«+ Antipsychotics Fak ¥; «+ Antidepressants 7a “+ Anti-anxiety agents a ta ¢* Antimanic “+ Hallucinogens1OPHARMACOL mB iileceieecon * Psychopharmacological agents are the drugs used to treat CNS - conditions related to behavior of a person. They are further sub-classified as antipsychotics, antidepressants, antianxiety 4 SS 8 agents, antimanic and hallucinogens. ~ © Drugs acting on CNS are classified in different categories: i ANTI-MANIACS AND ANTLPSYCHOTICS “— Baus acting EBD —P ANTLMANIACS AN cc ‘ t ANTI-ANXIETY AGENTS Antipsycho' ° Antipsychotics are used to treat schizophrenia. * Genetic predisposition is considered to be one of the causes of schizophrenia, there are three hypotheses, based on neurotransmitters used to explain pathogenesis of schizophrenia. Antipsychotics Typical antipsychotics Atypical antipsychotics a) Phenothiazines ” Aliphatic side chain Chlorpromazine Y Piperidine side chain | Thioridazine Y Piperazine as side chain | Trifluoperazine, Perfenazine, Fluphenazineb) Thioxanthenes c) Butyrophenones Flupenthixol, Thiothixene, Zuclopenthixol Haloperidol, Benperidol, Droperidol. d) Miscellaneous Pimozide, Penfluridol, Molindone, _Loxapine, Sulpiride, Amisulpride, Remoxipride. Y Clozapine, Olanzapine, Quetiapine, Zotepine, Risperidone, Ziprasidone, Paliperidone, Aripiprazole, Sertindole, Asenapine . ' : “> Mechanism of Action ° All typical antipsychotic drugs act as antagonists at D, and/or D;/D, dopamine receptors. ° Atypical antipsychotics block other monoamine receptors, especially 5-HT>, receptors. ° Typical antipsychotics produce competitive blockade of post- synaptic D, receptors in mesolimbic system. * Atypical antipsychotics have a high affinity for 5-HT,, receptors, but they have antagonistic action on a1, ACh M,, Histamine H, and Dopamine D, receptors. © All antipsychotic drugs exhibit a latent period of 2-3 weeks for attaining therapeutic effects. * Majority of them are given orally; however their when given by IM route. “23 bioavailability increases ten fold i o Sautecet * =They are primarily used to treat schizophrenia. * In drug-induced psychoses like delusions associated with LSD, Amphetamine-induced psychoses and delirium following infectious psychoses. Psychiatric indications * It involves use in Tourette’s syndrome which is marked by tics, grunts and vocalizations which are Neuro- psychiatric indications frequently obscene. © Huntington’s disease. Antipsychotic like Promethazine is used as pre- operative sedative * Droperidol is a short acting antipsychotic with Non- 3. | psychiatric indications antiemetic, sedative and anticonvulsant effects. * Prochlorpromazine is preferred for antiemetic effects ° It involves behavioral effects, tolerance and a . . , dependence. ° Toxic confusional states may occur with higher y doses of drugs having anticholinergic effects.Tolerance develops to sedative and autonomic effects but not to antipsychotic action. Withdrawal symptoms are manifested as dyskinesias. Physical dependence is not observed. 2. Neurological side effects © Dystonias, akathisia, parkinsoniasm and a rare neurolept-malignant syndrome appear during treatment. * Parkinsoniasm, Tardive dyskinesia. 3. Endocrinal side effects © It results in hyperprolactinamia which is manifested as galactorrhea in females and gynaecomastia in males. These drugs also inhibit release of FSH and LH leading to amenorrhoea and inhibition of ovulation. 4. Miscellaneous side effects * Drugs belonging to Phenothiazine groups are also known to cause jaundice, photosensitivity, corneal opacity, epileptogenic effects and poikilothermic effects. Effects vY Antacids | Decreased absorption of antipsychotic drugs Y Anticholinergics | Increased anticholinergic effects Y Antithyroid Increased risk of agranulocytosis (with Clozapine) drugs May precipitate extra-pyramidal symptoms with Chloroquine Phenothiazinesv Cigarette Increased metabolism of antipsychotics; higher smoking dose needed v Oral May potentiate hyperprolactinaemia contraceptives Y Levodopa Decreased efficacy of neuroleptics Enhancement of neurotoxicity and precipitation of v Lithium NMS (Haloperidol) erie * Depression is a common psychiatric disorder but the etiology of it is not clear. Depression could be: 1. Unipolar a) Reactive depression b) Endogenous depression 2. Bipolar mood disorder or manic depressive illness. 1, UNIPOLAR DEPRESSION a) Reactive depression * It isdue to stressful and distressing circumstances in life. b) Endogenous depression * It is major depression and results from a biochemical abnormality in the brain. Deficiency of monoamine (NA, 5-HT) activity in the CNS is thought to be responsible for endogenous depression. Symptoms are:*® Sadness, misery, hopelessness, Fatigue, apathy, loss of libido, low self-esteem, loss of interest loss of appetite, lack of and suicidal thoughts concentration and sleep disturbances. . BIPOLAR DEPRESSION 2. BIPOLAR DEPRESSION oe It is characterized by alternate episodes or periods of mania and depression. The patient has cyclical mood swings. It is less common and is associated with a_ hereditary tendency. Mania can be considered opposite of depression with elation, overenthusiasm, over- confidence, often associated with irritation and aggression. Selective serotonin Fluoxetine, fluvoxamine, paroxetine, | reuptake inhibitors (SSRIs) | citalopram, escitalopram, sertraline Tricyclic antidepressants | Imipramine, desipramine, clomipramine, (TCAs) amitriptyline, nortriptyline, doxepin Serotonin norepinephrine | Venlafaxine, desvenlafaxine, duloxetin, reuptake inhibitors milnacipran (SNRIs) Atypical antidepressants | Mianserine, amineptine, tianeptine, bupropion, reboxetine, mirtazapine, amoxapine, atomoxetine maprotiline, trazodone, nefazodone, vortioxetine. Monoamine oxidase (MAO) | Phenelzine, tranylcypromine, inhibitors moclobemide.serotonin reuptake inhibitors (SSRIs) Tricyclic antidepressants (TCAs) SSRIs block the reuptake of serotonin from the synapse into the serotonergic nerve endings by inhibiting the serotonin transporter (SERT). There is selectively increase levels of serotonin in synaptic cleft. They block reuptake of NE and 5-HT into their neuron by inhibiting respective transporters. It leads to more availability and a longer stay of NEand 5-HT at their respective receptor sites. Serotonin norepinephrine reuptake inhibitors (SNRIs) Inhibit the reuptake of both serotonin and norepinephrine at the presynaptic neurons by binding to SERT and NET like TCA. Unlike TCA, they do not have anticholinergic, a- blocking or antihistaminic effects— hence fewer side effects. Atypical antidepressants Atypical antidepressants act by enhancing the monoamine levels in the brain either by inhibiting their reuptake or preventing their degradation. Monoamine oxidase (MAO) Monoamine oxidase (MAO) is an enzyme which metabolizes NA, 5-HT and DA. Drugs which inhibit this enzyme, enhance the neuronal levels of monoamines like NA, DA and 5-HT. MAO exists as two isozymes— MAOA and MAOB. MAOA is selective for 5-HT.PRESYNAPTIC NEURON E PRESYNAPTIC NEURON Tricyclic = antidepressants ‘S-HT Receptor icAay antagonists POSTSYNAPTIC NEURON POSTSYNAPTIC NEURON Oral absorption of most antidepressant drugs is good; still the bioavailability is uncertain because of their first pass metabolism. The plasma half-life of most antidepressants is long, Plasma half-life for some antidepressants is low. The half-life is longer due to their metabolites except for Fluvoxamine, Paroxetine and Protriptyline. 1. Endogenous depression © Antipsychotics are used in Endogenous depression The choice of drug depends on the side effects and patient factors like age. SSRIs are the most commonly used antidepressants. In severe depression with suicidal tendencies, electroconvulsive therapy (ECT) is given.© Acute, recurrent, brief episodes of anxiety are known as panic | attacks. © Post-traumatic stress disorders, panic attacks and other anxiety disorders— all respond to antidepressants. 3. Ok . Isive di i (OCDs) * OCDs are characterized by repeated anxiety—provoking thoughts and compulsive behavior to overcome such anxiety. * OCDs respond to SSRIs/ clomipramine along with counselling. 4. Other anxiety disorders © SSRIs are effective in several anxiety states like posttraumatic stress disorders, phobias and social anxiety. 5. Disorders of pain * Antidepressants that inhibit the uptake of both serotonin and norepinephrine (SNRIs) are found to influence ascending pain pathway © They are effective in chronic pain, including diabetic neuropathy, backache, postherpetic neuralgia and fibromyalgia. 6. Other indications * Migraine, attention deficit hyperactivity disorder, chronic fatigue, urinary stress incontinence and chronic alcoholism—may result in depression- antidepressants are tried. oO” Oy ocD OCVELE ps \ =i r. = f ANXIETY Sd* Adverse Effects Selective Nausea, vomiting, insomnia,headache, serotonin restlessness, anxiety and sexual dysfunction. reuptake Inhibition of platelet function may result in inhibitors (SSRIs) ecchymosis. Tricyclic Sedation, confusion, postural hypotension, A tachycardia and sweating. antidepressants F ; 7 ‘ (TCAs) weight gain due to increased appetite. cardiac arrhythmias. Serotonin These drugs have serotonergic side effects like norepinephrine discontinuation syndrome. reuptake inhibitors (SNRIs) Trazodone causes nausea, sedation, postural hypotension and priapism leading to Atypical impotence. antidepressants | * Bupropion causes agitation and insomnia Mirtazapine and Mianserin cause sedation due to histamine H1-blockade. Monoamine Postural hypotension (in elders), weight gain, oxidase (MAO) dizziness and sexual dysfunction. inhibitors TCAs potentiate effects of directly acting sympathomimetics causing rise in BP and arrhythmias; but inhibit effects of indirectly acting sympathomimetics. Phenytoin, Chlorpromazine and Aspirin displace TCAs from their protein binding sites leading to increased effect of TCAs. Anticholinergic drugs aggravate toxicity of TCAs.Food articles containing tyramine, like cheese, beer, red wine, banana, yoghurt and pickled meat when used with MAO inhibitors can cause hypertensive crisis. MAO inhibitors with TCAs or with directly/indirectly acting sympathomimetics can cause hypertension, arrhythmias and seizures MAO inhibitors retard metabolism of drugs like morphine causing severe respiratory depression SSRIs inhibit metabolising enzymes like CYP2D6 and CYP3A4. As a result, plasma levels and toxicity of TCAs, Haloperidol, Clozapine, Warfarin, Dextromethorphan, Terfenadine, Astemizole and Cisapride | are increased SSRIs with MAO inhibitors result in elevated levels of 5-HT causing “serotonin syndrome” leading to hyperthermia, muscle rigidity, tremors and rapid changes in mental status along with cardiovascular collapse. WITH DEPRESSION DAVS Sy & Ga 33 cogs Journaling Aromatherapy wawaee es *& @& Usinga —_Eating your a warm, Drinking herbal weitea favorite food comforting _—teas or hot shower chocolate e © & Watching Practicing gaia, Saigo Wiauiaed hens anata Mike “I am ‘mindfulness tdevision shows ‘and this too exercisesAnxiety is tension or apprehension which is anormal response to certain situations inlife. It is a universal human emotion. © However, when it becomes excessive and disproportionate to the situation, it becomes disabling and needs treatment. Diazepam, chlordiazepoxide, lorazepam, alprazolam Benzodiazepines 5-HT agonist-antagonists | Buspirone, gepirone, ipsapirone Beta-blockers + 4, Sedative antihistamine | Hydroxyzine Propranolol These drugs act through non-GABAergic system and have low chances of side effects in comparison to BZDs. © These drugs exert their anxiolytic effects by acting as a partial agonist primarily at brain 5-HT1A receptors. ° By selective activation of the inhibitory presynaptic 5-HT1A receptor, they suppress 5-HT neurotransmission through neuronal system. 5-HT agonist- antagonists ® Worrying situations may lead to palpitation, tremors, GIT upset or even hypertension die to sympathetic overactivity. * These symptoms, reinforce anxiety and thus the visicous cycle continues. 1 2. | Beta-blockers | , Propranolol breaks the visicious cycle. Through its | | B-blocking action, it decreases palpitation, tremors, | GIT upset, hypertension and blood lactic acid levels. || *® Because of its cardiovascular actions, it is not a \| potential preferred anxiolytic.© Hydroxyzine is an antihistaminic with anxiolytic actions—but due to high sedation, it isnot used Sedative antihistamine + Pharmacokinetics * Buspirone is rapidly absorbed and metabolized in the liver, undergoes extensive first pass metabolism. Chlordiazepoxide Oral absorption is slow. Its t% is 6-12 hours, but active metabolites are produced which extend the duration of action. Sedation, light-headedness, psychomotor and cognitive | impairment, confusional state (especially in the elderly), increased appetite and weight gain, alterations in sexual function. Dizziness, nausea, abdominal discomfort, headache, rarely excitement | Pere litt tay Mania is characterized by an excessive desire and too much of euphoria. Majority of patients of mania experience cyclic episodes of mania followed by severe depression with periods of normal mood in between. Thus, The patient's condition moves between mania and depression. Hence, itis called as manic-depressive psychosis (MDP). Excessive NE/DA related activity precipitates mania and the drugs which reduce NE/DA relieve mania Ac Balanced neurotransmitter levels ; help in stabilization of mood. While manic episode is believed to result from elevated NE, depressive everel( ©) @) Highly insleeping energetic phase is associated with decrease in ; Feeling of (§) (®) Inflating cover exhilaration self-esteem| Anticonvulsants Sodium cain 1, Olanzepine cain 2. Risperidine Lamotrigine 3. Quetiapine 4. Aripiprazole The mechanism of action of Lithium is related to second messenger involved in a-adrenergic and muscarinic neurotransmission. * Inositol triphosphate (IP3) is inactivated to inositol diphosphate (IP2), inositol monophosphate (IP1) and then to inositol. ° Lithium selectively inhibits signal transduction in overactive neurons by blocking conversion of IP2 to IP1 and then to inositol. * As a result, the supply of free inositol to regenerate phosphatidyl inositol-diphosphate (PIP2) in hyperactive neurons is interrupted and ultimately release of IP3 and diacyl glycerol (DAG) is also reduced which decreases neuronal response to NE, DA and 5-HT. In addition, Lithium may uncouple receptors from their G-proteins. Sodium ions are so common for neurotransmission. Competition of lithium ions with sodium is also said to contribute to the action of lithium. Lithium inhibits IPPase and IMPase * Phosphoinositide cycle: Phosphoinositides: precursor of signaling molecules + Enzymes |PPase and |PPase: synthesis of myoinositol (mI) * Uthium MOA: “mi depletion 6 0 aa oO ‘@" %@ = © {JDrugs used in Parkinson's disease & Alzheimer’s disease Q DRUGS USED IN PARKINSONS | DISEASE | ¢* Introduction to Parkinson's disease “* Drugs for Parkinson's Disease OQ DRUGS USED IN ALZHEIMER'S DRUGS “* Introduction to Alzheimer's Disease j “* Drugs used in Alzheimer’s diseaseDRUGS USED IN PARKINSONS DISEAS OR ec teem Rec hyS Parkinson's disease is an extrapyramidal motor disorder characterized by rigidity, tremor and hypokinesia with secondary manifestations like defective posture and gait, mask-like face and sialorrhea; dementia may accompany. Symptoms of Parkinson's Disease ° If untreated the symptoms progress over several years to end-stage disease in which the patient is rigid, unable to move, unable to breathe properly; succumbs mostly to chest infections/embolism. During functioning of brain, there is a functional balance between dopaminergic and cholinergic system. In Parkinson’s disease (PD), there is a loss of dopaminergic neurons. It indirectly leads to hyperactivity of cholinergic neurons.© The mechanism of action of drugs used in treating PD is shown- Parkinson's Disease Drugs |Adamantane derivatives 1. Amantadine Anti-cholinergics: Dopa derivatives 1. Biperiden 1. Levodopa+ Benserazide I2. Procyclidine 2. Levodopa+ Carbidopa 3. Trihexyphenidyl= 3, Levodopa+ Carbidopa benzhexol SR }4. Diphenhydramine 4. Levodopa+ Carbidopa + 5. Orphenadrine Entacapone Dopamine agonists MAO-B inhibitors 1. Bromocriptine 2. Pergolide ride |. Cabergoline others 1. Entacapone 1. Selegiline| 2. Rasagiline }7. Apomorphine Drug used for treating Parkinson's disease are classified in to four categories: (i) Drugs which prevent dopamine levels Drugs which prevent dopamine degradation Drugs which stimulate dopamine receptors (iv) Drugs Which Restore DA-ACh Balance (v) Drugs which increase dopamine levels (Levodopais the precursor of DA. Levodopa can cross BBB and it is decarboxylated to DA(dopamine) in brain. DA itself does not cross BBB. If administered alone, only about 1% of Levodopa actually enters Cue Remaining 97-99% Levodopa gets metabolized in GIT and peripheral tissues by the enzyme E x: x) Con Mada} eT meee CRUEL Amos cee ism * To prevent its peripheral degradation, Levodopa is usually Coadministered with either Carbidopa or Benserazide, a peripheral dopa decarboxylase inhibitor. This combination lowers the dose of Levodopa and reduces incidence of peripheral side effects. (a) Adverse effects Excessive and abnormal choreiform movements of limbs, trunk, face and tongue. These effects are termed as Dyskinesias Vivid dreams Delusions Hallucinations vv ; y () Confusion > 0\ Sleep disturbances O Prolonged therapy of Carbidopa + Levodopa may cause schizophrenia-like symptoms in elderly. (b) Contraindications * Levodopa is contraindicated in psychoses, narrow angle glaucoma, cardiac arrhythmias and melanoma. |( Drug interactions * Pyridoxine (vitamin B6) enhances the extracerebral metabolism of Levodopa and decreases its therapeutic effects. * MAO-A inhibitors potentiate toxicity of Levodopa leading to hypertensive crisis. © Proteins ingested with meals may produce sufficient amount of amino acids, which compete with Levodopa transport both in GIT and brain; hence Levodopa should be given 30 minutes before meals. © TCAs decrease the absorption of Levodopa leading to hypertensive episodes. 2. COMT Inhibitors © COMT metabolizes DA and its precursor Levodopa, producing the inactive metabolite. © Hence, inhibition of peripheral COMT will result in increase in plasma half-life of Levodopa. * Selective COMT inhibitors like Tolcapone and Entacapone, not only diminish metabolism of Levodopa but also increase its bioavailability in brain. Pharmacological effects of Tolcapone and Entacapone are similar. 3. Amantadine ° Itisan antiviral drug. © It prevents DA uptake, facilitates presynaptic DA release, possesses weak antimuscarinic action and blocks glutamate NMDA receptor. © The first two actions help in treating Parkinson's disease. © Blocking of NMDA receptor contributes in reducing excitation-induced neurotoxicity and dyskinesia. © Amantadine alone or in combination with Levodopa and Carbidopa is used to treat PD. * Adverse effects include nausea, dizziness, insomnia, confusion hallucinations, odema. © = Its anti-muscarinic actions areSelegiline is an irreversible inhibitor of MAO-B, an enzyme in dopaminergic neurons responsible for metabolism of DA. It makes more DA available for stimulation of its receptors. Selegiline may retard progression of PD by reducing oxidative damage due to formation of free radicals produced during metabolism of DA. © These drugs directly stimulate DA receptors and do not depend on the formation of DA from Levodopa. They have following advantages: a) They do not require metabolic conversion to DA. b) They do not depend on the functional integrity of dopaminergic | neurons. c) They have longer duration of action and lesser on-off phenomenon as compared to Levodopa. d) They are more selective than Levodopa on DA receptors. e) They are less likely to generate damaging free radicals. The drugs under this category are centrally acting antimuscarinic drugs. In the absence of inhibitory control of DA, the activity of cholinergic system becomes dominant. Blockade of central muscarinic receptor by these drugs reduces cholinergic activity. The muscarinic antagonists are most commonly used to treat following conditions:- Early stages of the disease, 2, 3, Late-stage PD as an adjunct to Levodopa + Carbidopa therapy. Neuroleptic-induced extrapyramidal side effects.© The drugs in this category include: Trihexyphenidyl (beeen Procycliydine, Orphenadrine and Benztropine. DRUGS USED IN ALZHEIMER'S DRUGS Q Introduction to Alzheimer's Disease Alzheimer's disease isa progressive neurologic disorder | Alzheimer's disease is the most common cause of dementia — a continuous decline in thinking, behavioral and social skills that affects a person's ability to function independently. Problems with genes—even small ., changes to a gene—can cause diseases like Alzheimer's. Progression of Alzheimer’s Disease ‘Lbs ia Pen Other symptoms like depression, anxiety and disturbed sleep may also be seen. Pathological features include atrophy of the cerebral cortex and loss of neurons—mainly cholinergic neurons with multiple _ senile (amyloid) plaques and neurofibrillary tangles in the brain. Since there is loss of cholinergic neuronsee aeons * Choli inhihi * Tacrine, rivastigmine, donepezil, galantamine N : ( sit f ) * Piracetam, aniracetam, cerebrolysin * Piribedil, ginkgo biloba The loss of cholinergic activity in brain or patients with AD led to the | use of cholinesterase inhibiting drugs which can cross BBB. These drugs block degradation of Ach and increase availability of ACh in synaptic cleft. The drugs used to treat AD are: Tacrine, Donepezil, Rivastigmine and Galantamine. Tacrine is a long acting reversible anticholinesterase. It can be used for treatment of mild to moderate patients of AD. It is orally active and provides improvements in memory, cognition and general well being soon after initiation. Donepezil, Rivastigmine and Galantamine have better penetration in CNS. They are less toxic and better tolerated in comparison to Tacrine. Their clinical results are modest and temporary. — : > Their dosages are as follows: Y Donepezil: 5 mg once daily in|, evening increased maximum up to i 10 mg once daily after 4 weeks. ¥ Rivastigmine: 1.5 mg initially twice a day increased up to 3 mg twice a day after two weeks. rr ner 1.5v Galantamine: 4 mg twice initially, increased up to 8 mg twice a day | after one to two weeks. Transdermal Rivastigmine patch, to be applied once in a day is available. Use of these drugs is not associated with | hepatotoxicity except for peripheral cholinergic side effects like | diarrhea, nausea, vomiting and increased urination.“* CNS stimulants “* Nootropicsuc DELL ed © The drugs in this category have a marked influence on mental functions and behavior to produce excitement, euphoria, increase in motor activity and reduction in fatigue. They are sub-classified as follows: * Respiratorystimulants * Doxapram, nikethamide * Amphetamine, cocaine, methylxanthines * Convulsants * Leptazol, strychnine Respiratory stimulants are also called Analeptics. These drugs stimulate respiration and are sometimes used to treat respiratory failure. They may bring about temporary improvementin respiration. -~ ° They have alow safety margin and may produce convulsions. Q “ 1. Doxapram ed * It appears to act mainly on the brainstem and spinal cord and increase the activity of medullary respiratory and vasomotor centers. Doxapram in low doses can selectively stimulate respiration. DOSE:- 1-2 mg/kg/hr or 40-80 mg IM.> Adverse effects * Nausea, Cough, Restlessness, Muscle twitching, > Uses It is occasionally used IV as an analeptic in acute respiratory failure. 2. Apnoea in premature infants not responding to theophylline. Amphetamine and dextroamphetamine are sympathomimetic drugs. * Cocaine is a CNS stimulant, produces euphoria and is a drug of abuse. 1. Methylxanthines Caffeine, theophylline and theobromine are the naturally occurring xanthine alkaloids. The beverages—coffee contains caffeine; tea contains theophylline and caffeine; cocoa has caffeine and theobromine. > Actions a) CNS ° Mental alertness. Reduces fatigue, produce a sense of well- being. Improve motor activity and performance with a clearer flow of thought. Caffeine stimulates the Respiratory center, © Higher doses produce Irritability, nervousness, restlessness, insomnia, excitement and headache. High doses can result in convulsions.cvs Increase the cardiac output. produce peripheral vasodilatation. Caffeine causes vasoconstriction of cerebral blood vessels. Kidney The xanthine's have a diuretic effect and increase the urine output. Smooth muscle Xanthine's cause relaxation of smooth muscles especially the bronchial smooth muscle. Skeletal muscle Xanthine's enhance the power of muscle contraction and increase the capacity to do muscular work by both a central stimulant effect and the peripheral actions. > Pharmacokinetics Methylxanthines are well absorbed orally, widely distributed and are metabolized in the liver; t% 7-12 hr. In higher doses, t¥% may be prolonged due to saturation of metabolizing enzymes. Premature infants have a longer t% of 24-36 hr. > Adverse Effects Tremors Nervousness, Insomnia Tremors Tachycardia Hypotension Arrhythmias Headache Gastritis, nausea, vomiting, epigastric pain and diuresis.> Uses ° Headache * Bronchial asthma Apnoea in premature infants 1. Strychnine It is an alkaloid obtained from the seeds of Nux vomica. On administration, it produces tonic convulsions— opisthotonos followed by coma and death. It acts as a competitive antagonist of the inhibitory neurotransmitter glycine—mainly stimulates the spinal cord and in higher doses the entire nervous system. * Strychnine is of NO THERAPEUTIC VALUE. 2. Leptazol or pentylene tetrazol It isa CNS stimulant. By a direct effect on the central neurons, it produces convulsions. It is mostly used as an experimental drug to induce convulsions. Poisoning with leptazol is treated with diazepam. Mechanism of Action These drugs enter the nerve ending by active transport and displace DA/NE from storage vesicles by altering their pH. They have some property to inhibit DA metabolism by inhibiting MAO- B in the nerve ending. Due to inhibition of the enzyme, concentration of intraneuronal DA increases. This reverses the direction of transport mechanism so that DA is now released in to synapse by reverse transport rather than by usual exocytosis. This further increases DA concentration in the synaptic cleft.eB tote © Nootropics are drugs that improve memory and cognition. They are also called Cognition Enhancers. Nootropics can overcome or retard cognitive decline occurring in old age and in some diseased conditions. They can prevent the disruption of the process of memory consolidatio by hypoxia, trauma, seizures, Hypoglycemia and other factors. They should facilitate learning acquisition and memory consolidation and prevent or mitigate impairment of memory induced by ageing, amnestic agents and other aversive factors. They should facilitate inter-hemispheric transfer of information. They should improve tonic cortical control over sub-cortical centers. They should not induce any overt behavioral or autonomic effects on long term administration. Hydergine (dihydroergotoxin) Vincamine Meclofenoxate Pentoxifylline Pyritinol Cyclangate Nicergoline Herpestis monniera (Brahmi) Ginkgo biloba extract i i a aS1. Piracetam Piracetam is a cyclized derivative of GABA. It was first introduced as a nootropic agent. It has been shown to be beneficial in cognitive deficit occurring in several types of brain disorders. Mental performance is improved in children and ageing individual with memory deficits. Piracetam is devoid of significant autonomic, motor or behavioral effects, even at relatively high doses. Aniracetam and Oxiracetam are derivatives of Piracetam. The derivatives have actions similar to Piracetam. Dose of Piracetam is 2-3 gm daily in divided doses. > Uses In cognitive defects associated with presenility (Alzheimer’s disease) and ageing. In children with learning and attention deficit. Amnesia following cerebral trauma, drug abuse including alcoholism, seizures. Coexisting memory deficits in neurological and psychiatric illnesses. MECHANISM OF ACTION Nootropics like Pentoxifylline, Pyritinol, Cyclandate and Nicergoline function like cerebral protectors improving cerebral circulation. Improvement in brain metabolism and energy utilization may be involved, as also effects on central neurotransmitters. There is evidence that central cholinergic synapses may be part of the intrinsic system controlling memory storage. Nootropics may induce environment of neurotransmitters conducive to learning acquisition and memory retention. The mechanism of action includes increase in central cholinergic, noradrenergic and dopaminergic activity with concomitant reduction in serotonergic function.+ Introduction “* Opioid analgesics ** Opioid antagonists Opioids sored re reduced sex drive nny ‘wor an” PomOPIOID ANAL j Q Introduction ° Pain or algesia is an unpleasant subjective sensation. Pain is a warning signal and indicates that there is an impairment of structural and functional integrity of the body. It is the most important symptom that brings the patient to the doctor and demands immediate relief. Pain arising from the skin and integumental structures, muscles, bones and joints is known as SOMATIC PAIN Somatic pain. It is usually caused by inflammation and is well- defined or sharp pain. Pain arising from the viscera is vague, dull aching type, difficult to pinpoint to a site and is known as Visceral pain. It may be accompanied by autonomic responses like sweating, nausea and hypotension. VISCERAL PAIN It may be due to spasm, ischemia or inflammation. When pain is referred to a cutaneous area which receives nerve supply from the same spinal segment REFERRED PAIN as that of the affected viscera, it is known as referred pain. E.g. Cardiac pain referred to the left arm.* Analgesics * Analgesic isa drug which relieves pain without loss of consciousness. © Analgesics only afford Symptomatic relief from pain without affecting the cause. Analgesics are of 3 classes: Opioid or morphine type of analgesics Non-opioid or aspirin type of analgesics 4 Adjuvant analgesics Antiepileptics—pregabalin, lamotrigine. gabapentin, carbamazepine, Antidepressants—amitriptyline, venlafaxine, duloxetine, citalopram, escitalopram. Three types of endogenous peptides with analgesic activity are endorphins, enkephalins and dynorphins. They are derived from distinct precursor polypeptides. ° They are involved in modulating pain and form part of the complex pain inhibiting mechanisms in the brain and spinal cord. © Four major categories of endogenous opioid receptors have been | identified. They are as follows: ¥ wom) Hh KO ¥ x (kappa) 2S v & (delta) i Y o (sigma) 6The », k and o receptors mediate the main pharmacological actions of narcotic analgesics. © and k receptors are important for analgesia while sigma receptors are responsible for psychotomimetic effects. © The 6-receptors inhibit excitatory neurotransmission in the brain and periphery. * It is postulated that opioid receptor activation leads to decrease in c AMP production in the brain, opening up of K* channels and inhibition of intraneuronal Ca** transport, all of which induce inhibition of neuronal activity. et Igesics ° Drugs having agonistic activity, especially on p> receptors are used as analgesics. ° Morphine is the prototype drug in this category. © Other morphine agonists and mixed agonists- antagonists have actions similar to morphine. Morphine is readily absorbed from GIT. * Because of extensive first-pass metabolism, bioavailability is poor. © The drug is usually administered by intramuscular route. ° Half-life is 2.5 hours, peak effect is at 1 hour and duration of analgesia is 4 hours. * Morphine is metabolized by N-dealkylation and oxidation followed by glucuronide or sulphate conjugation. It has relatively poor access through BBB. Morphine acts through different receptors mentioned above. * It influences the activity of some neurotransmitters in brain. * It increases cholinergic and 5-HT activity; and inhibits nor- adrenergic, dopaminergic and GABAergic activity.© It releases histamine but inhibits release of substance P. These wide ranging effects contribute to various pharmacological actions. 1. Effects on CNS Analgesia Euphoria Sedation Respiratory depression Pupillary constriction Nausea and vomiting Antitussive effect Neuroendocrine effects 2. Effects on GIT Increase in tone and reduces motility in many parts of GIT. v v v v v v v v Severe constipation. Gastric emptying is delayed. Intra-biliary pressure is increased due to constriction of bilia sphincter and contraction of gall bladder. Gastric, intestinal, pancreatic and biliary secretions are decreased by morphine. BIN irae eeu n eG Pree A ) —LIVER Wa By3. Effects on CVS Y¥ Morphine causes hypotension and bradycardia. 4. Other actions ¥ Bronchoconstriction is due to release of histamine and increased vagal activity. ¥ Contraction of uterus, ureters and urinary bladder occurs occasionally. v Immunosuppressant effect is probably due to actions on CNS. Yv Morphine addicts may have risk of AIDS. Acute 1. For analgesia v For relief of acute severe pain @ e- in trauma, burns, _ post- ® e-- operative pain, myocartliah _ e @ infarction, renal and intestinal colic. PAIN SCALE Y In Terminal cancer patients Ch . ronic for analgesia and euphoria. 2. In left ventricular failure v Relieves symptoms by inducing marked Veno-dilatation and | decrease in pre-load. v Reduced sensitivity of respiratory center to stimuli from Congested lungs and increased CO, levels also contribute to decreased dyspnea. 3. In anesthetic pre-medication vY Morphine sulphate (8-12 mg) or Pethidine (50-100 mg) is given intramuscularly 1 hour before surgery to reduce pain during surgery.ec nee 1. | Acute abdomen v v Morphine can mask the symptoms; hence it should not be given in undiagnosed abdominal pain. Morphine induced respiratory depression and rise in intra-cranial tension, together with 5. | Hypothyroidism - Head injury miosis and vomiting may interfere with diagnosis. 3 Bronchial v Morphine may aggravate bronchial spasm and : asthma respiratory depression. 4 Chroniclung |” Respiratory insufficiency by morphine can : disease aggravate the symptoms v Slow metabolism of morphine can cause increased toxicity. 6. Hepatic failure v Reduced metabolism can cause higher toxicity leading to hepatic coma. v Morphine can cause constriction of biliary 7. Biliary colic sphincter. It is also to be avoided after cholecystectomy. 8 Ulcerative Y Production of colonic dilatation by morphine . colitis can complicate ulcerative colitis. v Nausea ¥ Vomiting v Drowsiness v Sweating Y Prurites Y Piloerection v Bradycardia ¥ Hypotension ¥ bronchospasm Antiemetc ef Tramadol Buprenorphine Respirat Death depre8810N fag meas | Meat teat Pain relief — I | ee a J 7 Cough rebel lect Morphine Fentanyl Blood 4} pressure ory Pupil constncton Addiction Shortness of if drug is rapidly breath} deliveredPethidine Less potent than morphine as analgesic but causes equal respiratory depression and vomiting eyeio® Shorter duration of action yoome/2™ Less sedative, antitussive and constipating agent. —_—_— It is used as an analgesic and preanaesthetic medicant Heroin Y More effective than morphine as analgesic. It — * crosses BBB. Y Itis metabolized to morphine in brain. It is most \ addictive and is not used clinically. Methadone Equipotentto morphine Oral active and longer duration of action used in the treatment of morphine deaddiction. Have shorter duration (30-60 minutes) of action Their uncontrolled use may lead to marked respiratory depression. Codeine Codeine and its derivatives Oxycodone, Dihydrocodeine, Hydrocodone are less effective as analgesics Large doses can induce excitement Tolerance and physical dependence are less marked. It is mainly used for antitussive action Pentazocine Pentazocine is an intermediate beween morphine Jaw xo nne veer and Pethidine for its potency as an analgesic aeriat It is an agonist at k-receptor and antagonist at }!- mame receptor i Its potency is much less than that of Nalorphine E . or Naloxone taxiv Its analgesic activity is partly mediated through p-receptors. It is useful Y in chronic neuropathic pain. Toxicity includes dependence, seizures and anaphylactoid reactions. eo It acts as a competitive antagonist to all types of opioid receptors and is a _ pure antagonist. In normal individuals, it does not produce any significant actions. | But in opium addicts, when given IV, it promptly antagonizes all the actions of morphine including respiratory depression and sedation and precipitates withdrawal syndrome. It also blocks the action of endogenous opioid peptides— endorphins, enkephalins and dynorphins. Given orally it undergoes high first pass metabolism and is metabolized | by the liver. Hence, it is given intravenously. Duration of action is 1-2 hours . It is metabolized by glucuronide conjugation. DOSE: 0.4 mg IV. NARCOTAN 0.4 mg/ml and 0.04 mg/ml Ampoules. > Uses * Naloxone is the drug of choice for Morphine overdosage. It is also used to Reverse neonatal asphyxia due to opioids used in labour. Diagnosis of opioid dependence. Naloxone has been found to be beneficial in Reversing hypotension.> Naltrexone © tis another pure opioid antagonist. It is More potent than naloxone. Orally effective. 4 Hasa longer duration of action of 1-2 days. Naltrexone is well absorbed when given orally but undergoes first pass metabolism. DOSE: 50-100 mg/day. NALTIMA 50 mg tal > Uses © Naltrexone is used for ‘opioid blockade’ therapy in post- addicts is found to be effective. Alcohol craving is also reduced by naltrexone and is used to prevent relapse of heavy drinking. ° Nalmefeneis a derivative of naltrexone. * Itis orally effective (but only an IV preparationis — available) and longer acting. * It has better bioavailability and is not hepatotoxic. It is used in opioid overdosage. * It blocks the p receptors in the gut and does not _ significantly penetrate CNS. It is used in the treatment of postoperative ileus following bowel resection.“* Drug addiction / és “* Drug tolerance ** Drug dependanceDRUG ADDICTION , DRUG ABL TOLERANCE & DEPENDANCE TremACeClCaa Cedi) Drug addiction has following features: The detrimental effects of drugs not only harm the individual but the society as well. There is always an intense craving to procure the drug by any means. There is development of tolerance and hence a need to increase the dose to get the same rewarding experience There are life-threatening or alarming withdrawal effects after cessation of the drug and hence there is a physical need to continue with use of the drug for the fear of abstinence syndrome. Q Drug Abuse * Drug abuse has following features: Recurrent substance use results in failure to fulfil his/her major obligations at work, school or home, e.g. poor performance at work, expulsion from school. Recurrent substance use even in situations where it should not be used e.g. during driving, operating a machine or even operating on the patient. Recurrent substance use punitive action, e.g. punishment for disorderly conduct. Recurrent substance use despite having interpersonal or family problems, eg. arguments or physical fight with spouse about consequences of abuse.eR rem oes ; * Tolerance develops if, after repeated administration, a given dose of a| drug produces a decreased effect than expected. | * Larger doses are needed to obtain the same effects with previous dose. * It is classified as pharmacokinetic (eg. Barbiturates) or | pharmacodynamic (e.g. opioids). | © There is another related Term: CROSS-TOLERANCE. When tolerance to primary drug develops, the individual also exhibits cross-tolerance to related classes of drugs, e.g. a patient with tolerance to morphine may show cross-tolerance to heroin. ong) tolerate \ mi \ © Dependence is a physiological state of neuroadaptation resulting from repeated administration of the drug, necessitating its continued use to prevent the appearance of distressing withdrawal syndrome which is manifested as opposite to the pharmacological effects of drugs. * Withdrawal or abstinence syndrome is a term used for the adverse (sometimes life-threatening) psychologic or physiologic reactions to an abrupt discontinuation of a dependence-producing drug. © The drugs of abuse which can endanger dependence are as follows: Drugs/agents having only mild psychological dependence. There 1. | are low withdrawal symptoms and no physical dependence, e.g. coffee, tea. Drugs/agents with moderate to severe psychological dependence. There are low withdrawal symptoms but slight physical dependence, e.g. Marijuana, Hashish, LSD, Amphetamine, Cocaine, Nicotine. Drugs/agents having moderate to severe psychological 3. |dependence with mild physical dependence, eg. | Benzodiazepines, Alcohol (moderate use). |Drugs/agents having severe psychological and physical | dependence, e.g. Opioids Barbiturates and Alcohol (heavy use). |