Pharmacology of Basal Ganglia Disorders PDF

Pharmacology of Basal Ganglia Disorders Introduction to Drugs Used To Treat Parkinson’s Disease Phase 1 Block 3 Dr Dan Mitchell Academic Lead for Pharmacology, Prescribing & Therapeutics [email protected]  Learning Ob...

Pharmacology of Basal Ganglia Disorders Introduction to Drugs Used To Treat Parkinson’s Disease Phase 1 Block 3 Dr Dan Mitchell Academic Lead for Pharmacology, Prescribing & Therapeutics [email protected]  Learning Objectives Describe the common and important classes of drugs used to treat Parkinson's Disease and their mechanisms of action within the central nervous system Describe the common side effects of the drugs used to treat Parkinson's Disease From the Phase 1, Block 3 Drugs List  Parkinson’s Disease (or Parkinsonism) Parkinsonism is a major movement disorder characterised by a triad of key symptoms: 1)Resting tremor 2)Skeletal Muscle Rigidity 3)Bradykinesia (Poorer quality movement) Non-motor symptoms such as mood disorders, sleep disorders and gastrointestinal dysfunction may also present Currently around 150,000 individuals in the UK with Parkinson’s  Parkinson’s Disease Pathology Principal pathology of Parkinsonism is NEURODEGENERATIVE and involves the irreversible loss of dopaminergic neurons, especially in the substantia nigra region of the basal ganglia Evidence of aggregates of the protein synuclein Neuroinflammation Progessive neuronal death Loss of these dopaminergic neurons leads to  PHARMACOLOGICAL STRATEGY FOR PARKINSONISM Restore and sustain dopamine activity in the CNS SYNAPTIC CLEFT POST-SYNAPTIC NEURON Dopaminergics - Levodopa Levodopa is a metabolic precursor to dopamine Naturally converted to dopamine in neurons for subsequent dopaminergic neurotransmission Levodopa is required in the CNS but if taken orally, it is broken down in the periphery by the enzyme Dopa Decarboxylase For Parkinson’s treatment, Levodopa is taken in combination with a Dopa Decarboxylase inhibitor – for example Carbidopa (Co-careldopa is a common formulation of Dopaminergics - Levodopa SYNAPTIC CLEFT POST-SYNAPTIC NEURON Dopaminergics - Levodopa Levodopa – common side effects include the following: Nausea – elsewhere in the nervous system, dopamine mediates the chemoreceptor trigger zone (CTZ) which controls nausea and vomiting Risk of dyskinesia – especially involuntary movements in the face and neck Psychological symptoms (e.g. hallucinations, compulsive behaviour) – dopamine is also involved in perception and reward processes  Dopaminergics – Dopamine Receptor Agonists Dopamine normally transmits signals via post- synaptic dopamine receptors Post-synaptic activity contributes to motor control and may also promote the survival of neural tissues Synthetic compounds such as Pramipexole and Ropinirole interact directly with dopamine receptors and exert agonist effects – mimicking the function of dopamine Dopaminergics – Dopamine Receptor Agonists SYNAPTIC CLEFT POST-SYNAPTIC NEURON  Dopaminergics – Dopamine Receptor Agonists Common side effects of drugs such as pramipexole and ropinirole include: Nausea and vomiting Dyskinesia, agitation Hallucinations and confusion (Often more frequent than levodopa)  Monoamine Oxidase B Inhibitors (MAOIB) Within neurons, dopamine can be broken down and inactivated by the intracellular enzyme Monoamine Oxidase B Drugs such as Selegiline selectively inhibit this enzyme to sustain neuronal dopamine levels Sustained neuronal dopamine levels support dopaminergic transmission and alleviation of Parkinsonism symptoms  Monoamine Oxidase B Inhibitors SYNAPTIC CLEFT POST-SYNAPTIC NEURON  Monoamine Oxidase B Inhibitors Common side effects of drugs such as Selegiline include: Nausea Sleep disturbances Constipation  Catechol-O-methyltransferase (COMT) Inhibitors Within the CNS, dopamine is inactivated by the COMT enzyme. COMT inhibitors such as Entacapone sustain dopamine levels in the CNS to maintain dopaminergic function and symptom alleviation Catechol-O-methyltransferase (COMT) Inhibitors SYNAPTIC CLEFT POST-SYNAPTIC NEURON  Catechol-O-methyltransferase (COMT) Inhibitors Common side effects of drugs such as Entacapone include: Nausea, abdominal pain Dyskinesia Constipation  Other drugs – more in Phase 2/3…! Other receptor systems and neurotransmitters have been found to influence motor control Targeting cholinergic function and N-methyl-D- aspartate (NMDA) receptors has also been shown to be valuable in the treatment of Parkinsonism More of this later in the MBCHB…..  Questions? Please contact me via [email protected] or MS Teams Further Resources: Medical Pharmacology & Therapeutics 6th Edition; Chapter 24 (available at ClinicalKey Student) Healthtalk.org: Coverage of dopamine receptor agonists and levodopa https://go.drugbank.com/drugs - a wealth of information on drug MoA with a large, easily searchable database