Drugs Acting on CNS & Antipsychotic Agents PDF

1 4. Antipsychotic Agents 9/1/2024  Objectives 2 At the end of the session you will able to understand  Nature of Psychosis & Schizophrenia  Different Hypothesis of schizophrenia  Antipsychotics drugs classification  Relate between p...

1 4. Antipsychotic Agents 9/1/2024  Objectives 2 At the end of the session you will able to understand  Nature of Psychosis & Schizophrenia  Different Hypothesis of schizophrenia  Antipsychotics drugs classification  Relate between pharmacological actions & adverse effects of antipsychotic drugs 9/1/2024  Psychosis 3  refers to a loss of contact with reality, a variety of mental disorders, disruptions in their thoughts and perceptions  characterized by one or more of the following symptoms:  Diminished and distorted capacity to process information and draw logical conclusions  Hallucinations  Delusions  Incoherence or marked loosening of associations  Catatonic or disorganized behavior  Aggression or violence 9/1/2024  Cont…. 4  Hallucinations: a person perceives to be real despite the lack of stimulus to cause them. may cause a person to see, hear, feel, taste, or smell something that is not there. auditory hallucinations appear to be the most common  Delusions: False beliefs that a person holds despite a lack of evidence or proof.  Disorganized thought: Having thoughts that are not logical, unrelated, or loosely connected.  A person’s thought process may drift away from the topic. Their speech may make no sense to others. 9/1/2024  Cont…. 5  Catatonia: The person may become unresponsive or oppose stimuli (negativism) or present with unintentional movements or activities that lack purpose (catatonic excitement).  Disorganized behavior: Unpredictable or inappropriate emotional responses that are not in line with the situation.  Negative symptoms: A decline in emotions, words, movements, or motivation (anhedonia). 9/1/2024 6 9/1/2024  Antipsychotic (Neuroleptic) Agents 7  Antipsychotic drugs are able to reduce psychotic symptoms in a wide variety of conditions, including: schizophrenia bipolar disorder psychotic depression drug-induced psychoses.  They also improve mood and reduce anxiety and sleep disturbances,  but they are not the treatment of choice when these symptoms are the primary disturbance in non- psychotic patients. 9/1/2024  Schizophrenia 8  It is a thought disorder characterized by divorcement from reality in mind of patient.  it may involve hallucinations, delusions , intense suspicion, felling of persecution or control by external forces (paranoia).  Schizophrenic symptoms have been divided into two major categories  Positive symptoms :1- hallucinations2- Delusions 3- paranoia  Negative symptoms : 1- Social withdrawal 2- Anhedonia (absence of pleasure) 3-Emotional blunting 9/1/2024  Schizophrenia - symptoms 9 Positive Symptoms Negative Symptoms Hallucinations Blunted emotions Delusions (bizarre, Anhedonia persecutory) Lack of feeling Disorganized Thought Perception disturbances Inappropriate emotions FUNCTION Mood Symptoms Cognition Loss of motivation New Learning Social withdrawal Memory Insight Demoralization Suicide  Cont…. 10 Positive symptoms : Commonly occur in acute phase of the illness Usually respond to antipsychotic drug therapy Negative symptoms: apathy, social withdrawal & lack of drive Occur in the chronic phase of illness Tend to be resistant to dug therapy 9/1/2024  Schizophrenia 11  Etiology Although there is strong evidence that schizophrenia has a biologic basis, the exact etiology is unknown. Genetic, perinatal, neurodevelopmental, and neuroanatomic factors may all be involved. Possible primary defects include excessive activation of CNS receptors for dopamine, and insufficient activation of CNS receptors for glutamate. 9/1/2024  Hypothesis of schizophrenia 12  dopamine hypothesis of schizophrenia  suggested that excessive dopaminergic activity underlies schizophrenia: 1. Drugs that increase dopaminergic activity, such as levodopa and amphetamines either:  Aggravate existing schizophrenia or  Induce a psychosis  Amphetamines and cocaine can cause a psychosis that resembles the positive symptoms of schizophrenia.  Low doses of amphetamine can induce a psychotic reaction in schizophrenics in remission. 9/1/2024  Cont,,,, 13  Some postmortem studies have reported increases in dopamine receptor density (in particular D2-like) :  In brains of schizophrenics who were not treated with antipsychotic drugs  Traditional antipsychotic drugs strongly block D2- in the CNS. Its clinical efficacy is highly correlated with the potency of individual agents to bind to this receptor 9/1/2024  Cont…… 14  Clinical response to antipsychotic drug treatment is correlated with a decrease in homovanillic acid  Homovanillic acid a primary dopamine metabolite, in cerebrospinal fluid (CSF), plasma, and urine  DA hypothesis is no longer considered adequate to explain all aspects of schizophrenia, especially the cognitive impairment 9/1/2024  glutamate hypothesis of schizophrenia 15  suggests the problem relates partially to deficient activity at glutamate receptors- Especially in the prefrontal cortex.  Psychotomimetic effects of phencyclidine (PCP), and ketamine (N-methyl D-aspartate , NMDA -blockers)  mimics negative, positive and disorganized symptoms  The Glu hypofunction has a role in schizophrenia  Possible beneficial effects seen with cycloserine, glutamate receptor agonist. 9/1/2024  Cont….. 16  AMPA receptor potentiators administered on medicated patients improve performance in attention, memory & distractibility tests  The effects of clozapine on negative symptoms and cognition may be through activation of the glycine modulatory site on the NMDA receptor. 9/1/2024  Serotonin hypothesis of schizophrenia 17  suggests that results from excess activity of 5-HT.  5-HT2A-receptor modulate the release of DA in the cortex, limbic region, and striatum  M-CPP (m-chlorophenylpiperazine) selective 5HT receptor agonist worsens psychotic symptoms  Hallucinogens such as LSD (lysergic acid diethylamide) & mescaline are serotonin (5-HT) agonists.  5-HT2A-receptor and possibly 5-HT2C stimulation was the basis for the hallucinatory effects of these agents. 9/1/2024  Cont…. 18  So pre-treatment with ritanserin (5HT antagonist) attenuates psychotic symptoms  5-HT2A-receptor blockers relieve the condition (atypical antipsychotics -clozapine & quetiapine). 9/1/2024  Classification of Antipsychotic 19 Typical, 1st gen, conventional, traditional neuroleptics,  discovered first, non selective, many side effects, rarely used nowadays.  affect D2 mainly- treat the +ve symptoms. Atypical  more selective, less side effects, 1stline treatment for schizophrenia.  Affect both DA & 5-HT receptors- treat +ve & -ve symptmos. 9/1/2024  Neuroleptic drugs 20 9/1/2024 Classification of Antipsychotic Drugs  Can be classified by potency, generation or chemical structure Classification by potency:  Conventional antipsychotic agents can be classified as low potency, medium potency, or high potency 9/1/2024 21 Antipsychotic Drugs: Relative Potency & Incidence of Side Effects oral dose Extrapyramid Sedation hypoten Anticholiner Drug (mg) al effects(EPS sion gic effects 22 Conventional Low potency Chlorpromazine 100 Moderate High High Moderate Thioridazine 100 Low High High High Moderate potency Triflupromazine 25 Moderate High Moderate Moderate Perphenazine 10 Moderate Moderate Low Low Loxapine 10 Moderate Moderate Low Low High potency Haloperidol 2 High Low Low Low Fluphenazine 2 High Low Low Low Atypical Agents Clozapine 50 Very low High Moderate High Risperidone 4 Very low Low Low None quetiapine 9/1/2024 Based on Chemical Structure 1. Phenothiazine Derivatives 1.1. With an alipahtic side chain – Chlorpromazine (CPZ), triflupromaizne 1.2. With a piperidine ring side chain- Thioridazine, mesoridazine, piperacetazine 1.3. With a piperazine ring side chain Fluphenazine, trifluoperazine 23 9/1/2024  Based on Chemical Structure… 2. Butyrophenones: Haloperidole, trifluperidole,penfluperidole 3. Thioxanthenes: Chlorprothixene, flupenthixol 4. Heterocyclics –Pimozide, Loxapine, Levosulpiride 5. Atypical neuroleptics: Clozapine, Olanzapine, Quetiapine,Risperidone, Iloperidone. Paliperidone, Ziprasidone, Lurasidone, Aripiprazole 6. RisperidoneMiscellaneous: Reserpine 24 9/1/2024 Broad category of antipschotic drugs 1st generation ('typical') & 2nd generation ('atypical') No clear distinction b/n them; however, grouping is based on Receptor profile Incidence of extrapyramidal side effects (less in atypical group) Efficacy in 'treatment-resistant' patients Efficacy against negative symptoms 25 9/1/2024  a) Typical antipsychotics Modeled on D2 antagonism Tend to produce Extrapyramidal side effects(EPSE): Parkinsonism – tremors, rigidity, slowness of movement, temporary paralysis Tardive dyskinesia –iatrogenic movement disorders caused by the antagonism of dopamine receptors involuntary movements of the mouth, lips,& tongue,Chewing, grimacing, etc Dystonia – involuntary muscle contractions Akathisia – inability to resist urge to move 9/1/2024 26 b) Atypical antipsychotics Atypicals do not induce EPSE Block D2 receptors and 5-HT receptors (↓EPSE) Less EPSE, less prolactin effects As opposed to typicals, these are more loosely bound to D2 receptors Easier dissociation higher occupation of D2 receptors by drug, higher incidence of EPSE 9/1/2024 27  Chemical classification 28  major chemical subgroups of older antipsychotic drugs are  phenothiazines (eg, chlorpromazine, thioridazine, fluphenazine)  thioxanthenes (eg, thiorhixene)  butyrophenones (eg, haloperidol).  Newer "second-generation" drugs have varied heterocyclic structure  Clozapine  Quetiapine  Loxapine  Ziprasidone and  Olanzapine  Aripiprazole  Risperidone 9/1/2024  NEUROLEPTICS 29  several diverse, heterocyclic structures with markedly different potencies.  The tricyclic phenothiazine derivative, chlorpromazine(CPZ) was the first neuroleptic drug used to treat schizophrenia.  Antipsychotic drugs developed subsequently, such as haloperidol  (100-fold as potent as chlorpromazine but have an increased ability to induce parkinson-like and other EPSE  Furthermore, these more potent traditional drugs are no more effective than chlorpromazine 9/1/2024  NEUROLEPTICS… 30  Variable absorption after PO administration  Most are unaffected by food, except  Ziprasidone and Paliperidone, the absorption of which increased with food.  Agents pass into brain, have large volume of distribution, bind well to plasma proteins  Metabolized by liver enzymes and some metabolites are active. 9/1/2024  NEUROLEPTICS… 31 Mechanism of actions 1. DA receptor blocking in the brain:  D1 and D5 receptors activate adenylyl cyclase, often exciting neurons,  D2, D3 and D4 receptors inhibit adenylyl cyclase, or mediate membrane K+ channel opening leading to neuronal hyperpolarization Clozapine= higher affinity for the D4, lower affinity for the D2 receptor ( Cause low EPS) Chlorpromazine and haloperidol 2. Serotonin (5-HT) receptor blocking in the brain:  particularly 5-HT2A receptors 9/1/2024 32 9/1/2024  Antipsychotics & receptors 33 9/1/2024  NEUROLEPTICS… 34 Actions  reflect a blockade at dopamine and/or serotonin receptors.  many of these agents also block cholinergic, adrenergic, and histaminergic receptors  undesirable side effects of these agents 1. Antipsychotic actions  All Neuroleptic agents can reduce hallucinations and delusions associated with schizophrenia (called Positive symptoms)  Antipsychotic effects may take several days to weeks to occur 9/1/2024  Actions… 35  Negative symptoms are not as responsive to therapy o Many atypical agents, such as clozapine, ameliorate the negative symptoms to some extent. 2. Extrapyramidal effects  Dystonias, parkinson-like symptoms, akathisia, and tardive dyskinesia occur with chronic treatment.  due to blocking dopamine receptors at areas other than mesolimbic area (extrapyramidal, nigrostriatal pathways  Atypical narcoleptics exhibit a lower incidence of these symptoms. They are effective in refractory cases of schizophrenia. 9/1/2024  Actions… 36 3. Antiemetic effects  except Aripiprazole and Thioridazine, most have antiemetic effects mediated by blocking D2-dopaminergic receptors of the CTZ of the medulla  atypical antipsychotic drugs are not used as antiemetics 4. Antimuscarinic effects  Thioridazine, chlorpromazine, clozapine, and olanzapine produce anticholinergic effects  blurred vision, dry mouth (except clozapine that increades salivation), confusion, constipation and urinary retension. 5. Hypersensitivity reactions - jaundice, photosensetivity (chlorpromazine), agranulocytosis (clozapine) 9/1/2024  Cont…. 37 Sensitivity to sun Chlorpromazine collect in skin -sunlight causes pigmentation changes – grayish- purple (look bruised) -in eye, brown cornea and pigmented lens (possibly permanent impairment) Agranulocytosis – 1.6% (with clozapine reduced WBC count lowered resistance to infection can be fatal So weekly blood count is needed 9/1/2024  Cont…..  Metabolic effect: - Changes in eating behavior and weight 38 gain. Mechanism: blockage of dopamine receptors in the medullary periventricular pathway.  40% - weight gain now attributed to ratio of binding to D2 and 5-HT2 & H1 receptors  Sexual dysfunction result from NE and SE blockade erectile dysfunction in 23-54% of men retrograde ejaculation. loss of libido  Seizures  Other effects: orthostatic hypotension & light-headedness (blockage of adrenergic receptors) 9/1/2024  Cont….. 39  Temperature regulation: they May cause lowering of body temp. due to heat loss as a result of vasodilation due to alpha1-blocking or central effect  ECG changes: prolongation of QT interval, abnormal configuration ST segment and T wave. Quinidine-like action  Sedation due to Antihistaminic effect( H1- blockage) 9/1/2024 40 Mechanism: prevent dopamine from inhibiting prolactin release from pituitary gland and that will lead to hyperprolactinemia. 9/1/2024 41 9/1/2024 42 9/1/2024  Limitations Of Conventional Antipsychotics 43  Approximately one-third of patients with schizophrenia fail to respond  Limited efficacy against Negative symptoms Affective symptoms Cognitive deficits  High proportion of patients relapse  Side effects and compliance issues 9/1/2024 44 9/1/2024 45 9/1/2024  Clozapine- 46 Pharmacokinetics Incompletely absorbed. Highly lipid soluble, Highly bound to plasma proteins  Undergo extensive first-pass hepatic metabolism. Excretion by the kidney. 9/1/2024  Clozapine- 47 Theraputic use Psychatric  Schizophrenia (primary indication)  Acute mania  Manic-depressive illness (bipolar affective disorder) Non-psychiatric  Nausea and vomiting.  Pruritus  Preoperative sedation. (Rare use 9/1/2024  Cont…. 48 9/1/2024  Therapeutic uses 49  Treatment of schizophrenia  Prevention of severe nausea and vomiting  used as tranquilizers to manage agitated and disruptive behavior secondary to other disorders. 9/1/2024  Treatment of Mania and Bipolar 50 Disorder  Manic episodes are characterized by heightened mood (euphoria), hyperactivity, excessive enthusiasm, and flight of ideas  Mania produces excessive sociability and talkativeness, excessive self-confidence, grandiose ideas.  Bipolar disorder also known as manic-depressive illness  It is a cyclic disorder characterized by recurrent fluctuations in mood.  Alternating episodes of mania and depression separated by periods in which mood is normal.  Mainstay of therapy is Lithium and other mood stabilizing drugs 9/1/2024  Mania and Bipolar Disorder 51  Carbamazepine, valproic acid, Lamotrigine  t/t of acute mania and for prevention of its recurrence  Gabapentin, oxcarbazepine, and topiramate  used to treat bipolar disorder  Aripiprazole, chlorpromazine, olanzapine, quetiapine, risperidone, and ziprasidone  treatment of manic phase of bipolar disorder.  Olanzapine + fluoxetine (combination) and Quetiapine are approved for the treatment of bipolar depression.  Benzodiazepines are also frequently used as adjunctive treatments for the acute stabilization of patients with mania 9/1/2024  Basic Pharmacology of Lithium 52  Lithium is a small monovalent cation 9/1/2024  Lithium… 53  It is believed to attenuate signaling via receptors coupled to the phosphatidylinositol bisphosphate (PIP2) second-messenger system.  Lithium is given orally, and the ion is excreted by the kidney.  Lithium salts can be toxic.  Their safety factor & therapeutic index are extremely low 9/1/2024  Lithium… 54  Common adverse effects may include  Headache  Dry mouth  Polydipsia  GIl distress (given with food),  Dizziness  Dermatologic reactions and  Sedation. 9/1/2024 55 5. Antidepressants 9/1/2024  Depression 56  Major depressive disorder is a depression of mood without any obvious medical or situational causes, manifested by an inability to cope with ordinary events or experience pleasure.  THE AMINE HYPOTHESIS OF MOOD  postulatesthat monoamines (N E and 5-HT), are neurotransmitters in pathways that function in the expression of mood. functional  in the activity of such amines  depression a functional  of activity result s in mood elevation 9/1/2024  DRUG CLASSIFICATION 57 9/1/2024  Mechanism of Antidepressant Drugs 58  Most cause potentiation of the neurotransmitter actions of NE, 5-HT, or both.  The only exception is bupropion, which has an unknown mechanism of action. TCAs  inhibit the reuptake mechanisms (transporters) of both NE and 5-HT in the brain. This presumably results in potentiation of their neurotransmitter actions at postsynaptic receptors. SSRIs  highly selective action on 5-HT transporters MAOIs   brain monoamine levels by interfering with their metabolism in the nerve endings resulting in an increase in the vesicular stores of NE and 5-HT. 9/1/2024  MOA… 59 9/1/2024  A. SSRIs 60  fluoxetine (the prototypic drug), citalopram, escitalopram, fluvoxamine, paroxetine, sertraline P’kinetics  well absorbed after oral administration  Peak levels 2 to 8 hours on average.  Food has little effect on absorption (except with sertraline, for which food increases its absorption).  Only sertraline undergoes significant first-pass metab.  All of these agents are well distributed  Metabolism by P450-dependent enzymes and glucuronide or sulfate conjugation occur extensively 9/1/2024   Fluoxetine differs from the other members of the class in two respects. 61  longer half-life (once-weekly dosing by sustained-release preparation )  the metabolite is as potent as the parent compound. 9/1/2024  SSRIs… 62 A. Actions:  block the reuptake of serotonin, leading to increased concentrations of the NT in the synaptic cleft and, ultimately, to greater postsynaptic neuronal activity.  take at least 2 weeks to produce significant improvement in mood, and maximum benefit may require up to 12 weeks or more 9/1/2024  SSRIs… 63 B. Therapeutic uses:  Depression  Psychotic disorder (obsessive-compulsive disorder, the only indication of fluvoxamine)  panic disorder,  generalized anxiety disorder,  posttraumatic stress disorder,  social phobias,  premenstrual dysphoric disorder, and  bulimia nervosa (only fluoxetine) 9/1/2024  SSRIs… 64 C. ADR  fewer and less severe adverse effects compared with MAOIs & TCAs  Sleep disturbances (fluoxetine or sertraline) Except,Paroxetine and fluvoxamine are generally more sedating  Sexual dysfunction, Loss of libido  Discontinuation syndrome in abrupt withdrawal 9/1/2024  B. Serotonin-Norepinephrine 65 Reuptake Inhibitors (SNRIs)  Venlafaxine, duloxetine  These agents, termed selective serotonin-norepinephrine reuptake inhibitors (SNRIs)  effective in treating depression in patients in whom SSRIs are ineffective.  effective in relieving physical symptoms of neuropathic pain, such as diabetic peripheral neuropathy. 9/1/2024  C. Tricyclic Antidepressants (TCAs) 66 Pharmacokinetics  well absorbed upon oral administration  B/c of lipophilic nature  Widely distributed and penetrate CNS  Variable half-lives e.g 4-17 hrs for imipramine  As a result of their variable 1st pass metabolism in the liver Inconsistent bioavalailability  TCAs are excreted as inactive metabolites via the kidney. 9/1/2024  TCAs… 67  block norepinephrine and serotonin reuptake into the neuron  thus, if discovered today, may be referred to as SNRIs except for their differences in adverse effects relative to this newer class of antidepressants.  Teritiary amines: Imipramine, amitriptyline, clomipramine, doxepin & trimipramine  Secondary amines: desipramine, nortriptyline  MOA:  Inhibition of NT reuptake  Blockage of receptors (5-HT, H, M)- responsible for many of unwanted effects of TCAs 9/1/2024  TCAs… 68 Pharmacological effects:  elevate mood, improve mental alertness, increase physical activity Therapeutic uses:  Effective in treating moderate to severe major depression  Imipramine - used to control bed-wetting in children (older than 6 years) (contraction of the internal sphincter of the bladder). 9/1/2024  TCAs… 69  ADR  Dry mouth, constipation, urinary retention, blurred vision, tachycardia, arrhythmias 9/1/2024 D. Monoamine Oxidase Inhibitors (MAOIs) 70  Monoamine oxidase (MAO)  is a mitochondrial enzyme found in nerve and other tissues, such as the gut and liver.  oxidatively deaminate and inactivate any excess neurotransmitter molecules (NE, DA, and 5-HT)  MAO inhibitors may irreversibly or reversibly inactivate the enzyme MAO  permitting neurotransmitter molecules to escape degradation  Therefore, NT accumulate within the presynaptic neuron and leak into the synaptic space.  cause activation of NE and 5-HT receptors  indirect antidepressant action 9/1/2024  MAOIs… 71 9/1/2024  MOIs… 72 P’KINETICS  MAOIs are well absorbed from the gastrointestinal tract. st  tend to have extensive 1 -pass effects that substantially decrease bioavailability  selegiline is available in transdermal and sublingual forms that bypass both gut and liver Class, BioA. (%) Plasma Active Metabolite Volume of Protein Drug t1/2 (hours) t1/2 (hours) Distribution (L/kg) Binding (%) MAOIs ND 11 ND ND ND Phenelzin Selegiline 4 8–10 9–11 8–10 99 9/1/2024  MAOIs… 73 ACTIONS:  Antidepressant, After several weeks of delays  Amphetamine-like stimulant effect Agitation or Insomnia  Selegiline and tranylcypromine THERAPUETIC USES:  t/t of depression unresponsive to other antidepressants.  Patients with low psychomotor activity  t/t of phobic states  now rarely used in clinical practice b/c of toxicity and potentially lethal food and drug interactions.  last-line agents 9/1/2024  MAOIs… 74 ADVERSE EFFECTS:  Severe and unpredictable side effects due to drug-food and drug-drug interactions  Tyramine in certain foods (red wines, cheeses and meats) Normally they are inactivated by intestinal MAO MAOIs inhibit the degradation of tyramine obtained from diet  causes  release of stored chatecholimens from nerve terminals resulting in headache, stiff neck, tachycardia, nausea, hypertension, cardiac arrhythmias, stroke Phentolamineor prazosin are helpful in the management of tyramine-induced hypertension. 9/1/2024  MAOIs… 75  Other possible side effects include:  drowsiness, orthostatic hypotension, blurred vision, dry mouth, dysuria, and constipation  MAOIs should not be coadministered with SSRIs  Life-threateiningserotonin syndrome  Both require washout periods (at least 2 Wk before the other with the exception of fluoxetine, which should be discontinued 6 Wk before MAOIs administration)  MAOIs and bupropion can produce seizures. 9/1/2024  E. Tetracyclic and Unicyclic Antidepressants (Atypical Antidepressants) 76  Bupropion, Mirtazapine, Amoxapine, Nefazodone, Trazodone and Maprotiline  Not more efficacious than the TCAs or SSRIs, but their side effect profiles are different. BUPROPION  Unique in that it  the craving and the withdrawal symptoms for nicotine in tobacco users trying to quit smoking  weak dopamine and norepinephrine reuptake inhibitor 9/1/2024 77 types of anesthesia A. General anesthesia B. Local anesthesia 9/1/2024 6. General Anesthetics 78 9/1/2024  General Anesthetics 79  are drugs which produce reversible loss of all sensation and consciousness.  The features of general anesthesia are:  Amnesia / unconsciousness  Analgesia Loss of all sensation, especially pain.  Muscle relaxation & Immobility  Loss of autonomic reflexes  Anxiolysis  These modalities are achieved by using combination of drug.  No single drug is capable of achieving these effects rapidly & safely. 9/1/2024  Pre-anesthetic medication 80 It is the use of drugs prior to anesthesia to make it more safe and pleasant. ★ Calm the patient & relieve pain. ★ Protect against undesirable effects of the subsequently administered anesthetics or the surgical procedure. ★ Facilitate smooth induction of anesthesia. ★ Lowered the dose of anesthetic required.  To relieve anxiety – benzodiazepines.  To prevent allergic reactions – antihistaminics.  To prevent nausea and vomiting – antiemetics.  To provide analgesia – opioids.  To prevent bradycardia and secretion – atropine. 9/1/2024  Pre-anesthetic medication … Drug Used to Example 81 Opiates Induce analgesia morphine  Anticholinergics  Prevent (N&V) secretion of fluids into the hyoscine respiratory tract  Protect the heart against vagal stimulation (bradycardia) Sedatives & Relieve anxiety diazepam anxiolytics Antihistamines Allergic reactions diphenhydramine Antiemetics Post surgical N&V. metoclopramide & prochlorperazine Thiopental Smooth induction of Anesthesia Neuromuscular Facilitate intubation & suppress skeletal succinylcholine, blockers muscle tone. vecuronium & 9/1/2024 atracurium  Classification of Anesthetics 82 9/1/2024  Induction, Maintenance & Recovery Induction is the period of time from administration of anaesthetic to the development of effective surgical anaesthesia in the patient. Maintenance provides a sustained surgical anaesthesia. Recovery is the time from discontinuation of administration of anaesthesia until consciousness and protective physiologic reflexes are regained. Minimum Alveolar Concentration (MAC)  Lowest concentration of the inhalational anesthetic in alveoli needed to produce immobility in response to painful stimulus. 85  Balanced anesthesia is achieved by a combination of I.V and inhaled anesthesia , Pre-anaesthetic medications and also sk. muscle relaxants.  Thus it will increase the beneficial effects & decrease the adverse effects of general anesthetics which will fulfill the patient needs. 9/1/2024  Stages of Anesthesia  Stage I – Analgesia 86  lasts from administration to loss of consciousness.  initially analgesia without amnesia. Later, both analgesia and amnesia  Reflex respiration is normal, The patient is conscious and conversational  Use is limited to minor operation because it is difficult to maintain  Stage II – Excitement  lasts from loss of consciousness to beginning of irregular respiration Delirious, amnesic, excitement (laughing & shouting), Respiration is irregular ↑ HR & B.P, mydriasis (rolling eye boll movement) incontinence of urine & faces-vomitting, irregular breathing exaggerated reflexes  Duration & intensity of this stage should be reduced  A rapid acting agent, propofol, is given IV before inhalation anaesthesia is admin. N.B: The excitement stage is absent with I.V. anesthesia due to rapid action of drugs. 9/1/2024  Cont….  Stage III – Surgical anesthesia  There is gradual loss of muscle tone and reflexes as the 87 CNS is further depressed.  Regular respiration and relaxation of skeletal muscles with eventual loss of spontaneous movement occur in this stage.  This is the ideal stage of anesthesia for surgery. Continuous careful monitoring is required to prevent undesired progression into Stage IV. Stage IV – Medullary paralysis  severe depression of the CNS, including the vasomotor center in the medulla the respiratory center in the brain stem.  Without circulatory and respiratory support, death rapidly ensues. 9/1/2024  An ideal anesthetic 88  Have anxiolytic, sedative & analgesic activity  Does not bring about emesis  Counter act vagal activity  Cause muscle relaxation  Possess rapid induction & recovery  chemically stable, non-flammable, non-toxic & easy to administer  Be inexpensive.  No currently available anesthetic agent possesses all these properties at tolerable doses,  hencethe need for pre-anesthetic medication arises to produce a balanced anesthesia. 9/1/2024  Mechanism of action of GA 89 MOA:  Disruption of the function of ionic channels  Disruption of lipids associated with ionic channels Enhancement of GABA A & glycine receptors leading to greater entrance of chloride ion , hyperpolarization , thus decrease neuronal excitability.  MoA GA……  Inhalational anaesthetics, barbiturates, benzodiazepines & propofol potentiate the GABA to open Cl channels.  Action of glycine in the spinal cord and medulla is augmented by barbiturates, propofol & many inhalational anaesthetics.  Ketamine selectively inhibits the excitatory NMDA type of glutamate receptor.  Certain fluorinated anaesthetics and barbiturates inhibit the neuronal cation channel gated by nicotinic cholinergic receptor  P’kinetics of inhalational Anesthetics 91  Anesthesia is produced when specific concentration is reached at the site of action.  This depends on PK properties of the agent  Pharmacokinetics of Inhalation anesthetics affect: - Rate of induction - Depth of anesthesia and Recovery  The depth of anesthesia depends on the potency of the agent & it's partial pressure in the brain. 9/1/2024  Cont… 92   MAC is an index of potency  Potency is inversely proportional to MAC value of anesthetic agents.  An anesthetic with low MAC is said to be potent  Factors controlling induction & recovery : 1-The anesthetic concentration in the inspired air---- Direct 2- Blood solubility : Blood gas partition coefficient--- Inverse relation (means it need more time to reach CNS to produce an effect.) 3- Rate and depth of ventilation------ Direct 93 9/1/2024  Factors affecting the partial pressure of an anesthetic attained in brain 94 1. Partial pressure of anesthetic  Pa.P the more ansethetic transferred to the blood 2. Pulmonary ventilation  Hyper ventilation will bring more anesthetic per minute & respiratory depression will have the opposite effect. 3. Solubility of the anesthetic in the blood  Determines induction and recovery  GA must first dissolve before its partial pressure is raised  Drugs with low blood solubility (e.g. N2o, desflurane) induce quickly. 4. Solubility of anesthetic in tissue  Determines its concentration in tissues 5. Cerebral blood flow  increase cerebral blood flow increase induction 9/1/2024  1. Inhalational Anesthetics 95 2 classes of inhalational anesthetics a) Volatile liquids b) Anesthetics gases 9/1/2024 Classification of inhalational anesthetics: A. Volatile liquids: 96  Halogenated volatile anesthetics: e.g. Halothane, enflurane, isoflurane, Desflurane, Sevoflurane, methoxyflurane, trichlorethyline, ethyl chloride  Ethers: Diethyl ether and divinylether (not used nowadays due to their disadvantages). B. Anaesthetic gases:  Nitrous oxide, cyclopropane and ethylene 9/1/2024  MOA of inhalational Anesthetics 97  interactions of the inhaled anesthetics with proteins comprising ion channels:  increase the sensitivity of the GABAA receptors to GABA causes a prolongation of the inhibitory Cl- ion current after a pulse of GABA release. Postsynaptic neuronal excitability is thus diminished  Other receptors are also affected  Glycine receptor activation  Blockage of nicotinic receptors 9/1/2024  Pharmacological actions of inhalation anesthetics 98 System  Pharmacological action CNS - ↓ metabolic rate. - ↑ ICP (due to cerebral vasodilatation)- All inhalation anesthetics contraidicated in head injuries - Dose -dependent EEG changes (Enflurane ,CI in epilepsy) CVs Cardiac depression - Hypotension, Bradycardia Except (Isoflurane ,Desflurane & Sevoflurane ). - Myocardial depression (Halothane, Enflurane). -Sensitize heart to catecholamines (Halothane highly) Halothane contraindicated in pheochromochytoma Respiratory - All respiratory depressants -Airway irritation (Desflurane-Enflurane due to pungent odor) Liver - Decrease hepatic flow - Hepatotoxicity (Only halothane) only in adults  I. Volatile liquids 99 A. Halothane - Prototype for newer inhalation anesthetics  It is a clear colorless, volatile liquid with Pleasant odor (chloroform like odour), non inflammable, non irritating and non explosive  Anesthetic of choice.  It is potent anaesthetic, with Slow induction and recovery but poor analgesic, thus, usually coadminstered with NO, opioids or local anesthetics. PK  Metabolized to toxic hydrocarbons (trifluoroethanol) and bromide ion (responsible for toxic rxn) fever,followed by anorexia, nausea, and vomiting, and patients may exhibit signs of hepatitis. (to avoid this, halothane anesthesia should not be repeated at less than 2- 3wk) 9/1/2024  Pharmacological actions: CNS  General anesthesia with rapid induction and recovery.   cerebral blood flow. CSF pressure.  Relaxation of skeletal muscles(but Weak).  Mild depression of respiratory centre C.V.S  Bradycardia (due to vagal stimulation and direct depression of SA node).  Inhibition of cardiac contractility (due to  of IC Calcium).  Hypotension (due to vasodilatation, cardiac depression, depression of VMC and ganglionic blocking action). 101 Halothane…. GIT: Inhibition of tone and motility. Uterus: Inhibition of uterine contractions. Respiratory System: Bronchodilation and respiratory depression. Skeletal Muscles: Relaxation (but inadequate for abdominal operations). Therapeutic uses:  Used in obstetrics to induce uterine relaxation  It dilates bronchi so preferred in asthma patient.  For induction 2-4% & for maintenance 0.5-1% is delivered by using special vapouriser.  In children preferred for inhalation induction ( unlike adults, not hepatotoxic) 9/1/2024  Halothane … Advantages of halothane: 102  pleasant smell, there fore is accepted by many patients, fro child  Very potent anesthetic (MAC= 0.75%), Non-irritant  Bloodless field for plastic surgery because of the fall in blood pressure.   Solubility in blood is intermediate reasonable induction & recovery.  No post operative nausea & vomiting  No bronchospasm, no coughing, hence suitable for tracheal intubation. Disadvantages of halothane:  Little analgesic activity  Little muscle relaxation  Fall in blood pressure because of myocardial depression 9/1/2024  Expensive  Halothane…. 103 Adverse effects:  Hepatotoxicity, Hangover, Shivering  CVS  Bradycardia (vagomimetic effect)  cardiac arrhythmias- Sensitizes heart to action of catecholamines  concentration-dependent hypotension (better to give direct acting vasoconistrictor, such as phenylepherine)  Malignant hyperthermia Contraindication:  Jaundice, Raised CSF pressure, Pheochromocytoma 9/1/2024  B. Enflurane 104  A halogenated compound  This gas is less potent than halothane, but it produces rapid induction and recovery. Have pungent odor -  2-8% is metabolized to F Excreted by Kidney, lead to nephrotoxicity C/I in kidney failure  It differs from halothane in that  fewer arrhythmias , Better analgesic properties  less sensitization of the heart to catecholamines  Better muscle relaxation, due to a more potent ‘curare-like’ effect,  Disadvantages:  CNS stimulation( not used in patients with seizure disorder)  Pungent odor not suitable for children  C. Isoflurane  A recently introduced isomer of enflurane, more potent, more volatile & less soluble in blood 105  Advantage  Undergoes little metabolism little fluoride ion produced.  does not induce cardiac arrhythmias and does not sensitize the heart to the action of catecholamines.  beneficial in patients with ischemic heart disease(IHD)  Muscle relaxation  No myocardial depression,  No hepatotoxicity, No nephrotoxicity  Disadv:  Un-pleasant odor( pungent)  Reparatory depression  Hypotension because of the decreased periferal vascular resistance.  Therapeutic status: widely used 9/1/2024  D. Nitrous oxide (gas Anesthetic)  It is cheap & commonly used anaesthetic.  a potent analgesic but a weak general anesthetic  combined with other, more potent agents to attain pain- free anesthesia.  Rapid induction and recovery (Low solubility blood)  move very rapidly in and out of the body.  It has rapid induction & recovery, non-irritant, not flammable, very potent analgesic activity  It has little effect on respiration, heart & BP  causes excitement at high concentration therefore the name laughing gas is given.  No…. 107 Advantage :  No muscle relaxation, No respiratory depression  Not hepatotoxic, minimal CVS adverse effects Dis Advantage : - Diffusion Hypoxia: (respiratory diseases). - Nausea and vomiting. Inactivation of B12→megaloblastic anemia. - Bone marrow depression- Leukopenia (chronic use). - Abortion – Congenital anomalies Contraindication  Pregnancy  Pernicious anemia.  Immunosuppression. 9/1/2024  2. IV Anesthetics 108 Thiopental, Methohexital, Etomidate, Ketamine, and Propofol  are used for the rapid induction of anesthesia, then maintained with an appropriate inhalation agent.  They rapidly induce anesthesia and must therefore be injected slowly.  Recovery from intravenous anesthetics is due to redistribution from sites in the CNS.  Analgesic activity: Opioids & ketamine  Amnesic action: benzodiazepines & ketamine.  Can be used alone in short operation & Outpatients anesthesia. 9/1/2024  A. Ultra–short Acting Barbiturates  THIOPENTAL , THIAMYLAL & METHOHEXAL THIOPENTAL 109  a potent anesthetic and a weak analgesic  require a supplement of analgesic Admn.  Has a high lipid solubility, they quickly enter the CNS & depress function, often in less than 1 minutes  Redistributed to skeletal muscles & adipose tissue serves as reservoir. Very rapid redistribution results recovery from anesthesia  Single dose induces hypnosis & anaesthesia without analgesia,  Injected i.v. (3-5mg/kg) as 2.5% solution.  Metabolism is relatively slowly by liver enzyme. 9/1/2024  Cont…. 110 Use - Induction in major surgery., Alone in minor surgery. - In head injuries : ↓ ICP. Adverse Drug Effect  CV collapse, minor effects on CVS, but in patients with hypovolumia or shock  severe hypotension.  Respiratory depression- apnea, coughing, chest wall spasm, laryngospasm, and bronchospasm. (concern for Asthma), shivering & delirium during recovery Contraindication-  Respiratory patients, COPD, Porphyria -severe hypotension, (hypovolemic & shock patient) 9/1/2024  B. Benzodiazepines  Midazolam, Diazepam & lorazepam 111  As preanesthetic medication & adjuvant in local anesthesia.  Diazepam and Lorazepam are not water-soluble, and their IV use necessitates non-aqueous vehicles, which cause pain and local irritation.  Midazolam is water-soluble and is the BZP of choice for parenterally administration.  at physiologic pH midazolam becomes lipid-soluble and can cross the BBB to produce its central effects  Slow onset of action compared with other IV anesthetics  Midazolam has more rapid onset, short half-life than other BZPs  FLUMAZENIL – can be used to accelerate recovery when excessive dose of IV bzps are administered. 9/1/2024  C. Opioid Analgesics  Fentanyl, sufentanil, remifentanil, alfentanil 112  IV, Epidurally, or Intrathecally.  Analgesic property used together with anesthetics  High doses OAs + large doses of BZPs for major cardiovascular surgical procedures  Fentanyl is short acting potent opioid related to Pethidine  Neuroleptanalgesia (Fentanyl + Droperidol )  A state of analgesia, sedation and muscle relaxation without loss  of consciousness. used for diagnostic procedures that require cooperation of the patient  Used for (intense analgesia) during endoscopies, angiographies, burn-dressings 9/1/2024 Neuroleptanesthesia(Fentanyl + droperidol + NO)  C. Opioid Analgesics ADE 113  Hypotension, Respiratory Depression, & Muscle Rigidity  post-anesthetic nausea and vomiting  Increase in ICP , Urinaryretention  Prolongation of labor & fetal distress Contraindication:  Head injuries, Pregnancy, Bronchial asthma.  Chronic obstructive lung diseases.  Hypovolemic shock (Large dose only)  Opioid effects can be antagonized by Naloxone 9/1/2024  D. Ketamine 114  given IV, IM (in Children),  rapid but in comparison to other I.V it’s slow  a short-acting, non-barbiturate anesthetic,  induces a Dissociative Anesthesia  the patient is unconscious but appears to be awake and does not feel pain.  provides sedation, amnesia, and immobility with or without loss of consciousness (hypnosis)  Fast onset of action & recovery. Dose 1-2mg/kg i.v. or 3- 5mg/kg i.m. MOA  blockade of the membrane effects of the excitatory NT glutamic acid at the NMDA receptor subtype 9/1/2024  D. Ketamine 115  Children tolerate better, Good for repeated use  Causes sympathetic stimulation, increase intracranial pressure  Preferred in asthmatic & hypotensive patients  highly lipophilic drug and is rapidly distributed into well- perfused organs (the brain, liver, and kidney).  the only intravenous anesthetic that possesses anesthetic and analgesic properties, as well as the ability to produce dose-related cardiovascular stimulation. 9/1/2024  Ketamine….. Uses: - Used as 1st drug of choice in hypovolemic, shock & elderly) patients -Potent bronchodilator (asthmatics), minor orthopedic procedure - dressing of burns, radiotherapy, marrow sampling, short duration surgery Adverse effects:  Risk of hypertension and cerebral hemorrhage- ↑ICP  postoperative : disorientation, vivid dreams, hallucination,  sensory and perceptual illusions  rise in BP, increased salivation Contraindications: HTN, Stroke, IHD, Head injuries  E. Propofol 117  It is liquid employed as 1% emulsion.  It has quick action used for both induction & maintenance for surgical procedures lasting 1hr.  Onset with in 40 sec, Narcotics required for analgesia.  It is similar to Thiopentone sodium but is more potent & has quicker action. Replaced thiopental  It decreases ICP. Doesn’t cause post-anesthetic nausea and vomiting  It is metabolized fast so quick recovery is possible  Dose 2mg/kg bolus i.v. for induction & 100-200 µg/kg/min for maintenance. 9/1/2024  Propofol…… 118  Useful for spinal surgeries,  It is safe in pregnancy  Propofol decreases blood pressure without depressing the myocardium. ADE-  CVS and respiratory depression, hiccups.  Excitation (involuntary movements)- like enflurane)  Pain at site of injection, Expensive.  Clinical infections due to bacterial contamination. 9/1/2024  E. Etomidate 119  A Ultrashort acting hypnotic (Non Barbiturates agent but lacks analgesic activity  Poor water solubility, so is formulated in a propylene glycol solution.  It has Rapid onset but short-acting.  Minimal CVS and respiratory depressant effects.  only used for patients with coronary artery disease or cardiovascular dysfunction, such as shock  ADE  Adrenal suppression - ↓ in plasma cortisol & aldosterone levels  Postoperative nausea & vomiting.  Pain: at the site of injection 9/1/2024 120 9/1/2024  7. Local Anesthetics  LA are applied locally and block the generation & conduction of nerve impulse of sensory impulses from the periphery to the CNS. without affecting consciousness.  The generation & transmission of nociception (pain) can be prevented by blocking voltage gated Na+ channel in afferent neuron.  They can act on any part of the nervous system & on every type of nerve. Advantages of LA over GA:  Unaltered consciousness,  function of vital organ is unaffected, safe for patients,  useful for minor & major operations.  MoA LA 122  Act by inhibiting sodium influx through sodium-specific ion channels in the neuronal cell - voltage-gated Na channels  action potential cannot rise and signal conduction is inhibited  All local anesthetics are membrane stabilizing drugs slows down speed of AP- ultimately stop AP generation  Reversibly decrease the rate of depolarization and repolarization of excitable membranes 9/1/2024  Local Anesthetics Classification 123 Injectables  2. Surface Anesthetics: - A. Low potency & short duration Usually applied on mucous  Procaine membrane or abraded  Chloroprocaine skin Include. B. Intermediate potency &  Cocaine duration  Lignocaine  Lignocaine (lidocaine)  Tetracaine  Prilocaine  Benoxinate C. High potency & long duration  Benzocaine  Tetracaine, Bupivacaine ,  Butyl amino benzoate Ropivacaine, Dibucaine  Oxethazaine 9/1/2024  Local Anesthetics(LA) 124  Local anaesthetics are weak bases with ampiphilic (lipohilic & hydrophilic) property linked through ester/amide linkage. Ester linked: cocaine, procaine Amide linked: lignocaine, bupivacaine Can be given in with Vasoconstrictor adrenaline Advantage  minimizes systemic toxicity and increases the duration of action.  Provides more bloodless field Disadavantage  Delays wound healing, Painful injection & chances of necrosis  Increased BP & arrythmia 9/1/2024  Lignocaine (Lidocaine)  most widely used local anesthetic.  Good for surface application and injection, Causes 125 vasodilation in injected area  Has fast onset of action (within 3 min) also anesthesia is more intense & longer lasting.  At physiologic pH, these cpds are charged; it is this ionized form that interacts with Na+ channel to inhibit its function and, thereby, achieve local anesthesia. Uses: Surface application, infiltration, nerve block, spinal & intravenous regional block anaesthesia. Also used as antiarrhythemic drug. Adverse effects: drowsiness, dysphoria & altered taste. Overdose may cause convulsion, coma & respiratory arrest.  Dose: 2-4% gel (Xylocaine gel), 100mg/ml spray, 1- 2% injection (with or without adrenaline) 9/1/2024  Cont…. Bupivacaine: Dose: 0.25-0.5% injection  Potent & long acting LA.  Causes more sensory block than motor block. Uses:  infiltration, nerve block, epidural & spinal anaesthesia.  Popular in obstetrics & postoperative pain relief. Adverse effect: cardiotoxic Ropivacaine  It is a congener of bupivacaine but less cardiotoxic  Cocaine 127  natural alkaloid from leaves of Erythroxylon coca.  good surface anesthetic  should never be injected causes tissue neurosis (protoplasmic poison) produces permanent CNS stimulation with marked effect on mood & behavior.  induces a sense of well being, delays fatigue & increase power of endurance.  The only indication for cocaine is in ovular anesthesia Procaine: - the first synthetic local anesthetic.  decline after the introduction of lignocaine  It forms poorly soluble salt with benzyl penicillin: procaine penicillin injected I.M acts for 24 hours. 9/1/2024 8. Opioid Analgesics & Antagonists 128 9/1/2024  OPIOIDS 129  are natural or synthetic compounds that produce morphine like effects.  They act by binding to specific opioid receptors in the CNS to produce effects that mimic the action of endogenous opioid peptides (enkephalins, endorphins & dynorphins).  Although the Opioids have a broad range of effects their primary use is to relive intense pain. 9/1/2024  Classification of opioids 130  Strong agonists:  Moderate Agonists  Fentanyl  Codeine  Heroin  propoxyphen.  Meperidine  Antagonists:  Methadone  Naloxone  Morphine &  Naltrexone.  Sulfentanil. 9/1/2024  Classification of opioids 131  may be classified in several ways  Spectrum of Clinical Uses analgesics, antitussives, and antidiarrheal  Strength of Analgesia strong, moderate, and weak  Ratio of Agonist to Antagonist Effects agonists(receptor activators [full or partial]), antagonists (receptor blockers), or mixed agonist- antagonists 9/1/2024  Cont…..  Morphine is a full agonist at the μ (mu)-opioid receptor, the major analgesic opioid receptor  Opioids may also differ in receptor binding affinity.  morphine exhibits a greater binding affinity at the μ-opioid receptor than does codeine.  Simple substitution of an allyl group on the nitrogen of the full agonist morphine plus addition of a single hydroxyl group results in naloxone, a strong μ-receptor antagonist.  Some opioids, eg, nalbuphine, a mixed agonist-antagonist, are capable of producing an agonist (or partial agonist) effect at one opioid receptor 132 subtype and an antagonist effect at another. 9/1/2024  Pharmacokinetics 133 A. Absorption  Most opioid analgesics are well absorbed when given by subcutaneous, IM , and oral routes.  Most well absorbed when taken orally, but morphine, hydromorphone, and oxymorphone undergo extensive first-pass metabolism  However, because of the first-pass effect, the oral dose of the opioid (eg, morphine) to elicit a therapeutic effect may need to be much higher than the parenteral dose. As 9/1/2024  Cont…. 134  there is considerable interpatient variability in first-pass opioid metabolism, prediction of an effective oral dose is difficult.  widely distributed to body tissues  They cross the placental barrier and exert effects on the fetus  result in both respiratory depression and, with continuous exposure, physical dependence in neonates.  Metabolized by hepatic enzymes and eliminated by the kidney 9/1/2024 135 Pharmacodynamics 1, Receptor Type  effects of the opioids are mediated by 4 receptors. 1. Mu (): Supra spinal analgesia, sedation, respiratory depression, Euphoria, Tolerance, Physical dependence, decreased GI motility, pupil constriction. 2. Kappa (): Spinal analgesia, dysphoria, pupil constriction. 3. Sigma (): dysphoria, hallucinations, pupil dilation. 4. Delta (): More important in the periphery but may also contribute to analgesia, may play a role in the development of tolerance  Endorphins have highest affinity for  receptors, enkephalins for  receptors, and dynorphins for  receptors 9/1/2024  Opioid receptor subtypes, their functions, and their endogenous peptide affinities. 136 9/1/2024  2. Celluar Action 137  The opioids have two well-established direct Gi/0 protein-coupled actions on neurons:  they close voltage-gated Ca 2+ channels on presynaptic nerve terminals and thereby reduce transmitter release, and  they open K+ channels and hyperpolarize and thus inhibit postsynaptic neurons.  The presynaptic action—depressed transmitter release—has for a large number of NT, including glutamate, acetylcholine, norepinephrine, serotonin, and substance P. 9/1/2024  3. Receptor distribution and neural mechanisms of analgesia 138  All three major receptors are present in high concentrations in the dorsal horn of the spinal cord  Receptors are present both on spinal cord pain transmission neurons and on the primary afferents that relay the pain message to them.  Opioid agonists directly inhibit dorsal horn pain transmission neurons, they also inhibit the release of excitatory transmitters from the primary afferents.  Although there are reports that heterodimerization of the μ- and δ- opioid receptors contributes to μ-agonist efficacy (eg, inhibition of presynaptic voltage-gated calcium channel activity) 9/1/2024  4. Tolerance and dependence 139  frequently repeated therapeutic doses of morphine or its surrogates, there is a gradual loss in effectiveness  To reproduce the original response, a larger dose must be administered.  Along with tolerance, physical dependence develops.  persistent activation of μ receptors such as occurs with the treatment of severe chronic pain appears to play a primary role in its induction and maintenance. 9/1/2024  5. Opioid-induced hyperalgesia 140  In addition to the development of tolerance, persistent administration of opioid analgesics can increase the sensation of pain, resulting in a state of hyperalgesia.  This phenomenon can be produced with several opioid analgesics, including morphine, fentanyl, and remifentanil.  Spinal dynorphin and activation of the bradykinin and NMDA(N-methyl- d-aspartate) receptors have emerged as important candidates for the mediation of opioid-induced hyperalgesia.  This is one reason the use of opioids for chronicpain is controversial. 9/1/2024  Organ System Effects of Morphine and Its Surrogates 141 1. Central nervous system effects  The principal effects of opioid analgesics with affinity for μ- receptors are on the CNS;  the more important ones include analgesia, euphoria, sedation, and respiratory depression.  With repeated use, a high degree of tolerance occurs to all of these effects A. Analgesia—Pain consists of both sensory and affective (emotional) components.  Opioid analgesics are unique in that they can reduce both aspects of the pain experience.  In contrast, NSAID analgesic drugs, eg, ibuprofen, have no significant effect on the emotional aspects of pain 9/1/2024  B. Euphoria. (DA release 142  patients or IV drug users who receive IV morphine experience a pleasant floating sensation with lessened anxiety and distress.  However, dysphoria, an unpleasant state characterized by restlessness and malaise, may also occur C. Respiratory depression  All of the opioid analgesics by inhibiting brainstem respiratory mechanisms.  Alveolar Pco2 may increase, but the most reliable indicator of this depression is a depressed response to a carbon dioxide 9/1/2024 challenge.  Cont….. 143  The respiratory depression is dose related  A small to moderate decrease in respiratory function, as measured by Paco2 elevation, may be well tolerated in the patient without prior respiratory impairment.  However, in individuals with increased ICP, asthma, COPD, or cor-pulmonale, this ↓ in respiratory function may not be tolerated. 9/1/2024  Cont…. 144 D. Cough suppression”  Suppression of the cough reflex is a well-recognized action of opioids.  Codeine in particular has been used to advantage in persons suffering from pathologic cough.  However, cough suppression by opioids may allow accumulation of secretions and thus lead to airway obstruction and atelectasis. E. Miosis—Constriction of the pupils 9/1/2024  Cont…. 145 F. Nausea and vomiting—The opioid analgesics can activate the brainstem CTZ to produce nausea and vomiting. G, Temperature: Homeostatic regulation of body temperature is mediated in part by the action of endogenous opioid peptides in the brain. E.G  administration of μ-opioid receptor agonists, such as morphine produces hyperthermia, whereas 9/1/2024  administration of κ-agonists induces hypothermia.  2. Peripheral effects 146 a. Cardiovascular system  Most opioids have no significant direct effects on the heart and, other than bradycardia  Meperidine, its antimuscarinic is an exception (can result in tachycardia)  Blood pressure is usually well maintained in subjects receiving opioids unless the cardiovascular system is stressed, in which case hypotension may occur. 9/1/2024  ↑PCO2 --↑ cerebral vasodilation----↑ in cerebral blood flow -- ↑ ICP Cont…. 147  Hypotension - due to -peripheral arterial and venous dilation, depression of vasomotor centre& release of histamine  increase in intracranial pressure. ↑PCO2 --↑ cerebral vasodilation----↑ in cerebral blood flow -- ↑ ICP B. Gastrointestinal tract  Opioid receptors exist in high density in the GIT, and the constipating effects of the opioids are mediated through an action on the enteric nervous system. 9/1/2024  Cont…. 148  In the stomach, motility may decrease but tone (persistent contraction) may increase  particularly in the central portion; gastric secretion of HCL is decreased. Small intestine resting tone is increased.  delays passage and allows increased absorption of water, which leads to constipation- used in the management of diarrhea C, Biliary tract—The opioids contract biliary smooth muscle, which can result in biliary colic.  The sphincter may constrict, resulting in reflux of biliary and pancreatic secretions and elevated plasma amylase and lipase levels  Cont…. 149 D. Renal: Renal function is depressed by opioids. due to decreased renal plasma flow.  In addition, μ-opioids have an antidiuretic effect in humans.  Opioids also enhance renal tubular sodium reabsorption.  Increased sphincter tone may precipitate urinary retention, especially in postoperative patients.  Occasionally, ureteral colic caused by a renal calculus is made worse by opioid-induced increase in ureteral tone. 9/1/2024  Cont… 150 e. Uterus: The opioid analgesics may prolong labor.  Although the mechanism for this action is unclear, both μ- and κ-opioid receptors are expressed in human uterine muscle.  Fentanyl and meperidine (pethidine) inhibit uterine contractility f. Endocrine—Opioids stimulate the release of ADH, prolactin, and somatotropin but inhibit the release of luteinizing hormone  Patients receiving chronic opioid therapy can have low testosterone resulting in decreased libido, energy, and mood.  Women can experience dysmenorrhea or amenorrhea G. Pruritus- histamine release - responsible for pruritus and 9/1/2024 occasionally urticaria  Mechanism of action of opiates 151  Opioids produce analgesia by binding to specific GPCRs located in brain & spinal cord regions involved in the transmission & modulation of pain Inhibit adenylyl cyclase → ↓ cAMP  Reduce neuronal excitability  b/cof the ↑ K+ conductance causes hyperpolarisation of the membrane  Reduce transmitter release  Due to inhibition of Ca 2+ entry 9/1/2024  Clinical Use of Opioid Analgesics 152 Analgesia Cough- Cough Suppression / antitussives Diarrhea Acute Pulmonary Edema Balanced anaesthesia Preanaesthetic medication Relief of anxiety and apprehension 9/1/2024  Clinical use of opiates 153 Analgesic effect: Selective relief of pain at doses which do not produce hypnosis or impair sensation They are more effective in prolonged, burning pain than sharp, intermittent pain, but neuropathic pain can be resistant  Therefore, opioids are mainly used for severe & constant pain Chronic pains such as in cancer patients may need continuous use of potent opioid analgesics 9/1/2024  Clinical use of opiates… 154 Analgesic effect….  Opioid analgesics are used during obstetric labor As opioids cross the placental barrier, care must be taken to minimize neonatal depression If it occurs, immediate injection of the antagonist naloxone will reverse the depression Opioids like meperidine produce less depression (particularly respiratory depression) in newborn infants than does morphine 9/1/2024  Clinical use of opiates… 155 Cough Suppression / antitussives:  Depression of cough centers in the medulla  Different molecular mechanism than analgesia or respiratory depression  Cough suppressed by dextro-isomers of opioids (e.g. dextromethorphan), compounds which have no analgesic activity 9/1/2024  Clinical use of opiates… 156 Diarrhea:  Opioids cause constipation beneficial for treatment of diarrhea  Diarrhea from almost any cause can be controlled with the opioid analgesics  But if diarrhea is associated with infection ,appropriate chemotherapy should be used  Synthetic drugs like loperamide have selective effect on GIT Poorly-absorbed & have little/no central effects 9/1/2024  Clinical use of opiates… 157 Shivering:  All opioid agonists have some propensity to reduce shivering  Meperidine is reported to have the most pronounced anti-shivering properties Singledoses of meperidine is effective in the treatment of postanesthetic shivering Via the action on subtypes of the α 2 adrenoceptor 9/1/2024  Clinical use of opiates… 158  Applications in anesthesia:  Used in cardiovascular surgery b/c of low cardiac depressant effects  Opioids can be used  Preoperatively b/c of their sedative, anxiolytic & analgesic properties  Intraoperativelyas adjuncts to other anesthetic agents & as a primary component of the anesthetic regimen  Postoperatively as analgesics 9/1/2024  Side effects of opiates… 159 Most opioid side effects associated with mu receptors  Respiratory depression (reduces sensitivity of respiratory centres in brain stem to CO2)  Euphoria, Sedation, Nausea & Vomiting  Increased ICP, Hypothermia  Constipations, Urinary retention  Tolerance & dependence  Bronchoconstriction (histamine release stimulated) 9/1/2024  A. Morphine 160  Is the major analgesic drug contained in crude opium.  It has a high affinity for µ & K low affinity for receptors. Mechanism of action:  Opioids exert their major effects by interacting with opioid receptors in the CNS & GIT.  It inhibits the release of many excitatory transmitters from nerve terminals carrying painful stimuli.  It also acts on the spinal cord and decrease the release of substance P, which modulate pain perception in spinal cord. 9/1/2024  A. Morphine 161  Action:  Analgesia: causes relief of pain.  Euphoria: produces a powerful sense of wellbeing, over confidence & over optimism.  Respiratory depression: by reduction of the sensitivity of respiratory center neurons to CO2.  Depression of cough reflex: morphine & codeine have antitussive properties. 9/1/2024  A. Morphine 162  Action:  Miosis: pin point pupil.  Emesis: directly stimulate chemo receptor trigor zone.  Constipation: by decreasing motility of smooth muscles.  Histamine release: release histamine from mast cells, which cause bronchoconstriction.  Urinary retention: because of release of the antidiuretic hormone (ADH). 9/1/2024  A. Morphine 163 Therapeutic Uses:  Analgesic  Treatment of diarrhea  Relief of cough Pharmacokinetics:  Absorption: slow & erratic from GIT  IM, SC or IV  Distribution: enters all body tissues including the fetuses of pregnant woman. Only small % crosses the B.B.B. (least lipophillic of the common opoids).  Elimination: metabolized in the liver & excreted in urine.  Tolerance & physical dependence: repeated uses produce 9/1/2024 tolerance.  A. Morphine 164  Adverse effects  Respiratory depression  constipation  orthostatic hypotension  urinary retention  cough suppression  biliary colic caused by morphine  Emesis,  increased intracranial pressure (ICP)  euphoria/dysphoria, sedation, and miosis. 9/1/2024  B. Heroin (Diacetyl morphine) 165  Does not occur naturally, produced by acetylation of morphine, which leads to 3x increase in potency.  Its greater lipid solubility allows it to cross B.B.B, causing a more exaggerated euphoria.  It has no accepted medical use. 9/1/2024  C. Codeine 166  Much less potent analgesic than morphine but it has a higher oral efficacy.  Shows good antitussive activity.  Has a lower abuse potential & rarely produce dependency.  Produce less euphoria than morphine.  It's used as antitussive, but now widely replaced by dextrometorphan, a synthetic cough depressant that has low potential for abuse. 9/1/2024  Meperidine (Pethidine) 167  Produce pharmacologic effect similar to morphine.  A predominant receptor agonist.  Has more effect in the CNS.  Used as analgesic and not used for the treatment of cough or diarrhea.  Result Tachycardia (antimuscarinic action)-  Safer in asthmatics (less histamine release) Uses- analgesia, preanaesthetic medication Analgesia during labour (less neonatal respi depression) Diphenoxylate and Loperamide  Are derivatives of meperidine devoid of central effects.  Slow GI motility and used as antidiarrheals. 9/1/2024  Tramadol 168  A synthetic codeine analogue but week receptor agonist.  Part of its analgesic effect is obtained by inhibition of uptake of norepinephrine and serotonine.  In the treatment of mild to moderate pain tramadol is as effective as morphine or meperidine. However it is less effective in severe and cronic pain. Advantage Less respiratory depression, constipation, sedation, urinary retention Less abuse potential but should never be used in patients with a history of addiction. Disadvantages: nausea , vomiting , Seizures precipitation (C/I in epilepsy) Serotonin syndrome with SSRI 9/1/2024  Opioid Antagonists 169  Bind with high affinity to opioid receptors but fail to activate the receptor mediated response. Naloxone  Is used to reverse the coma & respiratory deprssion of opioid overdose. (Antidote for opioid). Naltrexone  Actions similar to Naloxone but has longer duration of action. 9/1/2024