e disorders 3/18/2016 7677• BONE REMODELING – About 10% of the adult skeleton is replaced each year • Osteoclasts – osteoblasts • TREATMENT OF OSTEOPOROSIS • Nondrug strategies: – adequate dietary intake: • Ca2+ and vit D, exercise, and smoking cessation. – avoid drugs: e.g. glucocorticoids 3/18/2016 78ratide 3/18/2016 79• Pharmacologic therapy: • Bisphosphonates – Alendronate, ibandronate, risedronate, and zoledronic acid: • for prevention and treatment of: –postmenopausal osteoporosis • Mechanism of action – decrease osteoclastic bone resorption: • mainly through an increase in osteoclastic apoptosis 3/18/2016 8081pproved for the prevention and treatment of osteoporosis: –in women intolerant to bisphosphonates • Calcitonin (Salmon) – reduces bone resorption, but it is less than bisphosphonates – intranasal administrn SE: rhinitis 3/18/2016 82ide • Is a rh. parathyroid hormone • Stimulates osteoblastic activity – Reserved for: • Patients unresponsive to other drugs ======================== End of endocrine pharmacology 3/18/2016 83الفصل السادس Pharmacology II – السنة الثالثة ------------------------------------------برنامج الطب Drugs acting on the CNS • Text book: • Lippincott’s illustrated reviews: Pharmacology (by: Richard D. Howland – Mary J. Mycek)- 7th edition 6/25/2023 84ychotic drugs – Anti-epileptics – Anesthetics – Opioid analgesics 6/25/2023 856/25/2023 86ors, muscular rigidity – Bradykinesia, postural, gait abnormalities – Most: over 65 yrs (1%) 6/25/2023 87• Etiology – Unknown for most patients – Is correlated with destruction of: • dopaminergic neurons in the substantia nigra • Substantia nigra: • Figure 8.4 6/25/2023 8889• Neostriatum: – Overactivity of acetylcholine: • results in loss of the control of muscle movements • Secondary parkinsonism (pseudoparkinsonism): – Phenothiazines and haloperidol 6/25/2023 9091DRUGS USED IN PARKINSON’S DISEASE • Levodopa and carbidopa – In early disease: • 20% of DA neurones: –is adequate for conversion of L-dopa to dopamine – L-dopa + carbidopa • (Figure 8.5) 6/25/2023 926/25/2023 93idopa: • A DA decarboxylase inhibitor 6/25/2023 94• L-dopa Therapeutic uses: – Parkinson’s disease: • Patients typically experience a decline in response: –during the 3rd to 5th year of therapy • Withdrawal from the drug must be gradual 6/25/2023 956/25/2023 96a Interactions: 6/25/2023 9798ne and rasagiline – At LD, MD: Selectively inhibits: • MAO-B not MAO-A • (Figure 8.8). 6/25/2023 99100101– Entacapone and tolcapone: • Selectively and reversibly inhibit COMT – Both: reduce “off” phenomen 6/25/2023 102orexia • Dyskinesias, hallucinations, and sleep disorders – Hepatic necrosis: with tolcapone: • Largely replaced by Entacapone 6/25/2023 103r levodopa- fluctuations 6/25/2023 104• Side effects: – (Figure 8.10). 6/25/2023 105106• Bromocriptine: – Caution in MI or PVD 6/25/2023 107• Non-ergot drugs: – Apomorphine, pramipexole, ropinirole, and rotigotine: • Pramipexole and ropinirole: oral • Apomorphine: injectable • Rotigotine: –Transdermal • Apomorphine: – for acute “off” phenomenon 6/25/2023 1081096/25/2023 110• Amantadine – Antiviral: for influenza – Increases DA release – Tolerance develops more readily 6/25/2023 111• Antimuscarinic agents – Only adjuvant – Benztropine, trihexyphenidyl – Contraindicated in: • glaucoma, prostatic hyperplasia, or pyloric stenosis =============================== 6/25/2023 112xiolytic and Hypnotic drugs 6/25/2023 1136/25/2023 114• BENZODIAZEPINES – Safer and more effective • Mechanism of action: – BNZs target: • GABAA receptors • BNZs increase: – Frequency of Cl- channel openings • (Figure 9.3) 6/25/2023 115116• Actions : BNZs – Reduction of anxiety – Sedative/hypnotic – Anterograde amnesia – Anticonvulsant – Muscle relaxant • Therapeutic uses : • Anxiety disorders: – e.g. panic disorder, GAD, social anxiety disorder, posttraumatic stress disorder, obsessive– compulsive disorder, anxiety (phobias: flying) 6/25/2023 117Useful in patients who experience frequent wakening – Triazolam: • Short -acting • In treating individuals who have difficulty in going to sleep 6/25/2023 118• Seizures: – Clonazepam: Adjunctive to antiepileptics – Lorazepam and diazepam: status epilepticus • Duration of action: – Short -, intermediate-, and long-acting • (Figure 9.4) – 6/25/2023 1196/25/2023 120121ER ANXIOLYTIC AGENTS • Antidepressants: – First -line in addiction or dependence – Alone or combined with BNZ in first wks – Have become first-line treatment for GAD 6/25/2023 122w onset of action – Actions: • Mediated by: –5-HT1A receptors • Adverse effects: is low: – Sedation and cognitive dysfunction: • are minimal – Dependence is unlikely • Figure 9.7 6/25/2023 1231241256/25/2023 1261276/25/2023 128idem – Exhibits minimal rebound insomnia – Rapid onset: • Hypnotic effect: 5 hours – A sublingual tablet: • For mid- night awakening =============== 6/25/2023 129بسم الله الرحمن الرحيم Antidepressants 6/25/2023 130adness, hopelessness, inability to experience pleasure – Changes in (sleep patterns and appetite) – Suicidal thoughts • MECHANISM OF ANTIDEPRESSANT DRUGS • Most: – Potentiate: • NE and/or 5-HT in the brain • Biogenic amine hypothesis of depression • (Figure 10.1) 6/25/2023 131132• SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs): – Have greater selectivity (10Xs) for the serotonin transporter; • as compared to the NE transporter – Little blocking at: • Muscarinic, α-adrenergic, and H1 receptors – Safe in overdose – Largely replaced TCAs and MAOIs – Include fluoxetine, citalopram, escitalopram, fluvoxamine, paroxetine, and sertraline • (Figure 10.2) 6/25/2023 133134– Actions • Antidepressants: –at least 2 weeks –Max benefit: 12 weeks or more –80% respond to one drug • Therapeutic uses – Depression – Obsessive –compulsive disorder – Anxiety disorders • (Figure 10.3) 6/25/2023 1356/25/2023 136137gure 10.5) 6/25/2023 138139140141• Nefazodone and trazodone – Weak inhibitors of serotonin reuptake – Both agents are sedating (H1 block) – Trazodone is commonly used off-label for the management of insomnia • TRICYCLIC ANTIDEPRESSANTS – Block NE and 5-HT reuptake – Tertiary amines: • Imipramine, amitriptyline – Secondary amines: • Desipramine and nortriptyline 6/25/2023 142echanism of action – Inhibition of neurotransmitter reuptake – Maprotiline and desipramine are: • relatively selective inhibitors of NE reuptake – Block α-, M, H1 receptors – Onset: 2 weeks or longer • Therapeutic uses – Moderate to severe depression – Bed -wetting in children older than 6 years: – For Migraine headache and treat chronic pain syndromes (for example, neuropathic pain) 6/25/2023 1436/25/2023 144– Life -threatening arrhythmias in overdose – Block α-receptors – H1 block • Narrow TI: – 5 – 6 Xs dose of imipramine can be lethal • Drug interactions with the TCAs: – Figure 10.8. 6/25/2023 14523 146the gut and liver • Include: – Phenelzine, tranylcypromine, • Use of MAOIs is limited due to the complicated dietary restrictions • Mechanism of action: (Figure 10.9) 6/25/2023 1476/25/2023 148– High incidence of drug–drug and drug–food interactions • Therapeutic uses – Last - line agents in many treatment settings – For unresponive or allergic to TCAs and SSRIs • Adverse effects – Tyramine: aged cheeses and meats 6/25/2023 149– Hypertensive crisis: • Occipital headache, stiff neck, tachycardia, nausea, hypertension, cardiac arrhythmias, seizures, and, possibly, stroke – SE of MAOIs : • Drowsiness, orthostatic hypotension, blurred vision, dry mouth, and constipation ====================== 6/25/2023 150Antipsychotic Drugs 6/25/2023 151Schizophrenia 25.6.2023 1526/25/2023 153SCHIZOPHRENIA – About 1% of the population – Has a strong genetic component – Mesolimbic or mesocortical DA dysfunction • ANTIPSYCHOTIC DRUGS – First - and second-generation – First –generation antipsychotics: • Chlorpromazine, haloperidol: –D2 receptor antagonist – EPS • (Figure 11.2). 6/25/2023 1556/25/2023 156Figure 13.3 Relative affinity of clozapine, chlorpromazine, and haloperidol at D1- and D2- dopaminergic receptors. 25.6.2023 157• Second-generation antipsychotic drugs – Atypical antipsychotics – Most of second: inhibition of 5-HT – Lower incidence of EPS – E.g. Risperidone – Many of 1st gen: • block M, NA, and H1 recepors • (Figure 11.4). – 6/25/2023 1586/25/2023 159• All antipsychotics – reduce “positive” symptoms: • hallucinations and delusions: • Many SGA: – Ameliorate the negative symptoms: • blunted affect, apathy (careless) • impaired attention, cognitive impairment 6/25/2023 160• Neuroleptic is an antipsychotic drug that causes (Extrapyramidal symptoms: EPS) in human and catalepsy in rodents 25.6.2023 162• Extrapyramidal effects: EPS – Blockade of DA receptors in the nigrostriatal pathway – Dystonias - Tardive dyskinesia • For EPS : Use benztropine • Therapeutic uses – Treatment of schizophrenia – First -generation: • positive symptoms – Atypical antipsychotics: 5-HT2A : • negative symptoms 6/25/2023 163– Prevention of nausea and vomiting: • Most commonly, prochlorperazine – Quetiapine: for bipolar and refractory depression • Long -acting injectable (LAI) formulations: – Up to 2 to 4 weeks: for non-adherent pts: 6/25/2023 1646/25/2023 165• Maintenance treatment: – Two or more psychotic episodes: • Maintenance therapy for at least 5 years – Rate of relapse may be lower with SGAs ==============================