Neuropharmacology Notes PDF

Muscarinic and nicotinic signaling A: Muscarinic transmission to the sinoatrial node in heart. Acetylcholine (ACh) released from a varicosity of a postganglionic cholinergic axon interacts with a sinoatrial node cell muscarinic receptor (M2R) linked via Gi/o to K+ channel opening, w...

Muscarinic and nicotinic signaling A: Muscarinic transmission to the sinoatrial node in heart. Acetylcholine (ACh) released from a varicosity of a postganglionic cholinergic axon interacts with a sinoatrial node cell muscarinic receptor (M2R) linked via Gi/o to K+ channel opening, which causes hyperpolarization, and to inhibition of cAMP synthesis. Reduced cAMP shifts the voltage-dependent opening of pace- maker channels (If) to more negative potentials, and reduces the phosphorylation and availability of L-type Ca2+ channels (ICa). Released ACh also acts on an axonal muscarinic receptor (autoreceptor) to cause inhibition of ACh release (autoinhibition). B: Nicotinic transmission at the skeletal neuromuscular junction. ACh released from the motor nerve terminal interacts with subunits of the pentameric nicotinic receptor to open it, allowing Na+ influx to produce an excitatory postsynaptic potential (EPSP). The EPSP depolarizes the muscle membrane, generating an action potential, and triggering contraction. Acetylcholinesterase (AChE) in the extracellular matrix hydrolyzes ACh.  Toxication The major source of intoxicaCons is related with organaphosphate that used in agriculture and in the home pesCcide The dominant iniCal signs are those of muscarinic excess: miosis, salivaCon, sweaCng, bronchial constricCon, vomiCng, and diarrhea. Central nervous system involvement (cogniCve disturbances, convulsions, and coma) usually follows rapidly, accompanied by peripheral nicoCnic effects, especially depolarizing neuromuscular blockade.  Treatment (1) maintenance of vital signs—respiration in particular may be impaired; (2) decontamination to prevent further absorption (3) atropine parenterally in large doses, to control signs of muscarinic excess. (4) Therapy often also includes treatment with pralidoxime, and administration of benzodiazepines for seizures. Preventive therapy -pyridostigmine, and atropine Cholinesterase inhibitors toxicity PRALIDOXIME MALATYON CHOLINE ACETYL ACETYLCHOLINE ESTERASE Adrenergic receptors -𝛼1 𝑟𝑒𝑐𝑒𝑝𝑡𝑜𝑟𝑠 Receptor selectivity  Mixed 𝜶 𝒂𝒏𝒅 𝜷 blocers Labetalol, Carvedilol Used as antihypertensive Less reflex tashicardia Carvedilol also decreases lipid peroxidation and vascular wall thickening, effects that have benefit in heart failure. Labetalol is employed as an alternative to methyldopa in the treatment of pregnancy-induced hypertension.  ✤ drug A; barbiturates and alcohols ✤ drug B; benzodiazepines and some newer hypnotics Graded dose-dependent depression of CNS function is a characteristic of most sedative-hypnotics Mechanism of Action ✤ Barbiturates appear to act primarily at the GABA : ✤ These drugs have GABA mimetic as well as GABA facilitatory action to increase the duration of Cl– channel opening BZDs enhance frequency of Cl¯ channel opening PHARMACOKINETICS Long acting Phenobarbital ✤ Barbiturates are well absorbed from the g.i. tract. Short acting Secobarbital ✤ They are widely distributed in the body. Ultra-short acting Thiopental ✤ The rate of entry into CNS is dependent on lipid solubility. ✤ Highly-lipid soluble thiopentone has practically instantaneous entry, while less lipid-soluble ones (pentobarbitone) take longer; phenobarbitone enters very slowly. ✤ Barbiturates cross placenta and are secreted in milk; can produce effects on the foetus and suckling infant. UNWANTED EFFECTS ✤ After effects Drowsiness may last for only a few hours after a hypnotic dose of barbiturate, but residual CNS depression sometimes is evident the following day, and subtle distortions of mood and impairment of judgment and fine motor skills may be demonstrable. ✤ Paradoxical Excitement In some persons, barbiturates produce excitement rather than depression, and the patient may appear to be inebriated. ✤ relatively common among geriatric and debilitated patients ✤ Barbiturates may cause restlessness, excitement, and even delirium when given in the presence of pain and may worsen a patient’s perception of pain. Contraindicated ✤ in patients with porphyria. ✤ in the presence of pulmonary insufficiency. Rapid intravenous injection of a barbiturate may cause cardiovascular collapse before anesthesia ensues!!!!! Benzodiazepine > Barbiturate 1. BZDs produce a lower ceiling CNS depression than barbiturates. 2. They have a high therapeutic index. 3. BZDs have practically no action on other body systems. Only on i.v. injection the BP falls and cardiac contractility decreases. 4. BZDs cause less distortion of sleep architecture; rebound phenomena on discontinuation after regular use are less marked. 5. BZDs do not alter disposition of other drugs by microsomal enzyme induction. 6. They have lower abuse liability than barbiturates and similar drugs; tolerance is mild, dependence, drug seeking and withdrawal syndrome are less marked. 7. A specific BZD antagonist flumazenil is available which can be used in case of poisoning. Mechanism of Action ✤ act preferentially on midbrain ascending reticular formation (which maintains wakefulness) and on limbic system (thought and mental functions). ✤ Muscle relaxation is produced by a primary medullary site of action and ataxia is due to action on cerebellum. ✤ act by enhancing presynaptic/postsynaptic inhibition through a specific BZD receptor which is an integral part of the GABAA receptor–Cl¯ channel complex. ✤ increases the frequency of Cl¯ channel opening ✤ The BZDs also enhance GABA binding to GABAA receptor. ✤ BZDs do not themselves increase Cl¯ conductance; have only GABA facilitatory but no GABA mimetic action. Flumazenil: BZD Receptor Antagonist ✤ Flumazenil is a competitive antagonist at BZD receptor. ✤ It is used to prevent or reverse the CNS effect from BZD overdose. ✤ It has a short duration of action, which often necessitates multiple dosing. ✤ It will not reverse the effects barbiturates or alcohol. Atypical Anxiolytics Buspirone, selective anxiolytic, with minimal CNS depressant effects and has no anticonvulsant or muscle relaxant properties. The drug interacts with the 5-HT1A subclass of brain serotonin receptors as a partial agonist, Buspirone has a slow onset of action (>1 week) and is used in generalized anxiety disorders, but is less effective in panic disorders. Tolerance development is minimal with chronic use, and there is little rebound anxiety or withdrawal symptoms on discontinuance. Buspirone Side effects of buspirone include tachycardia, paresthesias, pupillary constriction, and gastrointestinal distress. Buspirone has minimal abuse liability and is not a schedule-controlled drug. The drug appears to be safe in pregnancy. Buspirone Side effects of buspirone include tachycardia, paresthesias, pupillary constriction, and gastrointestinal distress. Buspirone has minimal abuse liability and is not a schedule-controlled drug. The drug appears to be safe in pregnancy. Methanol ✤ Intoxication causes visual dysfunction, gastrointestinal distress, shortness of breath, loss of consciousness, and coma. ✤ Methanol is metabolized to formaldehyde and formic acid, which causes severe acidosis, retinal damage, and blindness. ✤ The formation of formaldehyde is reduced by prompt intravenous administration of fomepizole, an inhibitor of alcohol dehydrogenase, or ethanol, which competitively inhibits alcohol dehydrogenase oxidation of methanol The specific actions of antiseizure drugs on their targets are described as: (1) modulation of voltage-gated sodium, calcium, or potassium channels (2) enhancement of fast GABA-mediated synaptic inhibition (3) modification of synaptic release processes (4) diminution of fast glutamate-mediated excitation. 5 6 Inhibition of calcium channels Drugs that are used to treat absence seizures (e.g. etosuximide and valproate) all appear to share the ability to block T-type low-voltage-activated calcium channels. T-type channel activity is important in determining the rhythmic discharge of thalamic neurons associated with absence seizures. Gabapentin and pregabalin owes its antiepileptic effect mainly to an action on calcium channels. thereby reducing calcium entry into the nerve terminals and reducing the release of various neurotransmitters and modulators. 11 Phenytoin Depression of the CNS occurs particularly in the cerebellum and vestibular system, causing nystagmus and ataxia. The elderly are highly susceptible to this effect. Reversible cosmetic changes include gum hyperplasia, acne, hirsutism, and facial coarsening. Gingival hyperplasia may cause the gums to grow over the teeth. Long-term use may lead to development of peripheral neuropathies and osteoporosis. 15 Carbamazepine blocks sodium channels, thereby possibly inhibiting the generation of repetitive action potentials in the epileptic focus and preventing spread. is a first-line drug for treatment of focal seizures, generalized tonic–clonic seizures, trigeminal neuralgia, and bipolar disorder. is nearly completely metabolized by CYP3A4 is an strong inducer of the CYP and UGT enzymes, which increases the clearance of other drugs. It induces its own metabolism (autoinduction) !!!!!!!!!the rate of metabolism increasing during the first 4 to 6 weeks. After this time, larger doses become necessary to maintain constant plasma concentrations.!!!!!!! 18 Carbamazepine often causes nausea and visual disturbances during initiation of therapy, but these effects can be minimized by slow titration. With high initial doses or rapid dose escalation, carbamazepine has been associated with rash. In some cases, the dermatological reactions are serious (Stevens-Johnson syndrome and toxic epidermal necrolysis) causes leukopenia in 12% of children and 7% of adults, which may be transient or persistent and does not usually require discontinuation of treatment. At high levels, carbamazepine has an antidiuretic hormone–like action that can result in fluid retention in people with cardiac failure, especially in the elderly. Carbamazepine should not be prescribed for patients with absence seizures because it may cause an increase in seizures. 19 Levetiracetam / Brivarasetam binds selectively to a synaptic vesicular protein ‘SV2A’, and this may alter release of glutamate and/ or GABA across the synapse, thereby exerting anti- seizure effect completely absorbed orally, mainly excreted unchanged in urine with a t½ of 6–8 hours. It is neither oxidized by CYP enzymes nor induces or inhibits them. As such, it is free of drug interactions. 27 Levetiracetam / Brivarasetam binds selectively to a synaptic vesicular protein ‘SV2A’, and this may alter release of glutamate and/ or GABA across the synapse, thereby exerting anti- seizure effect completely absorbed orally, mainly excreted unchanged in urine with a t½ of 6–8 hours. It is neither oxidized by CYP enzymes nor induces or inhibits them. As such, it is free of drug interactions. 27 ANTIPSYCHOTICS University of Health Sciences. School of Medicine Department of Medical Pharmacology Nurdan TEKIN, M.D. Schizophrenia ❑ Patients with schizophrenia often experience disorders of perception, thinking, speech, and emotion. ❑ The symptoms of schizophrenia fall into three clusters. positive symptoms negative symptoms cognitive symptoms (delusions, hallucinations) (flattened affect, apathy, social withdrawal) (attentional and short-term memory deficits) 2 Typical antipsychotics a. High-potency drugs include uphenazine and haloperidol. Compared to the low-potency agents, they have higher affinity for the dopamine receptor and are more likely to cause extrapyramidal reactions. b. Low-potency drugs include thioridazine and chlorpromazine. Compared to the high-potency agents, they have more autonomic effects due to increased anticholinergic and antiadrenergic activity. They are less likely to produce acute extrapyramidal reactions and more likely to produce sedation and postural hypotension. 9 fl Atypical antipsychotics Atypical antipsychotic agents include clozapine, olanzapine, quetiapine, ziprasidone, risperidone, and aripiprazole. They have generally replaced the typical drugs for the initial treatment of first-episode patients. Clozapine is reserved for treatment-resistant patients due to its adverse effect profile. 10 Adverse effects and contraindications Selection of a specific antipsychotic agent for therapeutic use is often based on its associated adverse effects rather than therapeutic efficacy. The adverse effects of antipsychotic agents are due to their antagonist actions at the dopamine and histamine receptors in the CNS at muscarinic cholinoceptors and alpha-adrenoceptors in the periphery. 12 Tardive dyskinesia TD is a hyperkinetic movement disorder that may be irreversible. It generally occurs after chronic use of dopamine-receptor blocking agents. It is more likely to occur in the elderly or in institutionalized patients who receive longterm, high-dose therapy. TD is much more likely with typical antipsychotic agents than with atypical agents. Clinical manifestations may include smacking of lips, choreoathetoid movements of the tongue, facial grimacing, and choreiform or athetoid movements. Discontinuation of drug therapy is critical. 15 Endocrine and metabolic disturbances Hyperprolactinemia may occur due to D2-receptor antagonist activity in the anterior pituitary (tuberainfundibular pathway). In women, these disturbances include spontaneous or induced galactorrhea, loss of libido, and delayed ovulation and menstruation or amenorrhea. In men, these disturbances include gynecomastia and impotence. It is most common with typical agents. 17 Lithium Lithium is well absorbed orally and is neither protein bound nor metabolized. It first distributes in extracellular water, then gradually enters cells and penetrates into brain. The CSF concentration of Li+ is about half of plasma concentration. Lithium is handled by the kidney in much the same way as Na+. Nearly 80% of the filtered Li+ is reabsorbed in the proximal convoluted tubule. When Na+ is restricted, a larger fraction of filtered Na+ is reabsorbed, so is Li+, tending to raise serum Li+. 24 Lithium There is marked individual variation in the rate of lithium excretion. Thus, with the same daily dose, different individuals attain widely different plasma concentrations. Since the margin of safety is narrow, monitoring of serum lithium concentration is essential for optimising therapy; 0.5–0.8 mEq/L is considered optimum for maintenance therapy in bipolar disorder, while 0.8–1.2 mEq/L is required for episodes of acute mania. Toxicity symptoms occur frequently when serum levels exceed 1.5 mEq/L. Lithium is excreted in sweat and saliva as well, and secreted in breast milk. Mothers on lithium should not breastfeed. 25 Adverse Effects Many adverse effects associated with lithium treatment occur at varying times after treatment is started. Some are harmless, but it is important to be alert to adverse effects that may signify impending serious toxic reactions. A. Neurologic and Psychiatric Adverse Effects Tremor is one of the most common adverse effects of lithium treatment, and it occurs with therapeutic doses. Other reported neurologic abnormalities include choreoathetosis, motor hyperactivity, ataxia, dysarthria, and aphasia. Appearance of any new neurologic or psychiatric symptoms or signs is a clear indication for temporarily stopping treatment with lithium and for close monitoring of serum levels. B. Decreased Thyroid Function Lithium probably decreases thyroid function in most patients, but the effect is reversible or nonprogressive. Few patients develop frank thyroid enlargement, and fewer still show symptoms of hypothyroidism. 28 Adverse Effects C. Nephrogenic Diabetes Insipidus and Other Renal Adverse Effects Polydipsia and polyuria are common but reversible concomitants of lithium treatment The principal physiologic lesion involved is loss of responsiveness to antidiuretic hormone (nephrogenic diabetes insipidus). L Patients receiving lithium should avoid dehydration and the associated increased concentration of lithium in urine. D. Edema is a common adverse effect E. Cardiac Adverse Effects The bradycardia-tachycardia (“sick sinus”) syndrome T-wave flattening is often observed on the electrocardiogram but is of questionable significance. 29 Use During Pregnancy Renal clearance of lithium increases during pregnancy and reverts to lower levels immediately after delivery. Lithium is transferred to nursing infants through breast milk, in which it has a concentration about one third to one half that of serum. Lithium toxicity in newborns is manifested by lethargy, cyanosis, poor suck and Moro reflexes, and perhaps hepatomegaly. The issue of lithium-induced dysmorphogenesis is not settled. An earlier report suggested an increase in cardiac anomalies— especially Ebstein’s anomaly—in lithium babies. However, more recent data suggest that lithium carries a relatively low risk of teratogenic effects. Other Drugs The manic phase in bipolar disorder can be treated with antipsychotic drugs. Several antiseizure drugs are used in bipolar disorder. Valproic acid has antimanic effects equivalent to those of lithium Carbamazepine and lamotrigine are also used both in acute mania and for prophylaxis in the depressive phase. 33 Parkinson’s Disease Assist. Prof. Rümeysa KAYA University of Health Sciences International School of Medicine Department of Pharmacology  Pharmacological treatment Dopamine decarboxylase inhibitors Carbidopa, benserazide a dopamine decarboxylase inhibitor Combined with L-DOPA diminishes the metabolism of levodopa in the periphery, thereby increasing the availability of levodopa to the CNS. The addition of carbidopa lowers the dose of levodopa needed by four- to five-fold and, consequently, decreases the severity of adverse effects arising from peripherally formed dopamine. Side effect Nausea, Vomiting (D2 agonistic effect) orthostatic (postural) hypotension Dyskinesia (Involuntary movements) On-off phenomenon Coombs (+) hemolytic anemia (Autoimmune hemolytic anemia) Psychosis Contraindications; Malign melanOma : levOdOpa is a precursor of melanin and can activate malignant melanoma NarrOw-angle glaucOma : levOdOpa with caution as it can increase ocular pressure Tolcapone (Tasmar®) , Entacapone Reversible inhibition of catechol-O-methyltransferase (COMT) Reduce wearing off phenomenon in patients with levodopa and carbidopa Entacapone; Levodopa + Carbidopa + Entacapone peripheral action on COMT Duration of action short – 2 h No hepatoxicity Tolcapone Central and peripheral inhibition of COMT Long duration of action – 2 to 3 times daily Adverse effect: hepatoxicity  CNS STIMULANTS Assist. Prof. Rümeysa KAYA University of Health Sciences International School of Medicine Department of Medical Pharmacology Psychomotor stimulants 1. Methylxanthines Caffeine Theophylline (tea) Theobromine (chocolate)  Therapeutic uses Theophylline - Asthma Caffeine can be used in the treatment of Apnea of Prematurity ; - stimulates medullary respiratory centers - increases the sensitivity to CO2 Post-Lumbar Puncture Headache Psychomotor stimulants 2. Nicotine Nicotine is the active ingredient in tobacco. Although this drug is not currently used therapeutically (except in smoking cessation therapy), nicotine remains important because it is second only to caffeine as the most widely used CNS stimulant, and it is second only to alcohol as the most abused drug. Mechanism of action Nicotine binds to nicotinic acetylcholine receptor in the CNS Increases levels of dopamine Activates sympathetic nervous system and results in release of epinephrine.