ANTIEPILEPTICS -PHARMACOLOGY

Pharmacology MBBS - For BAMS students

1. Pharmacology of Antiepileptic Drugs FOR SECOND PROFESSIONAL BAMS STUDENTS Dr. Remya Krishnan MD PhD(Ay)

2. Basic Mechanisms Underlying Seizures and Epilepsy  Seizure: the clinical manifestation of an abnormal and excessive excitation and synchronization of a population of cortical neurons  Epilepsy : a tendency toward recurrent seizures unprovoked by any systemic or acute neurologic insults  Epileptogenesis : sequence of events that converts a normal neuronal network into a hyperexcitable network

3. How Does Epilepsy Develop? Acquired epilepsy Physical insult to the brain leads to changes that cause seizures to develop—50% of patients with severe head injuries will develop a seizure disorder Brain tumors, stroke, CNS infections, febrile seizures can all lead to development of epilepsy Initial seizures cause anatomical events that lead to future vulnerability Latent period occurs prior to development of epilepsy

4. How Does Epilepsy Develop? Genetic Epilepsies: Mutation causes increased excitability or brain abnormality Cortical dysplasia—displacement of cortical tissue that disrupts normal circuitry Benign familial neonatal convulsions

5. Anti epileptic drugs 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 eff

6. 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

7. Mechanisms Since the normal resting neuronal membrane potential is intracellularly negative, inhibitory processes make the neuron more electrically negative,  hyperpolarizing the membrane, while excitatory processes make the intracellular potential less negative or more positive,  depolarizing  the cell. On an ionic level, inhibition is typically mediated by inward chloride or outward potassium currents, and excitation by inward sodium or calcium currents.

8. 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

9. Choosing Antiepileptic Drugs  Seizure type  Epilepsy syndrome  Pharmacokinetic profile  Interactions/other medical conditions  Efficacy  Expected adverse effects  Cost

10. 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 Add-on therapy is used when a single drug does not completely control seizures

11. Classification of AEDs Classical Phenytoin Phenobarbital Primidone Carbamazepine Ethosuximide Valproate (valproic acid) Trimethadione (not currently in use) Newer Lamotrigine Felbamate Topiramate Gabapentin Tiagabine Vigabatrin Oxycarbazepine Levetiracetam Fosphenytoin In general , the newer AEDs have less CNS sedating effects than the classical AEDs

12. Cellular Mechanisms of Seizure Generation  Excitation (too much) Ionic—inward Na + , Ca ++ currents Neurotransmitter—glutamate, aspartate  Inhibition (too little) Ionic—inward CI - , outward K + currents Neurotransmitter—GABA

13. Neuronal (Intrinsic) Factors Modifying Neuronal Excitability  Ion channel type, number, and distribution  Biochemical modification of receptors  Activation of second-messenger systems  Modulation of gene expression (e.g., for receptor proteins)

14. Extra-Neuronal (Extrinsic) Factors Modifying Neuronal Excitability  Changes in extracellular ion concentration  Remodeling of synapse location or configuration by afferent input  Modulation of transmitter metabolism or uptake by glial cells

15. Mechanisms of Generating Hyperexcitable Networks  Excitatory axonal “sprouting”  Loss of inhibitory neurons  Loss of excitatory neurons “driving” inhibitory neurons

16. 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

17. 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 Quisqualate Regulation of second messengers (cAMP and Inositol) Modulation of synaptic activity  Modulation of glutamate receptors Glycine, polyamine sites, Zinc, redox site

18. Epilepsy—GABA  Major inhibitory neurotransmitter in the CNS  Two types of receptors GABA A —post-synaptic, specific recognition sites, linked to CI - channel GABA B —presynaptic autoreceptors, mediated by K + currents

19. AEDs That Act Primarily on GABA Benzodiazepines (diazapam, clonazapam) Increase frequency of GABA-mediated chloride channel openings Barbiturates (phenobarbital, primidone) Prolong GABA-mediated chloride channel openings Some blockade of voltage-dependent sodium channels

20. Gabapentin May modulate amino acid transport into brain May interfere with GABA re-uptake 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

21. 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

22. 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+ Channels

23. Ca 2+ Channels as Targets Absence seizures are caused by oscillations between thalamus and cortex that are generated in thalamus by T-type (transient) Ca 2+ currents Ethosuximide is a specific blocker of T-type currents and is highly effective in treating absence seizures

24. What about K+ channels? K+ channels have important inhibitory control over neuronal firing in CNS—repolarize 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

25. Classical AED Sodium channel blockers- Carbamazepine,Cenobamate , Ethotoin etc Calcium channel blockers-Nifedipine, Verapamil GABA enhancers- Valporate which increases the synthesis of GABA and reduce metabolism , Tiagabine which blocks neuronal uptake of GABA and Gabapentin which increases synaptic GABA .

26. Short time side effects

27. Long term side effects

28. Analgesics and Antipyretics Dr. Remya Krishnan MD PhD ( Ay)

29. Analgesics Analgesics, or pain killers, are a group of agents that relieve pain due to inflammation. There are two main types of oral analgesics . Nonsteroidal anti-inflammatory drugs (NSAIDs)/non-narcotic Narcotic/opioid NSAIDs are effective for superficial pain originating from the skin, muscles, and joints, whereas opioids work more effectively to numb pain arising from deeper organs.

30. MOA Local tissue injury releases prostaglandins. Prostaglandins have two major actions: Sensitize pain receptors and lower the threshold for painful stimuli Intensify the activation of the nerve endings by other inflammatory mediators such as bradykinin, serotonin, and histamine NSAIDs work by inhibiting the production of prostaglandins by inhibiting two types of cyclooxygenase enzymes

31. Actions & Examples COX 1 inhibition – Reduces fever, can produce gastric irritation and prevent platelet aggregation. COX2 inhibition- Specific anti-inflammatory effects Traditional NSAIDs – Acetaminophen, Aspirin,Naproxen , Diclofenac COX 2 inhibitors- Celecoxib, Valdecoxib etc Opioid analgesics- Hydrocodone, Oxycodone etc

32. CNS suppressants – Produce low and slow vitals- Low heart rate, low respiration, low brain activities Opium – A dark brown resinous material derived from poppy seeds ( Papaver somniferum capsules)- Morphine , Codeine, Papaverine alkaloids etc Morphine – Analgesia action-Inhibits the release of excitatory transmitters at substantia gelatinosa of dorsal horn, send inhibitory impulses through descending pathway at supraspinal level in cortex,midbrain and medulla

33. Opioid drugs, typified by morphine, produce their pharmacological actions, including analgesia, by acting on receptors located on neuronal cell membranes. The presynaptic action of opioids to inhibit neurotransmitter release is considered to be their major effect in the nervous system. The opioid drugs, typified by morphine, have the potential to produce profound analgesia, mood changes, physical dependence, tolerance and a hedonic ('rewarding') effect which may lead to compulsive drug use

34. MOA Within the central nervous system, opioids have effects in many areas, including the spinal cord. In the peripheral nervous system, actions of opioids in both the myenteric plexus and submucous plexus in the wall of the gut are responsible for the powerful constipating effect of opioids. In peripheral tissues such as joints, opioids act to reduce inflammation.

35. MOA Opioids have actions at two sites, the presynaptic nerve terminal and the postsynaptic neuron. The presynaptic action of opioids is to inhibit neurotransmitter release, and this is considered to be their major effect in the nervous system. However, the final effect of an opioid in the brain is the result, not only of its action at multiple presynaptic sites on both inhibitory and excitatory neurons, but also of its postsynaptic effects

36. MOA Morphine, by an action on m receptors, inhibits release of several different neurotransmitters including noradrenaline, acetylcholine and the neuropeptide, substance P. Pain is normally associated with increased activity in primary sensory neurons induced by strong mechanical or thermal stimuli, or by chemicals released by tissue damage or inflammation. Primary sensory neurons involved in pain sensation release predominantly substance P and glutamate in the dorsal horn of the spinal cord. Nociceptive information is transmitted to the brain via the spinothalamic tracts.

37. MOA Opioid receptors are present in many regions of the nervous system that are involved in pain transmission and control, including primary afferent neurons, spinal cord, midbrain and thalamus. The opioid drugs produce analgesia by actions at several levels of the nervous system, in particular, inhibition of neurotransmitter release from the primary afferent terminals in the spinal cord and activation of descending inhibitory controls in the midbrain.

38. MOA Neurotransmitter release from neurons is normally preceded by depolarisation of the nerve terminal and Ca++ entry through voltage-sensitive Ca++ channels. Drugs may inhibit neurotransmitter release by a direct effect on Ca++ channels to reduce Ca ++ entry, or indirectly by increasing the outward K + current, thus shortening repolarisation time and the duration of the action potential. Inhibition of Adenyl cyclase aso result in inhibition of neurotransmission

39. Tolerance & Dependance Tolerance and dependence are induced by chronic exposure to morphine and other opioids more than any other group of drugs. Tolerance means that higher doses of opioids are required to produce an effect. When the degree of tolerance is very marked, the maximum response attainable with the opioid is also reduced.