1
Q
agonistic drug effects
A
- incr synthesis of neurotransmitters
- inhibit degrading enzymes
- incr release of neurotransmitters
- bind to postsynaptic receptors (incr neurotransmitter effect/ block inhibitory effect)
- block deactivation (reuptake. degradation)
2
Q
antagonistic drug effects
A
- drug block synthesis of neurotransmitter
- cause neurotransmitter to leak from vesicle/ destroyed by enzyme (less released)
- drug block release of neurotransmitters
- activate autoreceptors (inhibit release)
- receptor blocker, no neurotransmitter effect
3
Q
BBB functions
ECF 15% of total brain vol
A
□ Modulate entry of metabolic substrates (glucose), level more stable in CSF > blood
□ Ion movement.
* Na-K-ATPase in barrier cells pump Na+ into CSF
* pump K+ out of CSF into blood
□ Prevent access to CNS by toxins, peripheral neurotransmitters (autonomic nerve endings –> blood stream)
4
Q
drug property — BBB
A
1) non-saturable: transmem diffusion
2) saturable: transporter system (influx & efflux)
drug uptake incr with neuroinflamm (porous cap walls, passage of non-lipid soluble Abx)
5
Q
1) non-saturable: transmem diffusion
A
- drugs with low MW, high lipid solubility
- not too high lipid solubility
- sequestrated in cap bed
- uptake by peripheral tissues
6
Q
Lipinski rule of 5 for BBB penetration
A
- <500 Da
- uncharged
- tertiary struc
- degree of protein binding
- lipid solubility
7
Q
2) saturable: transporter system (influx & efflux)
A
10x faster > transmem diffusion
regulated by:
- cerebral blood flow, co factors, hormones/ peptide modulator
- specific region of brain express transproters for reg. mole (L-dopa, vit B12)
- EFFLUX TRANSPORTERS (PGP, decr uptake of drug)
8
Q
strategies to cross BBB
A
- target transporters (improve PK to corss BBB)
- analogs of transported ligands (affinity to BBB transporters and CNS target receptor)
- BBB as the therapeutic target (porous cap walls in disease state)
9
Q
ASM rationales
A
1) decr mem excitability, alter Na, Ca2+ conductance during AP
2) enhance effect of inhibitory GABA neurotransmitters
10
Q
1st gen ASM – still effective
A
carbamazepine
Phenobarbital
phenytoin
sodium valproate
11
Q
2nd gen - better SE
A
gabapentin
lamotrigine
levetiracetam
pregabalin
topiramate
12
Q
lvl A for new onset focal onset epilepsy
A
CBMZP
LVT
PT
elderly:
lamo
gabapentin
others:
SV (b), TPM (c)
13
Q
lvl C for new onset GTC epilepsy
A
lamo
SV
cbmp
tpm
oxcarbazepine
14
Q
refractory = not respond to tx
A
1) used lvl A
2) tried another lvl A
3) tried agent B, C
4) refractory lvl
15
Q
refractory for focal onset epi
A
clobazam
lacosamide
pregabalin
perampanel
16
Q
refractory for GTC
adjunctive AEDs
A
clobazam
LVT
lamo
TPM
17
Q
tonic or atonic
A
SV
TPM
adjunct: lamo
X: CBMP, GP, Pregabalin, oxcarbazepine
18
Q
absence
A
ethosuximide
lamo
SV
clobazam
leve
TPM
X: CBMP, GP,PT, pregabalin
19
Q
focal tx
A
CBMP
Lamo
Leve
SV
oxcarbazepine
20
Q
CBMP MOA
A
Block voltage dependent Na+ channels, less Na+ influx
stabilise hyperexcited nerve mems, inhibit repetitive neuronal discharges & reduce synaptic propagation of excitatory impulses
21
Q
PK of 1st gen ASM Carbamazepine
A
F: 80%
Protein binding: 75-85%
E: 100% Hepatic
T1/2: 6 - 15hr
DDI: yes
22
Q
indication and dose of CBM
A
indicated for complex/ simple PARTIAL & GTC
except absence:
initiate 100-200mg OD, BD
- incr in 200mg/day increments until 400mg BD/TDS or optimum response. (max 2000mg/day)
- or maintain: 10mg/kg/day in 2-4 divided doses
23
Q
why titrate and monitor CBMP
A
1) autoinduction, accelerated elimination (t1/2 shortens w/ repeated doses)
2) PGx (HLA)-B*1502 allele – SJS, TEN
24
Q
CBMP ADR
A
NV, Hepatotoxicity
Peripheral neuropathy
Osteomalacia
Megaloblastic anaemia, leuko, aplastic, SJS
GIT
suicidal ideation
hyponatremia
Moderate: malformation neonatal
25
common CBMP ADR
nystagmus
NV
lethargy
dizz, drowsy
headache
blurred vision, diplopia (double vision)
unsteadiness
ataxia, incoordination
26
DDI of CBMP
Potent enzyme inducer CYP (1A2, 2C, 3A4)
CYP3A4 substrates: affects apixaban, contracep, azoles
CYP3A4i: grapefruit, clarithromycin (macrolides)
UGT, PGP: apixaban, dabigatran, digoxin, edoxaban, rivaroxaban
27
caution in what pop for CBP
renal: no dose adj
hepatic: no dose adj (but risk of hepatotoxicity)
elderly: lower doses
pediatrics: higher doses
28
preg and lact pop
preg: teratogenic risk (only is benefit > risk)
- folic acid suppl
- vit K in last period of preg
- TDM
- do not discontinue abruptly (Status epi), try switch to LEVE, LAMO
lact: can use (monitor infant for ADR - jaundice, V, poor suckling, skin rxn)
29
distribution of CBMP
* Highly protein bound 75-80%
* Albumin, a1-acid Glycoprotein
* Vd (immediate release) =1.4L/kg
1~2 L/kg
30
CBMP metabolism
* CYP3A4 (>99%)
* Form active metabolites, carbamazepine-10,11 epoxide
○ 30+ metabolites
* Undergoes autoinduction (stabilise in 2-3wks)
○ Induce own Metabolism
○ CL incr, t1/2 decr
○ Conc decline and stabilise with new Cl, t1/2
31
due to autoinduction how to dose CBMP
start at lower dose, incr gradually over initial few weeks to desired maintenance dose
32
monitor CBP
baseline & periodic: CBC, LFT, reticulocyte, Fe, renal, Na lvl (hyponatremia <136mmol/L-- switch to LEVE)
baseline: HLA-B*1502 pgx
monitor: osteoporosis, LDL
33
Phenobarbital MOA
Acting on GABA-A receptor subunits.
Increases duration chloride channels are open.
at site diff from benzodiazepines
34
PB indication
- AED (pediatric, neonatal IV LD --> IV/PO maintenance) long-acting 1-2d & child less likely to abuse
sedative-hypnotic <--- benzodiazepine
(PB: tolerance & dependence, withdrawal sx)
35
PB duration of action and indication
LA (1-2d): anticonvulsant
SA (3-8hr): sedative, hypnotic
ultrashort (20min): IV induction of anesthesia (thiopental)
36
PB PK
F: 100%
Protein binding: 50%
E: 75% H
T1/2: 72-124 hr
DDI: yes
37
PB ADR
Hepatotoxicity
Peripheral neuropathy
Osteomalacia
dysarthria, ataxia, incoordination
Megaloblastic anaemia
major: malformation neonatal
sedation and drowsiness
38
common PB ADR
sedation, drowsy
nystagmus
39
PB DDI
Potent enzyme inducer
CYP (1A, 2A6, 2B, 3A)
UGT
40
dose-dependent depression of CNS with benzo vs PB
as dose incr
hypnosis --> anesthesia --> medullary depression --> coma
benzo (will plateau, safety) > PB (continues to incr, no plateus)
41
phenytoin MOA
Block voltage dependent Na+ channels
increasing efflux or decreasing influx of sodium ions across cell membranes
42
PT indication & dose
1) partial/ focal GTC
LD: 15mg/kg/d (1-3 divided doses)
F/B: 5mg/kg/d (1-3 divided doses)
2) status epilepticus
LD: 20mg/kd + IV benzodiazepine
F/B: 5mg/kg/d in 2 divided doses
43
PT PK
F: 95%
Protein binding: 90%
E: 100% hepatic
T1/2: 12-60hrs
DDI: yes
44
PT DDI
Potent enzyme inducer
CYP (2C9, C19, 3A)
UGT, PGP
45
PT ADR
Hepatotoxicity
Gingival hyperplasia (gum growth)
Hirsutism (F facial hair)
Peripheral neuropathy, sensory loss
Osteomalacia
Megaloblastic anaemia
rash, SJS
Moderate: malformation neonatal
Affect neonatal cognition
46
common PT SE
nystagmus
NV
lethargy
dizz, drowsy
headache
blurred vision, diplopia (double vision)
unsteadiness
ataxia, incoordination
47
PT formulation
* Oral susp 125mg/5ml (Phenytoin acid 100%)
* Capsule, IV (salt form, phenytoin sodium 92%)
48
PT absorption
* But slow absorption
* Reduced at higher dose >400mg/dose (break up)
* Reduced with enteral feed interaction (space 2hrs)
49
PT distribution
* Vd 0.7L/Kg (0.5 - 0.8L/kg)
* Highly albumin bound 90%
○ Altered by displacement, incr Fu
○ Total lvls (bound + unbound)
§ Estimate Fu by eqn
○If low albumin --> incr free PT
50
PT correction for albumin <40g/L
C corrected = C observed/ [x . (alb/10) +0.1]
Guide estimation of PT in presence of hypoalbuminemia, renal impairment
albumin in g/L
Conc in mg/L
x is albumin coeff, varies
51
free PT conc = Total phenytoin lvl x correction factor
new Winter-tozer
X = 0.275 (crcl > 10ml/min)
x = 0.2 (crcl <10 ml/min, HD)
52
PT metabolism/ why need titrate and monitor
* narrow therapeutic range (40-100um)
* Zero order kinetics, non-linear b. dose & plasma conc
○ Capacity limited clearance
○ (conc incr, CL decr) non-proportional incr in conc, AUC
* Saturable protein binding
53
PT CI
absence seizure
teratogenic (congenital malformation, neurodev risk)
54
PT monitor
CBC, LFT, vit D, suicidal
plasma PT conc (free conc: if renal impair/ hypoalbumin)
monitor for osteoporosis, lipid (cholesterol, LDL)
55
valproic acid MOA
Block voltage dependent Na+ and Ca2+ channels
Inhibit GABA transaminases (incr GABA+ mimic its action)
strongly bound to plasma prot, displace other ASM (except PT)
56
VA indication
bipolar (fixed 500-700mg/day, 1-4 divided doses)
epilepsy -- absence, complex partial (10-15mg/kg/day. 1-4 divided dose), GTC (250mg/day)
migraine (off label)
57
VA PK
F: 100%
Protein binding: 75-95%
E: 100% hepatic
T1/2: 6-18hr, shorter in children
DDI: yes
58
VA ADR
Hepatotoxicity, Pancreatitis
alopecia
thrombocytopenia
hyperammonemia
haemorrhage
hypersensitivity (SJS, TEN)
(CI) major: malformation neonatal
Affect neonatal cognition
59
common VA ADR
NVD (take w/ after food)
weight gain
ataxia (poor muscle control), slurred speech
tremor
dizzy, drowsy , confusion
nystagmus (eyes not aligned)
F: painful/ irregular periods
60
special pop for SV
renal: NIL but monitor for clinical resp, free VA
hep: not recc, CI in severe
elderly: lower initial & maintenance doses (monitor ADR)
paediatric: weight based dosing
61
VA DDI
Potent enzyme inhibitor
CYP2C9
UGT
1) enhance CNS depressant effect: (nasal: azalastine, olopatadine)
- neuroleptics, MAOi, antidepressants, benzodiazepines
2) decr conc of VA: carbapenems, estrogen, barbiturates,
3) lamotrigine: enhance ADR and incr serum conc (lamo dose adj, decr)
4) incr conc of VA: CBP (plasma displace)
5) affect conc of other drugs (warfarin, NSAID, PHT)
62
VA absorption
F~1, (PO)
Inj, enteric coat, sustained release tablets, syrup
63
VA distribution
* Vd = 0.15L/kg
* Highly albumin bound ~90-95%
○ Displaced by endogenous (uraemia, hyperbilirubinaemia)
○ Compete for binding (PHT, NSAID, warfarin) displaces other ASM
* Saturable protein-binding within therapeutic range
○ Decr protein binding at higher conc
○ More Free at low albumin
64
VA monitor
base & periodic: LFT, CBC w/ PLT
as needed: PTT, NH3, pancreatic, hepatotoxic, suicidal sx, osteoporosis
preg
efficacy: n.o. of seizure ep, TDM (ref 50-100mg/L)
65
dose/ plasma conc related ADR
CNS - somnolence, fatigue, dizzy, visual disturbances, nystagmus, ataxia
GI - NV (CBMP, SV)
psychiatric - behavioral LEVE
cognition - speech TPM
66
ADR occurs more freq in
ASM combination therapy
- additive neurologic effect of ASM
- initiation of therapy (disappear when tolerance develops)
67
mitigate ADR
- initiate at low dose, slow titrate
- avoid large dose changes
- restrict to 1 drug only (if feasible)
- adjust admin schedule
* largest dose ON
*divide daily dose across day
* Sustained release formulation
* reduce TOTAL DAILY DOSE
68
idiopathic/ hypersensitivity related ADR
all ASM except some 2nd gen
- blood dyscrasia (aplastic, agranulo)
- hepatotox (1st gen)
- pancreatitis (SV)
- lupus like (1st gen)
- exfoliate dermatitis, severe skin inflamm
- TEN/ SJSJ
-megaloblastic anaemia (PT, assoc CBMP, PB)
occur in first few mnths of therapy
69
leve ADR
somonolence, dizzy
asthenia (weak), coordination difficulties (first 4 wks)
headache
Behavioural disturbances: irritable, aggression, decr renal function
rare: agranulocytosis, suicide, delirium, dyskinesia
70
leve uses
- 1st line for FOCAL SEIZURE
- adj: partial onset seizures, myoclonic, 1*GTC seizure
- safe: low intra & inter- variability.
(highly soluble and perm)
- safe for preg
71
LAMOtrigine ADR
NV
dizzy, somnolence
tremor, coordination difficulties, asthenia
headache
rash, SJS/TEN, DRESS
72
LAMO DDI
PK linear
1/2 reduced: CBP, PT (inducer)
1/2 incr: SV (inhibitor)
73
lamo uses
- adj/ mono: partial seizures, generalised (GTC)
- absence
- lennox-gastaut (severe childhood eoilepsy)
- safe for preg
- PK linear but t1/2 (reduced: CBP, PT) (incr: VA)
74
topiramate ADR
somonolence, headache
ataxia, coordination, fatigue
(psychomotor -- slow, speech, memory)
weight loss
glaucoma, hyperammonemia, metabolic acidosis
hyperthermia, paresthesia, kidney stones
neutropenia, mania, depression
75
TPM uses
- mono: partial seizure, GTC
- adjunct: lennox-gastaut
- prophy for migraine (not ACUTE)
- sulfamate-substituted monosaccharide
- safe: not a potent inducer of drug-metabolising enzymes
76
TPM monitor
before initiate: eating disorder sx (can cause weight loss)
baseline: electrolytes, SCr
periodic: metabolic acidosis, suicidal, osteoporosis
77
pregabalin, gabapentin adr
drowsy, ataxia, weight gain, dizzy
peripheral oedema
78
risk management
1) PGx testing (CBMZP)
2) dosing guidelines (lamo)
3) potential cross sensitivity rxn (ASMs w/ aromatic rings: CBMZP, PT, PB, LAMO
79
CBZ pgx testing
HLA-B*1502: risk of CBZ-induced SJS/ TEN
- Han chinese, other Asian ethnic grps (Malay, Indan, Thais)
- tested +ve: avoid CBP, PT
80
chronic (systemic) ADR
LT ASM therapy
drug-specific, not directly linked to plasma conc
may not be life-threatening but affects QOL
* gingival hyperplasia (PT)
* hirsutism (PT)
* alopecia (SV)
81
neurological ADR
CNS and resp depression for majority
peripheral neuropathy (long term PT, assoc CBMP, PB)
* may respond to folate suppl
82
metabolic ADR
- incr weight gain (SV) *reversible
- anorexia (TPM, felbamate) *reversible with discontinuation
83
endocrine ADR
- osteomalacia (PT, PB, CBMP)
incr CL fo vit D --> 2nd Hyperparathyroidism -- > incr bone turnover --> reduced bone density
84
neonatal congenital defects
CI; VA
1) major malformation risk
HIGH RISK: VA, PB, TPM
MOD RISK: SV, PT
2) neonatal cognition
VA, PT
85
suicidal ideation ADR
CBMZP, GP, LAMO, LEVE, PREGABALIN, TPM, SV
oxcarbazepine, tiagabine, zonisamide
*no changes to ongoing therapy unless discussed with physician
- closer monitoring of sx
86
lamotrigine initial dosing risk when __
risk of cutaneous reaction at
- higher starting doses
- rapid dose escalation
- concomitant SV
** slow titration
87
lamotrigine doses with SV
25mg EOD --> 25mg OD --> incr by 50mg OD (every 1-2 wks)
100-200mg/day with SV only
100-400 mg/day with other drugs that induce glucuronidation
88
lamo dose w/o CBP, SV
25mg OD --> 50mg OD --> incr by 50mg/day every 1-2 weeks
maintenance 225-375mg/d (2 divided dose)
89
lamo w/ CBP, PT, PB
50mg OD --> 100mg/d --> incr by 100mg/d every 1-2 weeks
maintenance: 300-500mg/d (2 divided doses)
90
potential cross sensitivity rxn (ASMs w/ aromatic rings)
CBMZP, PT, PB, LAMO
can form arene-oxide intermediate
immunogenic through int with proteins/ cellular maromolecules
91
which medication to choose
- efficacy and effectiveness (type of seizure/ epilepsy)
- tolerability (special grps, comorbidity)
- PK (DDI, hormonal, renal, liver failure)
- personal pref (formulation, freq)
- country (cost, availability)
92
adjust tx based on
1) seizure free? efficacy
- incr dose / add another ASM
2) SE tolerable?
- No = decr dose
93
when to discontinue ASM?
considered: after min of 2 yr w/o seizure
unless: pt with incr risk of seizure recurrence.
94
discussion for discontinuation
○ Reason
○ Taper schedule
- Personalise: seizure recurrence, seizure freq, n.o. of meds
○ Monitor before/ after ASM taper
○ Motivation, attitude, potential risks-benefit
95
risk of continuation vs relapse
continuation: chronic toxicity, teratogenicity
relapse: injury, SUDEP, employment
96
tapering schedule is individualised based on:
- risk factor for seizure recurrence
- seizure freq
- n.o. of medications
97
epilepsy resolved
past applicable age of age-dependent epilepsy syndrome (childhood, infancy)
seizure free for last 10 yrs
no seizure meds for last 5 yrs
98
why is it difficult to identify optimal dose on clinical grounds
1. plasma ASM conc correlates better with clinical effects (than dose)
2. assessment of therapeutic response is difficult
- ASM tx is prophylactic, seizure occur at irregular intervals
- difficult to ascertain whether prescribed dose suff to prod. LT seizure control
3. not always easy to recognise signs of toxicity
4. ASM subjected to PK variability (large diff in dosage in diff pts)
5. no lab markers for clinical efficacy or toxicity of ASM
99
indications for ASM TDM
Establish indiv therapeutic range
To assess lack of efficacy
To assess potential toxicity
To assess loss of efficacy (breakthrough)
100
Establish indiv therapeutic range
Reference range not effective for all
* Once stable: Document effective lvl which controls seizures whilst minimise SE
* Help in subsequent changes
* Anticipated PK changes
* DDI
* Medical conditions
101
reference ranges (PT, VA, CBP, PB)
CBP 4-12 mg/L
PT 10-20mg/L
PB 15-40 mg/L
VA 50-100 mg/L
102
To assess lack of efficacy
* Fast metaboliser
* Adherence issues
* Other problems
* Decide whether to change drugs vs rework diagnosis
103
To assess potential toxicity
* Changing physiology (preg)
* Slow metabolisers
* Change in disease/ drugs
- Renal -- uremia, hypoalbuminemia
- Liver -- CYP enzymes
- New drugs/ int
* Danger lvls (conc-dependent ADR)
104
To assess loss of efficacy (breakthrough)
* Change in physiology (Age, preg)
* Change in pathology
* Change in formulation
- Brand vs generic
- DF
* DDI
105
infor needed for TDM
○ Indication for ASM
○ Dose (when, how long, how much)
○ Sample from pt
- When taken, type
- Eg: short t1/2 take at trough to see maintenance efficacy
○ Clinical condition
- Seizure control (baseline vs current)
- Comorbidities
○ Other lab values
○ Other drugs (when, how long, how much)
106
special pop -- women of childbearing potential
* Receive counselling on family planning
* Potential risk to fetus
- Uncontrolled seizures
- Teratogenic potential of ASM
* Use OC
- Potent enzyme inducers make OC ineffective
- Alternative contraceptives needed (backup)
* lamo dose will decr due to OC = breakthrough seizures
107
contraception
potent enzyme inducers make OC inffective
consider other contaception options:
1. prog/ copper IUD
2. prog depot inj (10-12wka)
3. COC (>50ug of E) + barrier
108
special pop -- preg
VA is CI -- unless no suitable alt (epilepsy)
-- not for bipolar disorder (look for alt)
congenital malformation: CBP, PB, PT, TPM
dose-dep risk: CBP, PB, TPM
neurodev risk: PB, PT, TPM
109
special pop -- lactation
ASM not absolute CI for breastfeeding -- still encouraged to BF
PB, zonisamide, ethosuximide -- higher lvls in breastmilk
110
status epilepticus
○ considered an abnormally prolonged seizures (after t1)
○ Long term conseq (after t2)
- Neuronal death, injury, alteration of neuronal networks, depend on type and duration of seizures
t1, t2 depends on type of SE
TC: 5, 30mins
111
0-5min stabilisation phase
(ED, inpt, paramedincs)
1. stabilise: airway, brathing, circ, disability
2. time seizure from its onset, monitor vital signs
3. assess O2: intubate/ nasal mask
4. initiate ECG monitor
5. glucose (D50W IV)
6. IV access: electrolytes, hematology, toxicology, anticonvulsant drug lvls
112
5-20min initial therapy phase
benzodiazepine
1) IM midazolam (10mg/kg/dose, >40kg)
1) IV lorazepam (0.1mg/kg/dose, max 4mg/dose) can repeat
1) IV diazepam (0.15-.0.2 mg/kg/dose, max 10mg/dose, can repeat dose)
IV PB, rectal diazepam, IM midazolam
113
2nd therapy phase (if seizure continue)
20-40min
non-benzodiazepine ASM, single dose
IV fosphenytoin (20mg/kg, max 1500mg)
IV VA (40mg/kg, max 3000mg/dose)
IV levetiracetam (60mg/kg, max 4500mg/dose)
if all not avail: IV PB (15mg/kg)
114
3rd therapy phase (if seizure continues)
40-60mins
continuous admin, anesthetic doses
repeat 2nd line therapy
or anesthetic doses (thiopental, midazolam, pentobarbital, propofol)
- with continuous EEG monitoring
115
at any point if pt at baseline
symptomatic medical care
further diagnosis to identify causes (EEG, CT, LP)
116
benzodiazepines MOA
potentiates GABA effects -- inhibitory transmitter in brain regions
* acts via GABA receptors
* influx of CL- ions
= hyperpolarisation --> neurons not fired
117
benzodiazepine and AED
diazepam (43hr half life, long acting for seizure, epilepticus, sedation) -- but fast onset 30mins
lorazepam (12hr , intermediate-acting for anxiety, status epilepticus)
Clonazapam (30hr, LA, for panic disorders)
118
benzodiazepines ADR
- clonazepam, lorazepam, DIAZEPAM
* acute toxicity/ overdose
- severe resp depression esp W/ ALCOHOL
- tx with flumazenil - benzo antagonist
* droswy, confuse, amnesia, coordination
* tolerance and dependence
- must withdraw gradually
- abuse potential
119
tolerance vs dependence
depends on freq of use. tolerance develops faster for epilepsy > sedation use
Tolerance: Same dose wont give you same efficacy
dependence: will have withdrawal effects, addictives
- disturbed sleep, rebound ANX, tremor, convulsions
120
counselling points
1) adherence
2) missed dose (do not double)
3) if SR, EC do not crushed
4) avoid alcohol (CNS depressive effects)
5) take after food to reduce GIT upset
121
fluctuation index
CR is better to decr fluctuation, less peak-to-trough conc variation
less dose-dependent SE and less incidence of subtherapeutic drug conc
3153
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