Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
2017-2018
SEDATIVE/HYPNOTICS AND ANTISEIZURES
Dr. J. O. Cruz
1|P age
Pharmacology B S.Y. 2017-2018
SEDATIVE/HYPNOTICS AND ANTISEIZURES
Dr. J. O. Cruz
Newer AEDs are being developed based on the following • no appreciable plasma protein binding
mechanisms: • Exceptions- phenytoin, tiagabine, valproate
1. GABA transmission enhancement • Clearance via hepatic metabolism
2. Reduction of excitatory or glutaminergic • active metabolites
transmission • medium to long-acting
3. Changes in ionic conduction processes • slow plasma clearance
• t1/2=12 h or more
CURRENTLY AEDS ARE MAINLY FOR PALLIATION. • older AEDs (ex. phenytoin, etc.) induce CYP450
• potential for drug interactions
BASIC PHARMACOLOGY • have extended release formulations
2|P age
Pharmacology B S.Y. 2017-2018
SEDATIVE/HYPNOTICS AND ANTISEIZURES
Dr. J. O. Cruz
AEDS THAT BLOCK SODIUM CHANNELS OR ENHANCE permitted to reach steady state before
SODIUM CHANNEL INHIBITION incrementing the dose.
a. PHENYTOIN • Dose adjustment in hypoalbuminemia and in renal
b. CARBAMAZEPINE disease (because of ↑ protein binding)
c. LAMOTRIGINE (NEWER AGENT) • reduced protein binding raises the free
d. PRIMIDONE concentrations of phenytoin
For partial, secondarily generalized seizures, and • May affect thyroid function tests
generalized tonic-clonic seizures • Drug Interactions:
• Hepatic microsomal enzyme inducer-
PHENYTOIN – enzyme inducer increases inactivation of:
• OLDEST NON SEDATING AED (in therapeutic doses) • OCPs
• Use-dependence sodium channel blockade (same • Cyclosporine
with carbamazepine, lamotrigine, and valproate) • Quinidine
• Agent is able to preferentially inhibit the • Methadone
excitation of cells that are repetitively • Doxycycline
firing. Increase threshold for AP • Levodopa
• ↑ freq. of firing, ↑ block produced; can • Adverse Effects: (think of ocular effects)
block abnormal high freq. seizures but do • Shares many with other AEDS in this group:
not interfere with lower freq. activities of • nystagmus, extraocular muscle
normal cells dysfunction, diplopia, ataxia,
• SPECIFIC TARGET: Na Channels in the inactivated sedation
state • Long term use: gingival hyperplasia,
• Partial seizure and prevention of secondary seizure hirsutism, peripheral neuropathy, reduced
generalization DTRs, Vit D metab abnormalities,
• INEFFECTIVE IN ABSENCE TYPE osteomalacia,
• Use-dependency prolongs the inactivated • Teratogenicity
conformation and increases the number of • Rare toxicities: hypersensitivity and skin
abnormal cells in the inactivated state to rash, lymphadenopathy, fever and
control against partial and tonic-clonic agranulocytosis.
seizures
• Absorption kinetics depends on formulation CARBAMAZEPINE – enzyme inducer
• High plasma protein binding • related to the TCAs
• hepatic metab, active metabolites • non- sedating in usual doses
• Renal excretion, dose dependent elimination • Active metabolite: 10,11 epoxycarbamazepine
• 2 phases of metab: First order-low dose; zero order- • DOC for simple and complex partial seizures (slowly
high dose being replaced by newer agents)
• T1/2= 24h (average) • Also used for trigeminal neuralgia, bipolar disorders
• Oral preparations (Phenytoin sodium) is almost (manic phases)
100% but peak serum levels vary from 3 to 12 hours • Variable absorption rates but is completely
• The IM formulation is not used because it is more absorbed (peak levels by 6-8 h)
unpredictable because drug molecules may • Slow distribution
precipitate in muscle • 70% protein binding
• inactive prodrug fosphenytoin is preferred • First order metab; doesn’t undergo zero order (safer
as it is more soluble and is better absorbed than Phenytoin)
with IM administration • T1/2= 36 h but this decreases in time
• Steady state 5-7 d • 8-12 hours as the drug induces activity of
• Therapeutic levels is usually 10-20 mcg/ml. CYP450
• The usual adult starting dose is 300 mg/d • dosage adjustments in the first days of
with usual increments of 25-30 mg if treatment
needed. However, enough time should be • Oral formulation only
• Drug interaction:
3|P age
Pharmacology B S.Y. 2017-2018
SEDATIVE/HYPNOTICS AND ANTISEIZURES
Dr. J. O. Cruz
• Complete absorption
DRUGS THAT ACT AT THE T-TYPE CALCIUM
• Low protein binding 55%
• Phase 2 hepatic metab (via glucuronide conjugation CHANNELS
followed by renal excretion) a. VALPROIC ACID/VALPROATE
• Renal excretion b. ETHOSUXIMIDE
• T1/2= 24 hours
AEDs under this category are utilized for absence
• Concomitant intake of enzyme inducing
meds such as other AEDs shortens this to or petit mal seizures. Recall that in the awake
about 13-15 hours. state, the T type calcium channel is depolarized
• Valproic acid increases lamotrigine half-life and inactive. In petit mal, such channels are
by two fold so the starting dose should by activated during the awake state which is the
adjusted accordingly main feature in this type of seizure.
• Drug interaction:
• Half-life is reduced to 13-15h if taken with
enzyme inducing AEDs
4|P age
Pharmacology B S.Y. 2017-2018
SEDATIVE/HYPNOTICS AND ANTISEIZURES
Dr. J. O. Cruz
5|P age
Pharmacology B S.Y. 2017-2018
SEDATIVE/HYPNOTICS AND ANTISEIZURES
Dr. J. O. Cruz
• For Partial Seizures, adjunct for grand mal and • Strong sedative property
some pain conditions; also marketed as analgesics • May worsen ABSENCE seizure
• may also be effective for this seizures when • The drug acts on all GABA receptors and can
given alone, although this may require very potentiate GABA in the reticular nucleus
high doses. and thalamic relay cells
• Additional indications for both drugs • Enhance T-type calcium currents – underlie
include postherpetic neuralgia, the occurrence of absence seizures
neuropathic pain, and fibromyalgia. • pKa is near plasma pH 7.4
• Given at night time • pKA close to that of plasma pH 7.4 and
• SE: somnolence, dizziness, ataxia, tremors, hence slight changes in normal acid-base
headache balance can affect the ratio of ionized to
• Excreted unchanged, not metabolized in the liver non-ionized forms of the drug
• No effects on CYP450 • Distribution rates can vary
• No plasma protein binding
• T1/2=5 hours
• Multiple daily doses required
Limiting factors for the use of benzodiazepines: Inhibition of NMDA and AMPA subtypes of
1. Profound sedative effects glutamate receptors
2. Paradoxical hypersensitivity in children o Inhibit generation of seizure
3. Development of tolerance within a few months of o Protect neurons from seizure-
use induced injury
PHENOBARBITAL
NEWER AGENTS:
• Oldest available AED
a. LEVETIRACETAM
• Enhances GABA by keeping Cl- channels open
b. TIAGABINE
• Not selective for GABA A receptors
• Potentiate GABA A receptors in RETICULAR c. TOPIRAMATE
NUCLEUS and THALAMIC RELAY CELLS d. VIGABATRIN
(enhances T-type calcium currents =
responsible for absence seizures) LEVETIRACETAM
• Other MOAs in higher doses: • Possible MOA:
• Na+ ion conductance inhibition 1. Modification of glutamate and GABA release by
• N- and T-type calcium channel blockade selective binding to SV2A
• Reduction of glutamate release 2. Blockade of N-type calcium channels and
• Alternative drug for tonic-clonic and partial calcium release from storage
seizures; seizures in infants, febrile seizures • Current use: MONOTHERAPY
• Being replaced by other agents
• tonic-clonic seizures
6|P age
Pharmacology B S.Y. 2017-2018
SEDATIVE/HYPNOTICS AND ANTISEIZURES
Dr. J. O. Cruz
7|P age
Pharmacology B S.Y. 2017-2018
SEDATIVE/HYPNOTICS AND ANTISEIZURES
Dr. J. O. Cruz
8|P age
Pharmacology B S.Y. 2017-2018
SEDATIVE/HYPNOTICS AND ANTISEIZURES
Dr. J. O. Cruz
9|P age
Pharmacology B S.Y. 2017-2018
SEDATIVE/HYPNOTICS AND ANTISEIZURES
Dr. J. O. Cruz
10 | P a g e
Pharmacology B S.Y. 2017-2018
SEDATIVE/HYPNOTICS AND ANTISEIZURES
Dr. J. O. Cruz
al.)
FLUMAZENIL
Lone marketed benzodiazepine antagonist
↑ Dose = hypnosis is achieved, greater degree of CNS Used for cases of BZD overdose and the newer
depression (graded dose-dependent effect) agents but have no action against barbiturates,
o Linear relationship between dose and degree of CNS meprobamate, alcohol, and anesthetics
effect exists for the older agents such as alcohols and
Competitive inhibitor for the BZD binding site in the
barbiturates (Drug A).
o Further ↑ dose = general anesthesia, respiratory GABA A receptor.
depression, coma, and death o More consistent in reversing SEDATIVE
o Benzodiazepines and newer drugs (Drug B) appears EFFECTS but less predictable in respiratory
to have a deviation from this linear relationship depression.
o Proportionately more drug increments are needed to Rapid action, short half-life (0.7-1.3h), rapid hepatic
achieve CNS effects beyond hypnosis (hence safer) as clearance
depicted in the dose response curves. o Repeated administration may be required
ADVERSE EFFECTS:
SEDATIVE HYPNOTICS INCLUDE THE FOLLOWING: o Agitation, confusion, nausea, dizziness
1. Benzodiazepines (most common) o Chronic users – may trigger severe
2. Barbiturates (most replaced by BZDs) abstinence syndrome
3. Melatonin receptor antagonists o BZD + tricyclic antidepressant (TCA) +
a. Ramelteon Flumazenil = arrhythmias or convulsions
b. Tasimelteon
4. 5-HT Receptor agonist BASIC PHARMACOLOGY
a. Buspirone I. KINETICS
5. New Hypnotics (EZZ) Lipophilicity – major factor in determining the rate of
a. Eszopicline absorption; also determines how fast the sedative-
b. Zalepton hypnotic can enter the CNS
c. Zolpidem
11 | P a g e
Pharmacology B S.Y. 2017-2018
SEDATIVE/HYPNOTICS AND ANTISEIZURES
Dr. J. O. Cruz
12 | P a g e
Pharmacology B S.Y. 2017-2018
SEDATIVE/HYPNOTICS AND ANTISEIZURES
Dr. J. O. Cruz
II. DYNAMICS
13 | P a g e
Pharmacology B S.Y. 2017-2018
SEDATIVE/HYPNOTICS AND ANTISEIZURES
Dr. J. O. Cruz
BZ PROTOYPES AND
ZOLPIDEM WITH DURATION
OF ACTION:
SHORT ACTING= 3-8 H
INTERMEDIATE= 10-20 H
LONG= 1-3 DAYS
BZDs ARE USED FOR ACUTE
ANXIETY STATES AND FOR
RAPID CONTROL OF PANIC
ATTACKS.
ALPRAZOLAM AND
CLONAZEPAM – greater
efficacy than other BZDs in
longer term treatment of
panic and phobic disorders
14 | P a g e
Pharmacology B S.Y. 2017-2018
SEDATIVE/HYPNOTICS AND ANTISEIZURES
Dr. J. O. Cruz
15 | P a g e
Pharmacology B S.Y. 2017-2018
SEDATIVE/HYPNOTICS AND ANTISEIZURES
Dr. J. O. Cruz
HYPNOSIS
• Current/commonly used: BZs and newer agents
• BZs with longer T1/2 and active metabolites- more
daytime somnolence (ex. Lorazepam, flurazepam)
• BZs at hypnotic doses possible anterograde
amnesia
• Newer agents: rapid onset, less morning-after SE
16 | P a g e