Pharmacology of Dopamine week 8 PDF

Pharmacology of Dopaminergic Neurotransmission 1 Objectives Demonstrate knowledge of dopaminergic neurotransmission in the CNS Explain the cellular mechanisms of dopamine as a central neurotransmitter Identify receptors involved in dopaminergic neurotrans...

Pharmacology of Dopaminergic Neurotransmission 1 Objectives Demonstrate knowledge of dopaminergic neurotransmission in the CNS Explain the cellular mechanisms of dopamine as a central neurotransmitter Identify receptors involved in dopaminergic neurotransmission Describe the role of dopamine in the control of movement and in thought disorders List the pharmacological agents that affect dopaminergic neurotransmission 2 Dopamine Dopamine belongs to the catecholamine family of neurotransmitters. CNS dopamine affects several functions, such as motivation, arousal, attention, motor control, emotion, mood, inhibition of prolactin secretion, emesis, and sleep regulation. Therapeutic target for a number of important central nervous system (CNS) disorders, including Parkinson’s disease and schizophrenia. DA is also a precursor for the other catecholamine neurotransmitters norepinephrine and epinephrine. 3 4 Synthesis of Dopamine 5 Dopamine Storage and Release The vesicular monoamine transporter (VMAT) transports DA into the vesicle against its concentration gradient. Upon nerve cell stimulation, the DA storage vesicles fuse with the plasma membrane in a Ca2+ dependent manner, releasing DA into the synaptic cleft. In the cleft, DA can bind to both postsynaptic DA receptors and presynaptic DA autoreceptors 6  Dopamine Reuptake and Inactivation Most of the DA released into the synaptic cleft is transported back into the presynaptic cell by dopamine transporter (DAT) which is then taken into the vesicle for further release or degraded by MAO or COMT MAO exists in two isoforms : MAO-A (in both CNS and periphery) MAO-B (concentrated in the CNS) 7 Dopamine Dopamine (DA) is the therapeutic target for a number of important central nervous system (CNS) disorders, including Parkinson’s disease and schizophrenia. 8  Dopamine Receptor Subtypes Dopamine receptors are members of the G protein- coupled family of receptor proteins. The properties of dopamine receptors were initially classified by their effect on the formation of cyclic AMP (cAMP) 9 Dopamine Receptors Are G-protein coupled type of receptors Activation of D1 class receptors leads to increased cAMP Contains D1 and D5 receptors Activation of D2 class receptors inhibits cAMP generation Contains D2, D3 and D4 receptors 10 11 Dopamine Receptors D1 & D2- involved in motor control D2 – plays a role in schizophrenia Pre-synaptic DA receptors – most are D2 type and regulate DA by decreasing its synthesis and release. 12  Dopaminergic pathways in the CNS There are four main dopaminergic pathways: 1. The Nigrostriatal pathway Contains about 80% of the brain’s DA. Substantia nigra > corpus striatum. Involved in the stimulation of purposeful movement. Degeneration results in the abnormalities of movement that are characteristic of Parkinson’s disease Am, amygdaloid nucleus; Hip, hippocampus; Hyp, hypothalamus; Str, corpus striatum. 13  Dopaminergic pathways in the CNS cont. 2. Mesolimbic pathway Ventral tegmental area (VTA) > the nucleus accumbens (nAc) Plays an important and complex role in pleasure and positive reinforcement (reward). 3. Mesocortical Dopamine Pathways From the VTA to the prefrontal cortex Highly involved in cognition, working memory, and decision-making. Disorder of these pathways may be involved in the development of schizophrenia 14  Dopaminergic pathways in the CNS cont. 4. Tuberoinfundibular pathway. Hypothalamus> pituitary glands Inhibits prolactin secretion. 15  Dopaminergic pathways in the CNS cont. The postrema is located on the floor of the fourth ventricle Contains a high density of dopamine receptors (mostly of the D2 class). Function as blood chemoreceptors. Stimulation of DA receptors in this area activates the vomiting centers of the brain and causes emesis. Drugs that block dopamine D2 receptors are used to treat nausea and vomiting. 16 PARKINSON’S DISEASE 17 https://medpics.com/Health-Help:parkinsonism-its-symptoms-causes-and-treatment:429 PARKINSON’S DISEASE There is a selective loss of dopaminergic neurons in the substantia nigra pars compacta The extent of loss is profound, with at least 70% of the neurons destroyed at the time symptoms first appear; often, 95% of the neurons are missing at autopsy. The destruction of these neurons results in the core motor features of the disease: ✓ Bradykinesia, or slowness of movement ✓ Rigidity, resistance to passive movement of the limbs ✓ Impaired postural balance predisposes to falling ✓ A characteristic tremor when the limbs are at rest. 18 20 Pharmacologic Agents Used in Parkinsonism 21 Pharmacologic Interventions in Therapy of Parkinson’s disease 1. Restoration of dopaminergic activity with levodopa and dopamine agonists alleviate many of the motor features of the disorder. 2. Complementary approach Restoration of the normal balance of cholinergic and dopaminergic Influences on the basal ganglia with antimuscarinic drugs 22  Levodopa Levodopa (the immediate metabolic precursor of Dopamine) Pharmacokinetics Oral bioavailability: 5% (the first-pass effect is very large; 95% is metabolized in the gut wall and in the liver) Additional amounts are converted into dopamine and therefore only 1-3% enter the brain. 23  Levodopa Adverse effects The most profound adverse effect o levodopa is its propensity to cause dyskinesias , or uncontrollable rhythmic movements o the head, trunk, and limbs. These appear in at least half of all patients within 5 years of starting the drug, and they generally worsen as the disease progresses. 24  Levodopa As patients continue on levodopa therapy, they require higher doses to produce a clinically significant improvement in symptoms. They develop fluctuations in motor function that include periods of freezing and increased rigidity, known as “off” periods, alternating with periods of normal or even dyskinetic (excess involuntary) movement, known as “on” periods. 25  Levodopa Therapeutic Uses Levodopa ameliorates all signs of parkinsonism. Bradykinesia is the most sensitive to improvement. The drug however does not cure the disease and responsiveness fluctuates and decreases with time. 26  Carbidopa Carbidopa is a DOPA decarboxylase inhibitor that does not cross the blood-brain barrier. When given with levodopa, the peripheral metabolism of levodopa is reduced with the following consequences: 1. The half-life of levodopa is increased. 2. More levodopa is available for entering the brain (this reduces by about 75% the daily requirement) 3. The gastrointestinal and cardiovascular effects of levodopa are substantially reduced. 4. CNS adverse effects are increased. Levodopa is usually given in combination with carbidopa. 27  Dopamine Receptor Agonists Dopamine receptor agonists: – Ergot derivatives such as bromocriptine (D2 agonist) and pergolide (agonist for both D1 and D2). – Major adverse effects fibrosis of cardiac valves, thus replaced by the newer agent. – A newer agent>>pramipexole (agonist for D3>D2) 28  Advantage of DA agonist over levodopa Nonpeptide molecules do not compete with levodopa or other neutral amino acids for transport across the BBB. They do not require enzymatic conversion by AADC, and they remain effective late in Parkinson’s disease. Have longer half-lives than levodopa, which allows for less frequent dosing and a more uniform response to the medications. AADC=Aromatic l-amino acid decarboxylase 29  Dopamine Receptor Agonists Adverse effects Nausea, peripheral edema, and hypotension. Cognitive effects: excessive sedation, vivid dreams, and hallucinations, particularly in elderly patients. 30  Monoamine Oxidase (MAO) Inhibitors Selegiline and Rasagiline: Selective inhibitors of MAO-B (at low dose) Selegiline metabolized into amphetamine Improve motor function in Parkinson’s disease and can augment the effectiveness of levodopa therapy. 31 CATECHOL-O-METHYLTRANSFERASE (COMT) INHIBITORS Entacapone Selective COMT inhibitors Decrease the peripheral metabolism of levodopa and thereby make more levodopa available to the CNS Reduce the “off” periods associated with decreasing plasma levodopa levels. 32 Other Antiparkinsonian Drugs Amantadine: An antiviral drug with antiparkinsonian effect Used to treat levodopa-induced dyskinesias that develop late in the disease. It may reduce dyskinesia by blocking excitatory NMDA receptors. 33  Centrally Acting Antimuscarinic Agents Benztropine Muscarinic receptor antagonists that reduce cholinergic tone in the CNS. Reduce tremor more than bradykinesia and are therefore more effective in treating patients for whom tremor is the major clinical manifestation 34 Summary of Dopaminergic Therapy of Parkinson’s Disease 35 SCHIZOPHRENIA 36 SCHIZOPHRENIA It is a psychotic illness Has two major clinical features: Positive symptoms - hallucination, delusion, racing thoughts) Negative symptoms - emotional blunting, social withdrawal, lack of motivation, lack of emotion 37 SCHIZOPHRENIA (cont..) Cognitive impairment – disorganized thoughts, difficulty concentrating/following instructions/completing tasks Possibly depression 38  Neurochemical Basis of Schizophrenia The main neurotransmitters involved in the pathogenesis of schizophrenia are dopamine and glutamate Two hypotheses: The dopamine dysregulation hypothesis The NMDA hypofunction (glutamate underactivity) hypothesis 39  Neurochemical Basis of Schizophrenia Schizophrenia is caused by increased and dysregulated levels of DA neurotransmission in the brain. 1. Treatment with DA receptor antagonists, specifically D2 antagonists, relieves a number of the symptoms of schizophrenia (NOT all patient response to the treatment) 2. Patients taking drugs that increase DA levels or that activate dopamine receptors in the CNS, including amphetamines, cocaine, and apomorphine, develop a schizophrenia-like state that subsides when the dose of the drug is lowered. 3. Hallucinations are a known adverse effect of levodopa therapy for Parkinson’s disease. 4. Decreased DA levels, with clinical improvement in some schizophrenic symptoms. 40  The Dopamine Hypothesis 1. Mesolimbic hyperactivity is responsible for the positive symptoms of schizophrenia. 2. A decreased activity in the mesocortical pathway would account for the negative symptoms of schizophrenia. 41 The NMDA hypofunction hypothesis An antagonist at NMDA receptors causes symptoms similar to those of schizophrenia. Dopaminergic neurons and excitatory glutamatergic neurons often form reciprocal synaptic connections, which could account for the efficacy of DA receptor antagonists in schizophrenia. No useful therapies for schizophrenia that act at glutamate receptors 42 Schizophrenia Treatment 43 First Generation Antipsychotics Also called classical or typical agents Are potent D2 antagonists (but also affect other receptors – 5HT2, alpha, histamine, and muscarinic receptors) Helpful in alleviating the positive symptoms 44 First Generation Antipsychotics Chlorpromazine (low potency) Haloperidol (high affinity for D2 receptor) Adverse effect: Strong extrapyramidal effects (rigidity, bradykinesia, dystonia, tremor, akathisia) Tardive dyskinesia (TD)>> irreversible Neuroleptic malignant syndrome (NMS), a rare but life- threatening syndrome (especially with haloperidol) 45 Second Generation Antipsychotics Are D2/5H2a antagonists They also have an effect on other receptors – alpha, histamine, and muscarinic receptors Effective in positive and negative symptoms Less Extrapyramidal symptoms E.g. clozapine, olanzapine, risperidone 46  Second Generation Antipsychotics (atypical agents) Milder extrapyramidal adverse effect profile because of their relatively rapid dissociation from the D2 receptor. Clozapine has not been used as a first-line agent because of a small but significant risk of agranulocytosis (approximately 0.8% per year) and seizures. 47  Conclusion Treatments for both Parkinson’s disease and schizophrenia modulate dopaminergic neurotransmission in the CNS. In Parkinson’s disease, the degeneration of dopaminergic neurons that project to the striatum is responsible for motor symptoms, including resting tremor, rigidity, and bradykinesia. Pharmacologic treatment of Parkinson’s disease depends on agents that increase dopamine release or activate dopamine receptors in the caudate and putamen and thereby help restore the balance between the direct and indirect pathways. 48 Conclusion Schizophrenia is treated by inhibiting dopamine receptors at various sites in the limbic system. The pathophysiology of schizophrenia is not fully understood, and this lack of knowledge about etiology limits rational drug development. Pharmacology of the typical antipsychotic agents has formed the basis of the dopamine model of schizophrenia, The effectiveness of the atypical antipsychotic agents, which affect the function of several different receptor types, has highlighted that the dopamine hypothesis simplifies. The atypical agents represent an attractive new modality for treating schizophrenia because they have fewer extrapyramidal effects and are more effective for some disease symptoms than the typical antipsychotics. 49 Interactive questions 50  Case Mark S is a 55-year-old man who goes to see his physician because he notices a tremor in his right hand that has developed gradually over a number of months. He finds he can keep the hand quiet if he concentrates on it, but the shaking quickly reappears if he is distracted. His handwriting has become small and difficult to read, and he has trouble using a computer mouse. His wife complains that he never smiles anymore and that his face is becoming expressionless. She also says that he walks more slowly and he has trouble keeping up with her. As Mr. S enters the examination room, his doctor notices that he is walking hunched over and has a short, shuffling gait. The doctor finds on physical examination that Mr. S has increased tone and cogwheel rigidity in his upper extremities, particularly on the right side, and that he is significantly slower than normal at performing rapid alternating movements. The physician determines that Mr. S’s symptoms and signs most likely represent the early stages of Parkinson’s disease, and she prescribes a trial of levodopa. 51 Questions 1.How does the selective loss of dopaminergic neurons result in symptoms such as those Mr. S is experiencing? 2.What will be the effect of levodopa on the course of Mr. S’s disease? 3.How will Mr. S’s response to levodopa change over time? 4. Is levodopa the best choice for Mr. S at this stage of his disease? 52 Questions 53