Pharmacology of Antiepileptic Drugs
1) Seizures occur due to abnormal neuronal excitation and synchronization in the brain, while epilepsy is characterized by recurrent seizures. 2) Antiepileptic drugs work by enhancing inhibition (GABA) or reducing excitation (glutamate/sodium channels) in the brain. 3) Common antiepileptic drugs include phenytoin, carbamazepine, valproate, lamotrigine, topiramate, levetiracetam, which have different mechanisms of action and side effect profiles.
Epilepsy and antiepileptics. Dr.Ashok Kumar Batham,M.D.,DrAshok Batham
This presentation provides relevant description and classification of epilepsy with easy-to-remember mechanism-based and chemistry-based classifications of Anti-epileptic Drugs (AEDs). General features and salient details of all the Anti-epileptic Drugs (AEDs) are provided that can be used as short-notes. Hopefully, this presentation would be useful to students of medicine, pharmacology, pharmacy, clinical pharmacy, and representatives of pharmaceutical companies.
complete and detail study on the topic of anti epileptic drugs . the topic contain drugs of epilepsy with their uses, side effect, mechanism of action, classification of epileptic drugs.
basic information of receptors
ANTIEPILEPTIC DRUGS . mechanism of action of convulsionMsSapnaSapna
Anticonvulsants are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder and borderline personality disorder, since many seem to act as mood stabilizers, and for the treatment of neuropathic pain. A type of drug that is used to prevent or treat seizures or convulsions by controlling abnormal electrical activity in the brain.
Epilepsy and antiepileptics. Dr.Ashok Kumar Batham,M.D.,DrAshok Batham
This presentation provides relevant description and classification of epilepsy with easy-to-remember mechanism-based and chemistry-based classifications of Anti-epileptic Drugs (AEDs). General features and salient details of all the Anti-epileptic Drugs (AEDs) are provided that can be used as short-notes. Hopefully, this presentation would be useful to students of medicine, pharmacology, pharmacy, clinical pharmacy, and representatives of pharmaceutical companies.
complete and detail study on the topic of anti epileptic drugs . the topic contain drugs of epilepsy with their uses, side effect, mechanism of action, classification of epileptic drugs.
basic information of receptors
ANTIEPILEPTIC DRUGS . mechanism of action of convulsionMsSapnaSapna
Anticonvulsants are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder and borderline personality disorder, since many seem to act as mood stabilizers, and for the treatment of neuropathic pain. A type of drug that is used to prevent or treat seizures or convulsions by controlling abnormal electrical activity in the brain.
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Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
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NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
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2. Basic Mechanisms Underlying
Basic Mechanisms Underlying
Seizures and Epilepsy
Seizures and Epilepsy
Seizure: the clinical manifestation of an
abnormal and excessive excitation and
synchronization of a population of cortical
neurons
Epilepsy: a disease characterized by
spontaneous recurrent seizures
Epileptogenesis: sequence of events that
converts a normal neuronal network into an
epileptic network
4. Simple Partial Seizure
Simple Partial Seizure
• Focal with minimal spread of abnormal
discharge
• normal consciousness and awareness are
maintained
5. Complex Partial Seizures
Complex Partial Seizures
Local onset, then spreads
Impaired consciousness
Clinical manifestations vary with site of
origin and degree of spread
– Presence and nature of aura
– Automatisms
– Other motor activity
Temporal lobe epilepsy
most common
6. Secondarily Generalized Seizures
Secondarily Generalized Seizures
Begins focally, with or without focal neurological
symptoms
Variable symmetry, intensity, and duration of tonic
(stiffening) and clonic (jerking) phases
Typical duration up to 1-2 minutes
Postictal confusion and somnolence
7. Generalized Seizures
Generalized Seizures
In generalized seizures,
both hemispheres are
widely involved from
the outset.
Manifestations of the
seizure are
determined by the
cortical site at which
the seizure arises.
Present in 40% of all
epileptic Syndromes.
8. Generalized seizures
Generalized seizures
• Absence seizures (Petit mal): sudden onset and
abrupt cessation; brief duration, consciousness is
altered; attack may be associated with mild clonic
jerking of the eyelids or extremities, postural tone
changes, autonomic phenomena and automatisms
(difficult diagnosis from partial); characteristic 2.5-3.5
Hz spike-and wave pattern
• Myoclonic seizures: myoclonic jerking is seen in a
wide variety of seizures but when this is the major
seizure type it is treated differently to some extent from
partial leading to generalized
9. Generalized Seizures (cont)
Generalized Seizures (cont)
• Atonic seizures: sudden loss of postural tone;
most often in children but may be seen in adults
• Tonic-clonic seizures (grand mal): major
convulsions with rigidity (tonic) and jerking
(clonic), this slows over 60-120 sec followed by
stuporous state (post-ictal depression)
10. • Recruitment of neurons throughout the cortex
• Major convulsions, usually with two phases:
• 1) Tonic phase: muscles will suddenly tense up, causing the
person to fall to the ground if they are standing.
• 2) Clonic phase: muscles will start to contract
• and relax rapidly, causing convulsions
• Convulsions:
− motor manifestations
− may or may not be present during seizures
− excessive neuronal discharge
• Convulsions appear in Simple Partial and Complex Partial
Seizures if the focal neuronal discharge includes motor centers;
they occur in all Generalized Tonic-Clonic Seizures regardless of
the site of origin.
• Atonic and absence Seizures are non-convulsive
•
Generalized Tonic-Clonic Seizures
Generalized Tonic-Clonic Seizures
11. Status Epilepticus
Status Epilepticus
• More than 30 minutes of continuous seizure
activity
• Two or more sequential seizures spanning
this period without full recovery between
seizures
• Medical emergency
12. Antiepileptic Drug
Antiepileptic Drug
A drug which decreases the frequency and/or
severity of seizures in people with epilepsy
Treats the symptom of seizures, not the
underlying epileptic condition
Goal—maximize quality of life by minimizing
seizures and adverse drug effects
Currently no “anti-epileptogenic” drugs
available
13. Therapy Has Improved Significantly
Therapy Has Improved Significantly
• “Give the sick person some blood from a
pregnant donkey to drink; or steep linen in it, dry
it, pour alcohol onto it and administer this”.
– Formey, Versuch einer medizinischen Topographie
von Berlin 1796, p. 193
14. Current Pharmacotherapy
Current Pharmacotherapy
• Just under 60% of all people with epilepsy can
become seizure free with drug therapy
• In another 20% the seizures can be drastically
reduced
• ~ 20% epileptic patients, seizures are refractory
to currently available AEDs
16. General Facts About AEDs
General Facts About AEDs
• Good oral absorption and bioavailability
• Most metabolized in liver but some excreted
unchanged in kidneys
• Classic AEDs generally have more severe CNS
sedation than newer drugs (except
ethosuximide)
• Because of overlapping mechanisms of action,
best drug can be chosen based on minimizing
side effects in addition to efficacy
18. MECHANISM OF ACTION OF ANTIEPILEPTIC DRUGS
Antiepileptics inhibit the neuronal discharge or its spread in one or
more of the following ways:
(1) Enhancing GABA synaptic transmission: barbiturates, benzo-
diazepines, gabapentin, levetiracetam, tiagabine, vigabatrin, topira-
mate, valproate; the result is increased permeability to chloride ion,
which reduces neuronal excitability. Valproate and topiramate block
GABA transaminase and tiagabine blocks reuptake of GABA.
(2) Reducing cell membrane permeability to voltage-dependent
sodium channels: carbamazepine, lamotrigine, oxcarbazepine,
phenytoin, topiramate, valproate.
(3) Reducing cell membrane permeability to calcium T-channels:
valproate, ethosuximide; the result is diminishing of the generation
of action potential.
(4) Inhibiting excitory neurotransmitter glutamate: lamotrigine.
23. Targets for AEDs
Targets for AEDs
• Increase inhibitory neurotransmitter system—
GABA
• Decrease excitatory neurotransmitter system—
glutamate
• Block voltage-gated inward positive currents—
Na+ or Ca++
• Increase outward positive current—K+
• Many AEDs pleiotropic—act via multiple
mechanisms
24. Epilepsy—Glutamate
Epilepsy—Glutamate
The brain’s major excitatory neurotransmitter
Two groups of glutamate receptors
– Ionotropic—fast synaptic transmission
• NMDA, AMPA, kainate
• Gated Ca++
and Gated Na+ channels
– Metabotropic—slow synaptic transmission
• Regulation of second messengers (cAMP and
Inositol)
• Modulation of synaptic activity
Modulation of glutamate receptors
– Glycine, polyamine sites, Zinc, redox site
26. Glutamate Receptors as AED Targets
Glutamate Receptors as AED Targets
• NMDA receptor sites as targets
– Ketamine, phencyclidine, dizocilpine block channel
and have anticonvulsant properties but also
dissociative and/or hallucinogenic properties; open
channel blockers.
• AMPA receptor sites as targets
– Since it is the “workhorse” receptor can anticipate
major sedative effects
27. Felbamate
Felbamate
• Antagonizes the glycine site on the NMDA
receptor and blocks Na+ channels*
• Very potent AED lacking sedative effect (unlike
nearly all other AEDs)
• Associated with rare but fatal aplastic anemia,
hence is restricted for use only in extreme
refractory epilepsy
28. Topiramate
Topiramate
• Acts on AMPA receptors, blocking the glutamate binding
site, but also blocks kainate receptors and Na+
channels, and enhances GABA currents (highly
pleiotropic*)
• Used for partial seizures, as an adjunct for absence and
tonic-clonic seizures (add-on or alternative to phenytoin)
• Very long half-life (20h)
29. Epilepsy—GABA
Epilepsy—GABA
Major inhibitory neurotransmitter in the
CNS
Two types of receptors
– GABAA—post-synaptic, specific
recognition sites, CI-
channel
– GABAB —presynaptic autoreceptors,
also postsynaptic, mediated by K+
currents
31. Clonazapam
Clonazapam
• -Benzodiazepine used for absence seizures
(and sometimes myoclonic): “fourth-line AED”
• -Most specific AED among benzodiazepines,
appearing to be selective for GABAA activation
in the reticular formation leading to inactivation
of T-type Ca2+ channels, hence its useful for
absence seizures
• -Sedating; May lose effectiveness due to
development of tolerance (≤6 months)
32. Lorazapam and Diazepam
Lorazapam and Diazepam
• Benzodiazepines used as first-line treatment for
status epilepticus (delivered IV – fast acting)
• Sedating
33. Phenobarbital
Phenobarbital
– Barbiturate used for partial seizures, especially in
neonates. Oldest of the currently used AEDs
– Very strong sedation; Cognitive impairment;
Behavioral changes
– Very long half-life (up to ~5days); #Induces P450
– Tolerance may arise; Risk of dependence
– Primidone, another barbiturate metabolized to
Phenobarbital, and Phenobarbital are now seldom
used in initial therapy, owing to side-effects
34. Tiagabine
– Interferes with GABA re-uptake
Vigabatrin (not currently available in US)
– elevates GABA levels by irreversibly inhibiting
its main catabolic enzyme, GABA-
transaminase
AEDs That Act Primarily on GABA
AEDs That Act Primarily on GABA
35. Na+ Channels as AED Targets
Na+ Channels as AED Targets
• Neurons fire at high frequencies during seizures
• Action potential generation is dependent on Na+
channels
• Use-dependent or time-dependent Na+ channel
blockers reduce high frequency firing without
affecting physiological firing
36. A = activation gate
I = inactivation gate
McNamara JO. Goodman & Gilman’s. 9th ed. 1996:461-486.
Anticonvulsants:
Anticonvulsants:
Mechanisms of Action
Mechanisms of Action
Na+
Na+
Carbamazepine
Phenytoin
Lamotrigine
Valproate
Na+
Na+
I I
Voltage-gated sodium channel
Open Inactivated
X
37. Phenytoin, Carbamazepine
– Block voltage-dependent sodium channels at high firing
frequencies—use dependent
Oxcarbazepine
– Blocks voltage-dependent sodium channels at high
firing frequencies
– Also effects K+ channels
Zonisamide
– Blocks voltage-dependent sodium channels and T-type
calcium channels
AEDs That Act Primarily on Na+
AEDs That Act Primarily on Na+
Channels
Channels
38. Phenytoin
Phenytoin
• First-line for partial seizures; some use for tonic-
clonic seizures
• Highly bound to plasma proteins – displaced by
Valproate; #Induces P450 resulting in increase
in its own metabolism, but its metabolism is also
increased by alcohol, diazepam
• Sedating
• Fosphenytoin: Prodrug for Phenytoin, used for
IM injection
39. Carbamazapine
Carbamazapine
• A tricyclic antidepressant used for partial
seizures; some use in tonic-clonic seizures
• #Induces P450 resulting in increase in its own
metabolism;
• Sedating; Agranulocytosis and Aplastic anemia
(elderly); Leukopenia (10% of patients);
Hyponatremia; Nausea and visual disturbances
40. Oxcarbazapine
Oxcarbazapine
• Newer drug, closely related to Carbamazapine,
approved for monotherapy, or add-on therapy in
partial seizures
• May also augment K+ channels*
• Some #induction of P450 but much less than
that seen with Carbamazapine
• Sedating but otherwise less toxic than
Carbamazapine
41. Zonisamide
Zonisamide
• Used as add-on therapy for partial and
generalized seizures
• -Also blocks T-type Ca2+ channels*
• -Very long half-life (1-3days)
42. Lamotrigine
Lamotrigine
• Add-on therapy, or monotherapy for refractory
partial seizures
• Also inhibits glutamate release and (perhaps)
Ca2+ channels (=pleiotropic*)
• Metabolism affected by Valproate,
Carbamazapine, Phenobarbital, Phenytoin
• Less sedating than other AEDs; (Severe
dermatitis in 1-2% of pediatric patients)
43. Ca
Ca2+
2+
Channels as Targets
Channels as Targets
• General Ca2+ channel blockers have not proven
to be effective AEDs.
• Absence seizures are caused by oscillations
between thalamus and cortex that are generated
in thalamus by T-type (transient) Ca2+ currents
44. Ethosuximide
Ethosuximide
• Acts specifically on T-type channels in thalamus,
and is very effective against absence seizures.
• Long half-life (~40h)
• Causes GI disturbances; Less sedating than
other AEDs
45. Gabapentin
Gabapentin and its second generation
and its second generation
derivative
derivative Pregabalin
Pregabalin
• -Act specifically on calcium channel subunits
called α2δ1. It is unclear how this action leads to
their antiepileptic effects, but inhibition of
neurotransmitter release may be one
mechanism
• -Used in add-on therapy for partial seizures and
tonic-clonic seizures
• -Less sedating than classic AEDs
46. What about K+ channels?
What about K+ channels?
• K+ channels have important inhibitory control over
neuronal firing in CNS—repolarizes membrane to
end action potentials
• K+ channel agonists would decrease
hyperexcitability in brain
• So far, the only AED with known actions on K+
channels is valproate
• Retiagabine is a novel AED in clinical trials that
acts on a specific type of voltage-dependent K+
channel (M-channel)
47. Valproate (Valproic Acid)
Valproate (Valproic Acid)
• First-line for generalized seizures, also used for
partial seizures
• Also blocks Na+ channels and enhances
GABAergic transmission (highly pleiotropic*)
• Highly bound to plasma proteins; #Inhibits P450
• CNS depressant; GI disturbances; hair loss;
weight gain; teratogenic; (rare: hepatotoxic)
48. Regulation of Neurotransmitter release
Regulation of Neurotransmitter release
• Several AED have actions that result in the
regulation of neurotransmitter release from the
presynaptic terminal, such as lamotrigine, in
addition to their noted action on ion channels or
receptors.
• Levetiracetam appears to have as its primary
action the regulation of neurotransmitter release
by binding to the synaptic vesicle protein SV2A:
50. • Many AEDs act on multiple targets, increasing
their efficacy
• Felbamate, lamotrigine, topirmate, valproate
Pleiotropic AEDs
Pleiotropic AEDs
51. Drug Interactions
Drug Interactions
• Many AEDs are notable inducers of cytochrome
P450 enzymes and a few are inhibitors.
• Of the classic AEDs, phenytoin, carbamazipine,
phenobarbital, and primidone are all strong
inducers of cytochrome P450 enzymes. They
are autoinducers, in other words they increase
their own metabolism.
• Valproate inhibits cytochrome P450 enzymes.
52. Pharmacokinetic Considerations
Pharmacokinetic Considerations
• Most AEDs undergo complete or nearly complete absorption when
given orally.
• Fosphenytoin (prodrug) may be administered intramuscularly if
intravenous access cannot be established in cases of frequent
repetitive seizures
• Diazepam (available as a rectal gel) has been shown to terminate
repetitive seizures and can be administered by family members at
home.
• Phenytoin, fosphenytoin, phenobarbital, diazepam, lorazepam and
valproate are available as IV preparations for emergency use.
• Most AEDs are metabolized in the liver (P450) by hydroxylation or
conjugation. These metabolites are then excreted by the kidney.
Gabapentin undergoes no metabolism and is excreted unchanged
by the kidney.
54. Status Epilepticus
Status Epilepticus
• Treatment
– Diazepam, lorazapam IV (fast, short acting)
– Followed by phenytoin, fosphenytoin, or phenobarbital
(longer acting) when control is established