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, hunger- CONTROL 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,
transmission
• Basics same as in ANS • Neurotransmitters • 4 processes of neurotransmission • EPSP & IPSP*
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
Neurochemical transmission
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*
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-4isoxazole 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
Neurotransmitters Ago Antago
Exc/In h
Inh Exc Inh Inh Inh
Atr, Pirenz. Ex Bethaneco Atro l Nicotine
ACh
M2 N
DA
GABA Glycine
D1 D2
GABA A GABAB Baclofen
Phenothi Bromo Phenothi
Biccuculine Saclofen Strychnine
NT Contd…. NT NA Rec α1 α2 β1 β2 Histamine H1 H2 Ago Phenyl Clonidine Antago Prazo Yohimbine Exc/Inh Exc Inh Exc Inh
Dobutamine Atenolol Albuterol
Mepyramine Exc Exc Ranitidine
H3
Opioids Mu,delta, Kapa Naloxone
Rimonobant
Inh Inh Inh
Endocanab CB1 & 2
ACTIONS OF DRUGS IN THE CNS CNS Depressants CNS Stimulants Drugs that selectively modify CNS function