6 hrs. multiple doses
- Prothrombin Complex Concentrate - derived from irradiated plasma, clotting factors II, VII, IX, X. Immediate reversal.
- FFP - partial effect, not recommended unless bleeding
Anticonvulsant drugs
Increase GABA
- Benzodiazepines (BDZ receptor to increase Cl opening frequency
- Barbiturates - increase Cl opening duration
Antagonise glutamate
- Topiramate
Reduce excitatory activity
- Phenytoin
- Carbamazepine
- Lamotrigine
- Valproate
All block Na+ channels
Gabapentin - block A2D subunit of Ca channels
Keppra - unknown
Phenytoin
Antiepileptic drug
Action to block Na channels
Indicated for status epileptics and treatment of epilepsy
Dose 20mg/kg IV or 50-200mg PO
Presented clear colourless solution, diluted in N/saline to 10mg/ml or as tablets
PK
- IV 100% bioavailability PO 90%
- Low Vd, 90% PB bound
- Liver metabolism, cytochrome P450 inducer Zero order kinetics. small therapeutic range
- inactive metabolites renally excreted
PD
- CNS - reduce seizures
- CVS - May have class 1 antiarhythmics. can reduce BP
Idiosyncratic
- acne
- gum hyperplasia
- BM depression
- peripheral neuropathy
- hirsutism
-coarsening facial features
- teratogenic
Leveteracetam
focal / generalised seizures
unclear mechanism
Oral or IV
IV 60mg/kg status epileptics max dose 4.5g
20-30mg/kg maintenance BD
IV 500mg/5ml clear colourless
PK
- PO + IV same 100% bioavailability
- < 10% PB, low Vd
- Enzymatic hydrolysis
- renal excretion, mostly unchanged
PD
- CNS - antiseizure, somnolescence, mood disturbance
- idiosynratic - Steven-Johnson
Hepatic enzyme inducers
Increase activity - faster metabolism of drugs
PCBRAS
- Phenytoin
- Carbamazepine
- Barbiturates
- Rifampicin
- Alcohol
- Smoking
Hepatic enzyme inhibitors
Reduce activity - slower metabolism of drugs
OADEVICES
- omeprazol
- allopurinol
- disulfrim
- erythromycin
- valproate
- isoniazid
- cimetidine
- ethanol (acute)
- sulphonamide
