Pharmacology Unit 4 lecture 1.PDF

Pharmacology Unit 4 – Drugs and the CNS - Lectures 1 – CNS Neurotransmitters & Drugs CNS Drugs - CNS drugs are extremely widely used: o For therapeutic purposes (e.g. for depression, epilepsy etc.) o As “lifestyle” drugs (e.g. caffeine, nicotine, alcohol etc.) o As drugs of abuse (e.g. cannabis, coc...

Pharmacology Unit 4 – Drugs and the CNS - Lectures 1 – CNS Neurotransmitters & Drugs CNS Drugs - CNS drugs are extremely widely used: o For therapeutic purposes (e.g. for depression, epilepsy etc.) o As “lifestyle” drugs (e.g. caffeine, nicotine, alcohol etc.) o As drugs of abuse (e.g. cannabis, cocaine etc.) - Since the brain is an extremely complex organ, the mechanism of action of many CNS drugs is not clear o Although the cellular effect of the drug may be known, how this relates to functional outcome may not be (e.g. dopamine receptor antagonists used in schizophrenia) CNS Drugs - Neuronal interconnections o Many neurotransmitter systems are interconnected, so modifying one is likely to affect the others too - Sheer number of neurons and synaptic connections o ~100 billion neurons in human brain o Each neuron may be connected to up to 10,000 other neurons o 1,000 trillion synaptic connections - Adaptive responses o The effect of many drugs takes weeks to develop, so it is likely that they are caused by long-term changes rather than the immediate effect of the drug on its target - Tolerance and dependence o Drugs of abuse (Global NTs – active all over brain – GABA & glutamate – excitatory and inhibitory – modulate other NTs) - Neuronal interconnections o Many neurotransmitter systems are interconnected, so modifying one is likely to affect the others too o Neurotransmitters released from nerve terminals can act postsynaptically or pre-synaptically o Some neurotransmitter receptors excite pre- or post-synaptic cells, others inhibit pre-or post-synaptic cells cells o Some neurotransmitter receptors are located presynaptically to enhance neurotransmitter release (facilitatory receptor), others reduce neurotransmitter release (inhibitory receptor). This can be on the same neuron that released the neurotransmitter (autoreceptor). - Sheer number of neurons and synaptic connections omplexity of each neuron and its connections o ~100 billion neurons in human brain o Each neuron may be connected to up to 10,000 other neurons o 1,000 trillion synaptic connections Lecture 2 - Cholinergic Neurotransmission & Cholinergic Drugs Acetylcholine - Location in the brain - Important sites are: o Cells in nucleus basalis which project to cortex o Cells in septum which project to hippocampus o Cells in striatum (short interneurons) (Cholinergic transmission in brain – process same as in periphery – brain has nicotinic & muscarinic receptors) Synthesis, storage, release, termination, metabolism 1. Choline is taken into the neuron via carrier mediated transport 2. Choline is acetylated by choline acetyltransferase using acetyl CoA as a source of acetyl groups 3. Acetylcholine is actively packaged into vesicles by an amine transporter 4. Release is via classical Ca2+-mediated exocytosis 5. Termination/metabolism is via enzymatic degradation by acetylcholinesterase (target for treatment of Alzheimer's) Receptor targets Acetylcholine exerts its effects via: - Nicotinic receptors o ligand-gated ion channel receptors o for fast excitatory synaptic transmission - Muscarinic receptors o G-protein coupled receptors o For slow excitatory OR inhibitory synaptic transmission o M1, M3, M5 are EXCITATORY and Gq-linked (act via DAG & IP3 as second messengers) o M2 & M4 are INHIBITORY and are Gi linked (reduce cAMP in the cells) Physiological response - At the cellular level Nicotinic receptors - Widespread in the brain - Located both presynaptically and postsynaptically - Presynaptic receptors facilitate the release of other neurotransmitters (facilitatory presynaptic receptors) - Postsynaptic receptors facilitate excitation of postsynaptic neurons Muscarinic receptors - Widespread in the brain - Located both presynaptically and postsynaptically - Inhibitory and excitatory effects on presynaptic and postsynaptic neurons. o For example, muscarinic ACh receptors can be presynaptic inhibitory autoreceptors supressing release of Ach from cholinergic neurons. Physiological response - At the behavioural level Acetylcholine is required for: - Arousal (via cells in the nucleus basalis that project to the cortex) - Learning and memory (via cells in the septum that project to the hippocampus) - Motor control (via cholinergic interneurons in the striatum) Pathophysiological role Alzheimer’s disease (most common neurodegenerative disorder) - Loss of cholinergic nucleus basalis neurons (projecting to the cortex) and septal neurons (projecting to the hippocampus) underlies the learning and memory deficits typical of Alzheimer’s disease - Thus, anticholinesterases are used in the treatment of this disease Parkinson’s disease - Loss of dopaminergic substantia nigra neurons (projecting to the striatum) underlies the motor deficits typical of Parkinson’s disease (see dopamine lecture) - Striatal cholinergic interneurons oppose the effects of dopamine in the striatum and hence exacerbate the deficits. Thus, cholinergic antagonists are used in the treatment of this disease (e.g. trihexyphenidyl and benztropine). Alzheimer’s Disease - General features - A progressive neurodegenerative disorder - Symptoms include: o Loss of memory o Overall impairment in cognitive function - Is mainly associated with aging - Approx 5% of the population over 65 and up to 90% of the population over 95 have Alzheimer’s disease (There is a loss of cholinergic neurons (more so in beginning) and global brain shrinkage (more towards end)) Alzheimer’s disease – Pathophysiology - AD is associated with two characteristic features: - Neuritic plaques (containing the b-amyloid peptide) - Neurofibrillary tangles (containing the abnormally phosphorylated tau protein) Note: Drugs lecanemab stimulates immune system to clear amyloid deposits from brain – overall efficacy and safety skills yet unknown Alzheimer's Disease – Pathophysiology It is also ssociated with brain shrinkage and loss of (mainly cholinergic) neurons in the hippocampus and basal forebrain (nucleus basalis) Alzheimer's Disease – Drug treatment - All current drug therapy simply provides relief from Alzheimer’s symptoms - They do not provide a cure for the disease, nor do they slow the degeneration of the cholinergic neurons - The symptoms of AD are mainly treated using cholinesterase inhibitors (drugs that enhance cholinergic transmission by inhibiting acetylcholinesterase) o Tacrine o Donepezil o Rivastigmine ▪ CNS selective so fewer peripheral side effects o Galantamine ▪ Also acts as a positive allosteric modulator of nicotinic receptors - Also NMDA receptor antagonists (e.g. memantine); see glutamate lecture