3. Drugs acting on CNS

Drugs acting on the Central Nervous System Dr.mohan a Asst.Professor KMCIC Anatomy of CNS • • • • • • • • • • • Frontal lobe Higher functions, motor cortex Parietal  Somato-sensory Thalamus Relay center for sensory pathway Hypo Autonomic, emotion, circardian, thirst, hungerCONTROL Limbic Learning, memory, emotion, addiction Basal ganglion Extrapyramidal control Reticular formation Sleep-wakefullness Midbrain Vision, hearing Medulla Vital functions Cerebellum Posture, balance Sp.cord integration????? * Some actions are well established • DA pathway & Parkinsonism • NA, 5HT and depression • DA & Schizo. Less well established • Link bet. Cellular disturbances and epilepsy –Simple- not established BBB • Tight junction & Glial cells around capillaries • Absent- Floor of iv vent[CTZ-area post rema], Pineal gland, around pitutary • Defecient in new born • Pathological HTN, Inflammation, heat/cold stress, infection, radiation • Do not cross Mol.wt.>60000, polar, Lipid soluble cross • Imp Precursors-levodopa, Neuro-chemical transmission • Basics same as in ANS • Neurotransmitters • 4 processes of neurotransmission • EPSP & IPSP* Neurochemical transmission Neurotransmitters: Neurohormones: Neuromodulators: originates from nonsynaptic sites, yet influences the excitability of nerve cells Neuromediators: Substances that participate in eliciting the postsynaptic response to a transmitter Neurotrophic Factors:substances produced within the CNS that assist neurons in their attempts to repair damage Neurotrnsmission-4 processes 1. • • • 2. • • • • Neurotransmission NT Released by neurones Criteria Immediate EPSP oR IPSP Neuromodulators NT released by neurones and astrocytes Long duration Long term changes in synaptic transmission [Synaptic plasticity] Eg. CO2, Adenosine, PG, NO* Neurotrnsmission-4 processes 3. Neuromediators: • II messengers [cAMP, cGMP, Inositol phosphate] 4. Neurotropic factors: • Released by Neurones, astrocytes, microglia • Longer duration • Regulates growth & morphology of neurones • Eg.Cytokines, Chemokines, growth factors Neurohormones: released circulation-Vasopressin, oxytocin* EPSP &IPSP EPSP •Opening-Na+ channels •↓Cond. Of Cl-channels •↓Cond.of K+channels •Changes in int.metabolism IPSP •Opening Cl-channels •↑Cond. K+chnnels •Activation of enzymes-those ↑inhibitory rec. or that ↓Exc.rec. Central Neurotransmitters GABA - inhibitory neurotransmitter Receptors: GABA A receptors are inotropic receptors,selectively permeable to Cl– These receptors are selectively inhibited by picrotoxin and bicuculline-convulsions GABA B receptors are metabotropic receptors, selectively activated by the antispastic drug baclofen Supraspinal and spinal interneuronsinvolved in pre- and postsynaptic inhibition Glycine: - inhibitory Local interneurons in the spinal cord & brain stem Inhibitory: Cl– conductance Glutamate: excitatory neurotransmitter KA (kainate): hippocampus, cerebellum, spinal cord mediate fast depolarization AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid ) mediate fast depolarization NMDA (N-methyl-D-aspartate) -Long term potentiation Glutamate Excitotoxicity Acetylcholine:was the first compound to be identified pharmacologically as a transmitter in the CNS Spinal cord –Motoneuron-Renshaw cell synapse neurons in the neostriatum,medial septal nucleus, reticular formation Dopamine:All dopamine receptors are metabotropic. Substantia nigra to the neostriatum Ventral tegmental region to the limbic cortex D1 – D5 Norepinephrine: hypothalamus , limbic system enhances excitatory inputs by both indirect and direct mechanisms Attention and arousal α1, α 2, and ß 5-Hydroxytryptamine :neurons in the raphe or midline regions of the pons and upper brain stem 5-HT1A: Inhibitory: K+ conductance, cAMP 5HT2 5HT3 5HT4 Except for the 5-HT3 receptor, all of these receptors are metabotropic. 5-HT3 receptor is ionotropic. Histamine :ventral posterior hypothalamus regulate arousal, body temperature, and vascular dynamics H1 H2 H3 H4 Peptides:enkephalins, endorphins, neurotensin, substance P, somatostatin, cholecystokinin, vasoactive intestinal polypeptide, neuropeptide Y, and thyrotropin-releasing hormone Diffusible Mediators NO Arachidonic acid A NT Rec M1 M2 N Neurotransmitters Ago Antago Exc/Inh Ex Inh Exc Atr, Pirenz. Bethanecol Atro Nicotine ACh DA GABA Glycine 5HT D1 D2 GABA A GABAB Baclofen Phenothi Bromo Phenothi Biccuculine Saclofen Inh Inh Inh Strychnine 5HT Ketanserin Exc Ondansetron (Inh) NT Contd…. NT NA Rec α1 α2 Ago Phenyl Clonidine Antago Prazosin Yohimbine Exc/Inh Exc Inh β1 β2 Histamine H1 H2 Dobutamine Atenolol Albuterol Exc Inh Mepyramine Exc Exc Ranitidine Inh Inh Inh H3 Opioids Mu,delta, Kapa Endocanab CB1 & 2 Naloxone Rimonobant ACTIONS OF DRUGS IN THE CNS CNS Depressants CNS Stimulants Drugs that selectively modify CNS function