Pharmacology Unit 4 lecture 2.PDF
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Pharmacology Unit 4 – Lecture 2 - Dopaminergic Neurotransmission & Dopaminergic Drugs Dopamine – Location in the brain Most important sites are: - Cell bodies in substantia nigra (degeneration here associated with motor effects seen in Parkinson's) which project to striatum (nigrostriatal pathway) -...
Pharmacology Unit 4 – Lecture 2 - Dopaminergic Neurotransmission & Dopaminergic Drugs Dopamine – Location in the brain Most important sites are: - Cell bodies in substantia nigra (degeneration here associated with motor effects seen in Parkinson's) which project to striatum (nigrostriatal pathway) - Cells in ventral tegmental area which project to nucleus accumbens (associated with award), frontal cortex and amygdala (mesolimbocortical pathway) - Cells ventral hypothalamus which project to the median eminence and pituitary gland (tuberohypophyseal system) (associated with hormone release – dopamine supresses prolactin secretion) Synthesis, storage, release, termination, metabolism 1. Tyrosine is taken into the neuron via carrier mediated transport 2. Tyrosine is converted to dopamine in 2 steps catalysed by tyrosine hydroxylase and DOPA decarboxylase 3. Dopamine is actively packaged into vesicles by an amine transporter 4. Release is via classical Ca2+-mediated exocytosis 5. Termination is via uptake by a dopamine transporter 6. Degradation is via monoamine oxidase, aldehyde dehydrogenase and catechol-o-methyltransferase Receptor targets Dopamine exerts its effects via: - D1-type receptors - D2-type receptors Receptor targets (All G-protein coupled receptors) - D1-type receptors (act on D1 and D5 subtypes) o D1 via Gs (AC (adenylyl cyclase) and ⬆️ cAMP) o D5 via Gs (AC and⬆️ cAMP) - D2-type receptors (act on D2, D3, D4 subtypes) o D2, D3 and D4 via Gi (AC and ⬇️ cAMP) or Gq (PLC & ⬆️ IP3/DAG) Physiological response – at the cellular level D1 type receptors - Activation of the D1 type of dopamine receptor mainly causes excitation of the post-synaptic neuron (Basal ganglia – direct and indirect pathways) D2 type receptors - Widespread in the brain - Located both presynaptically and postsynaptically - Mostly inhibitory effects on presynaptic and postsynaptic neurons. o For example, D2 receptors can be presynaptic inhibitory receptors and/or presynaptic inhibitory autoreceptors supressing release of dopamine from dopaminergic neurons. - Also stimulates or inhibits hormone release (Drugs used to treat schizophrenia are D2 antagonists) Physiological response – at the behavioural level Dopamine is required for: - Motor control (nigrostriatal pathway) o Dopamine is required to control voluntary movement o Destruction of the nigrostriatal pathway causes severe movement difficulties in rats - Mediating effects of rewarding stimuli (mesolimbocortical pathway) o Dopamine mediates the ‘hedonic’ impact of natural rewards (e.g. food/sex) o Destruction of the mesolimbocortical innervation (esp. that to nucleus accumbens) prevents rats from learning about natural rewards - Neuroendocrine function (tuberohypophyseal pathway) o Dopamine inhibits prolactin and stimulates growth hormone secretion Pathophysiological role - Parkinson’s disease o Loss of dopaminergic nigrostriatal neurons and subsequent loss of striatal dopamine is what underlies this disease (motor deficits (and also motivational defiict – nucleus accumbens)) o Thus, dopamine replacement is the first-line therapy for this disease (e.g. L-DOPA (the DA precursor!)) - Schizophrenia o Drugs which release dopamine (e.g. amphetamine) can cause schizophrenia-like symptoms o Hyperactivity of mesolimbocortical DAergic pathway has been implicated in schizophrenia o Thus dopamine antagonists (esp. D2 receptor) are used to treat this disorder - Drug addiction o Many drugs of abuse (e.g. amphetamine and cocaine which release and block o DA reuptake respectively) hijack the DA reward system to mediate their rewarding effects Parkinson’s disease - general features - A progressive neurodegenerative disorder - Symptoms include: o Tremor at rest o Muscle rigidity o Bradykinesia - Is mainly associated with aging (greatest risk factor) but can also affect younger adults (young onset PD) and even children (Juvenile PD) - Affects 1% of the population over the age of 65 Parkinson's disease – pathophysiology - Associated with degeneration of dopaminergic neurons of the nigrostriatal pathway and formation of Lewy bodies (misfolded proteins containing alpha -synuclein) - Consequent loss of dopamine from the striatum is what underlies the motor symptoms - Symptoms only manifest after 60% of the nigral dopamine neurons have already degenerated and 80% of striatal dopamine has been lost (the post-synaptic/remaining neurons can compensate by upregulating the remaining dopamine – so 80% loss before notice) (protein involved in Parkinson’s – synuclein – clumps of lewy bodies – thought to be main cause of neuronal death. 10% of Parkinson’s is genetic. Impact between genetics and enviroment - β-blockers increase risk, salbutamol decreases risk (regulates α-synuclein), caffeine reduces risk, rotadome is an organic pesticide that was banned because it increases risk) Parkinson's disease – drug treatment - All current drug therapy simply provides relief from Parkinsonian symptoms (there are no drugs that target α-synuclein or that are disease modifying) - They do not provide a cure for the disease, nor do they slow the unrelenting degeneration of the nigrostriatal neurons - The symptoms of PD are mainly treated using drugs that enhance dopaminergic transmission by a variety of methods: o Drugs that replace dopamine (L-DOPA) o Drugs that inhibit dopamine metabolism (COMT inhibitors, MAO inhibitors) o Drugs that mimic dopamine action (dopamine receptor agonists) o Drugs that release dopamine - It is also treated using drugs that block muscarinic acetylcholine receptors (cholinergic interneurons in the striatum oppose effects of dopamine) (cf. acetylcholine as a neurotransmitter) Parkinson's disease - L-Dopa - The most effective treatment for Parkinson’s disease is dopamine replacement using the dopamine precursor L-DOPA (levodopa) - This is usually given with a DOPA decarboxylase inhibitor that is unable to cross the blood-brain barrier (e.g. carbidopa, benserazide) so that conversion to dopamine only occurs in the brain (thus reducing peripheral side effects) - About 80% of patients respond positively to levodopa with ~20% restored to virtually normal motor function - However, its effectiveness wears off as the disease progresses, suggesting that intact dopamine neurons are at least partially required for its effectiveness Parkinson’s disease - Side effects of L-DOPA - The main side effects of levodopa treatment are: o Dyskinesias o On-off effects (fluctuations in drugs efficacy) - Dyskinesias o Abnormal involuntary movements affecting the face and limbs o These manifest in the majority of patients within 2 years of starting levodopa therapy o They can be reduced by lowering the dose but this causes symptoms to reappear - On-off effects o Rapid fluctuations in clinical state where the symptoms reappear suddenly and can last for minutes to hours (eventually side effects can become worse than the symptoms – constantly trying to adjust doe) o The reason for this is unclear but may be related to changes in plasma levodopa concentrations Parkinson's Disease – other drug treatments - Inhibition of dopamine metabolism: o MAO-B inhibitors e.g. selegiline o COMT inhibitors e.g. entacapone - Dopamine receptor agonists o Non-selective dopamine receptor agonists (e.g. apomorphine) o Slightly selective D2 receptor agonists (e.g. bromocriptine, pergolide, cabergoline) o Selective D2 receptor agonists (e.g. pramipexole, ropinirole) - And … - Muscarinic cholinergic antagonists o Since the cholinergic interneurons in the striatum oppose the effects of dopamine, blocking their actions (e.g. trihexyphenidyl and benztropine) partly overcomes the loss of dopamine - NMDA receptor antagonists o Non-competitive antagonist of the NMDA receptor (e.g. amantadine); see glutamate lecture Schizophrenia - Schizophrenia is a severe and disabling brain disease - It affects ~1% of the population - It normally manifests in early adulthood o In men, schizophrenia usually appears in late teens or early 20s o In women, it usually appears in late 20s or early 30s - It is thought to be a ‘neurodevelopmental’ disorder (occurs in utero but doesn't manifest for 2 or 3 decades) in which certain brain structures (esp. the cerebral cortex) do not develop properly - The disease can be relapsing & remitting or chronic and progressive Schizophrenia – clinical symptoms (Positive and negative symptoms important for pharmacological perspective Positive = symptoms added onto behaviour, negative = loss of behaviour) Schizophrenia – Neurochemical theories - Clues to the neurochemical nature of schizophrenia came from analysing the effects of known anti-schizophrenic drugs (i.e. the drugs came first and the neurochemical theory came after) - Neurotransmitter systems that have been implicated in schizophrenia include: o Dopaminergic system (most evidence is in favour of this theory) o Glutamatergic system - And also o Serotonergic system o Noradrenergic syste Schizophrenia – the dopamine hypothesis - The *dopamine hypothesis of schizophrenia states that overactivity in the dopaminergic system leads to the disease - It is based on two main observations: 1) All anti-schizophrenic drugs act as antagonists at dopamine receptors and clinical potency correlates with D2 receptor affinity 2) Amphetamine (which releases dopamine from neurons) causes schizophrenic-like symptoms in users - *Proposed by Arvid Carlsson who received the Nobel Prize for Medicine in 2000 Schizophrenia – mechanism of action anti-schizophrenic drugs All antipsychotic drugs act as antagonists at dopamine D2 receptors - In addition to the dopaminergic system, they may also affect other neurotransmitter systems: o Noradrenergic, histaminergic, cholinergic, serotonergic - These mostly contribute to the side effect profile of antipsychotics - However, activity at 5-HT receptors also provides clinical benefit or a reduced side-effect profile: o They can act as antagonists at 5-HT2A and as agonists at 5-HT1A receptors - Nevertheless, it is now well accepted that it is primarily their antagonism of dopamine receptors that accounts for the antipsychotic activity of these drugs Schizophrenia - Mechanism of action of anti-schizophrenic drugs – ACUTE - All antipsychotic drugs are antagonists at dopamine D2 receptors - Blocking the effects of dopamine released from the mesolimbic pathway accounts for the antipsychotic effects (i.e. reduce positive symptoms) - Blocking the effects of dopamine released from the nigrostriatal and tuberohypophyseal pathways account for the side effects - Clinical efficacy correlates strongly with affinity for the D2 receptor - Antipsychotic effects require ~80% block of D2 receptors (D2 antagonists at striatum – Parkinson’s like side effects) (Reward and motor pathway: Parkinson’s = decreased motor – agonist – side effects of drugs – addiction Schizophrenia = increased award – antagonist – side effects of drugs – slow movement. Dopamine inhibits prolactin – antagonist – increased prolactin –side effect – gynecomastia (breast development)) Schizophrenia - mechanism of action of anti-schizophrenic drugs – CHRONIC The clinical effects of antipsychotics takes weeks to develop … thus their acute pharmacological effects cannot account for their antipsychotic activity! - This has led investigators to look for longer-term adaptive changes common to antipsychotic drugs: o Antipsychotic drugs initially transiently increase the activity of DAergic neurons o Their longer-term effect is to decrease the activity of DAergic neurons Schizophrenia - Clinical effects of anti-schizophrenic drugs - Anti-schizophrenic drugs are also known as antipsychotic drugs, neuroleptic drugs and major tranquillisers - More than 40 different drugs are in clinical use. - Antipsychotic drugs are only effective in ~70% of patients - The remaining ~30% are ‘treatment-resistant’ - Moreover, they can only control the positive symptoms of schizophrenia - They DO NOT control the negative symptoms o Thus, while occurrence of delusions/hallucinations etc. can be suppressed, schizophrenic patients remain withdrawn and emotionally flattened Schizophrenia - Classification and examples of anti-schizophrenic drugs Classical ‘typical’ antipsychotics Recently-developed ‘atypical’ antipsychotics - Chlorpromazine - Sulpiride - Haloperidol - Clozapine - Thioradazine - Risperidone - Flupenthixol - Sertindole - Quetiapine This distinction is not clearly defined but depends on: - Incidence of side-effects (atypical < typical) - Efficacy in treatment resistant patients (atypical > typical) - Efficacy against negative symptoms (atypical > typical) - Receptor profile (atypical more selective or dopamine D2 receptor) Schizophrenia – side of effects of anti-schizophrenic drugs - Blocking the effects of striatal dopamine (from the nigrostriatal pathway) leads to motor disturbances o Acute dystonia ▪ Parkinsonian-like syndrome with involuntary movements ▪ Common in first few weeks of treatment (hence acute) ▪ Reversible on stopping treatment o Tardive dyskinesia ▪ Severe disabling involuntary movements affecting the face and limbs ▪ Occur after months or years of treatment (hence tardive) ▪ Often gets worse on stopping treatment - The occurrence of motor side effects is less frequent with the newer ‘atypical’ antipsychotics - Blocking the tuberohypophyseal pathway leads to hormonal imbalances o Increase in plasma prolactin concentration ▪ Dopamine via the D2 receptor is responsible for inhibiting prolactin secretion ▪ Thus blocking these receptors causes an increase in plasma prolactin concentration ▪ This can cause breast swelling, pain and even lactation (gynecomastia) in men as well as women - Note: In addition to their effects on dopamine receptors, neuroleptics also affect: - 1) histamine receptors 2) cholinergic muscarinic receptors 3) α-adrenoceptors. At normal clinical doses, neuroleptics can produce a number of side effects: - Sedation (due to H1 block) (Histamine - awakeness) (Often causing daytime drowsiness and difficulty in concentrating) - Anticholinergic effects (due to muscarinic block) (Dry mouth, constipation, blurred vision, urinary retention etc.) - Postural hypotension (due to a-adrenoceptor block) - Neuroleptic malignant syndrome (Muscle rigidity, fever, autonomic instability, delerium) - Miscellaneous reactions (Jaundice, urticaria (hives), leucopenia/agranulocytosis (reduction in white blood cells), antipsychotic malignant syndrome)
