Lec 1.pdf

Zagazig University Faculty of Pharmacy Department of Pharmacology and Toxicology STUDENT BOOK OF PHARMACOLOGY-II Third Year-Second Semester By Staff Members of Pharmacology Department 1 ...

Zagazig University Faculty of Pharmacy Department of Pharmacology and Toxicology STUDENT BOOK OF PHARMACOLOGY-II Third Year-Second Semester By Staff Members of Pharmacology Department 1  ‫رسالةالكلية‬ ‫إن غاية كلية الصيدلة جامعة الزق ازيق هي إعداد وإمداد المجتمع المحلي‬ ‫واإلق ليمي والدولي بصيادلة ذوي كف اءة عالية ق ادرين علي تصميم وتصنيع‬ ‫الدواء بجودة عالية وعمل الرق ابة الدوائية بمعايير عالمية والتعامل معه وضمان‬ ‫توصيله بشكل آمن وفعال إلي محتاجيه ومراقبته إكلينيكياً وكذلك القيام‬ ‫باألبحاث الدوائية التي تخدم مجال العلوم الصيدلية وكذلك ق ادرين علي‬ ‫المنافسة ومواصلة التعليم الصيدلي المستمر لضمان تقديم أفضل خدمة صحيحة‬ ‫مجتمعية‪.‬‬ ‫‪2‬‬  List of contents Page Title Central nervous system acting agents 5 Neurodegenerative disorders and spasticity 6 Sedatives -Hypnotics 13 Antiepileptic drugs 21 Antipsychotic agents 28 Antidepressants 32 Drugs for treatment of mania 40 Pain control with general and local anesthetics 41 Opioids 47 Central nervous system stimulants 56 Drugs used in coagulation disorders 64 Drugs used in bleeding disorders 71 Autocoids 74 Anti-inflammatory, antipyretic and analgesic agents 81 Antihyperlipidemic drugs 89 Drugs used for treatment of anemia 95 Respiratory system pharmacology 99 Gastrointestinal pharmacology 108 References 119 3  CENTRAL NERVOUS SYSTEM ACTING DRUGS Overview: ❑ Central nervous system (CNS) drugs act primarily by: 1. Affecting the synthesis, storage, release, reuptake, or degradation of neurotransmitters 2. Activating or blocking receptors. ❑ Some CNS neurotransmitters (e.g., aspartate, glutamate, histamine, and tachykinins) are excitatory; others (e.g., dopamine, GABA, glycine, and opioid-processing peptides) are inhibitory; and still others (e.g., acetylcholine, norepinephrine, and serotonin) are both excitatory and inhibitory, with these actions exerted via different receptors. ❑ Long-term administration of drugs sometimes causes up-regulation or down-regulation of receptors. Up-regulation is evoked by receptor antagonists, whereas down-regulation is evoked by receptor agonists or reuptake inhibitors. Neurotransmission In The Central Nervous System: ❑ Transmission in CNS is mediated by hormones, chemical agents, electrolytes or amino acids. ❑ The CNS, unlike the peripheral ANS, 1. The CNS communicates through the use of multiple neurotransmitters, whereas the ANS uses only two primary neurotransmitters, acetylcholine and norepinephrine. 2. The CNS contains powerful networks of inhibitory neurons that are constantly active in modulating the rate of neuronal transmission. Neurotransmitters may be divided to: 1. Excitatory Neurotransmitters: ❑ e.g. Acetylcholine, NE, dopamine, glutamate and aspartate. ❑ They act by depolarization and excitation of cells by increasing Na+ or Ca++ influx. ❑ They may also increase mobilization of cytosolic calcium from endoplasmic reticulum. 2. Inhibitory Neurotransmitters ❑ e.g. gama amino butyric acid (GABA) and Glycine. ❑ They act by hyperpolarization of the cell and then lowering its resting membrane potential by increasing Cl- ion influx. 4  NEURODEGENERATIVE DISEASES Parkinson’s Disease (PD): ❑ Parkinsonism is a progressive neurological disorder of muscle movement, characterized by: 1. Resting tremors, muscular rigidity, 2. Bradykinesia (slowness in initiating and carrying out voluntary movements), 3. Postural and gait abnormalities. 4. Loss of decision making and depression. 5. Most cases involve people over the age of 65, among whom the incidence is about 1 in 100 individuals. Etiology of Parkinson’s Disease o The cause of Parkinson’s disease is unknown for most patients. The disease is correlated with destruction of dopaminergic neurons in the substantia nigra with a consequent reduction of dopamine actions in the corpus striatum, parts of the basal ganglia system that are involved in motor control. ❑ Substantia nigra: The substantia nigra, part of the extrapyramidal system, is the source of dopaminergic neurons that terminate in the neostriatum. Each dopaminergic neuron makes thousands of synaptic contacts within the neostriatum. ❑ Neostriatum: o Normally, the neostriatum is connected to the substantia nigra by neurons that secrete the inhibitory transmitter GABA at their termini. o In turn, cells of the substantia nigra send neurons back to the neostriatum, secreting the inhibitory transmitter dopamine at their termini. o This mutual inhibitory pathway normally maintains a degree of inhibition of both areas. o In Parkinson’s disease, destruction of cells in the substantia nigra results in the degeneration of the nerve terminals that secrete dopamine in the neostriatum o Thus, the normal inhibitory influence of dopamine on cholinergic neurons in the neostriatum is significantly diminished, resulting in overproduction or a relative over activity of acetylcholine by the stimulatory Role of substantia nigra in Parkinson’s neurons.This triggers a chain of abnormal signaling, disease. DA=dopamine, GABA=ᵞ- resulting in loss of the control of muscle movements. aminobuteric acid, Ach=acetylcholine 5 ❑ Secondary parkinsonism: o Drugs such as the phenothiazines and haloperidol, whose major pharmacologic action is blockade of dopamine receptors in the brain, may produce parkinsonian symptoms (also calledpseudo parkinsonism). o These drugs should be used with caution in patients with Parkinson’s disease. ❑ Strategy of treatment o In addition to an abundance of inhibitory dopaminergic neurons, the neostriatum is also rich in excitatory cholinergic neurons that oppose the action of dopamine. Many of the symptoms of parkinsonism reflect an imbalance between the excitatory cholinergic neurons and the greatly diminished number of inhibitory dopaminergic neurons. Therapy is aimed at: 1. Restoring dopamine in the basal ganglia and, 2. Antagonizing the excitatory effect of cholinergic neurons, thus reestablishing the correct dopamine/acetylcholine balance. ANTI-PARKINSON DRUGS o Amantadine SYMMETREL o Apomorphine APOKYN o Benztropine COGENTIN o Biperiden AKINETON (antimuscarinic) o Bromocriptine PARLODEL o Carbidopa LODOSYN o Entacapone COMTAN o Pramipexole MIRAPEX o Trihexyphenidyl ARTANE o Procyclidine KEMADRIN o Levodopa (w/Carbidopa) SINEMET, PARCOPA o Selegiline (Deprenyl) ELDEPRYL, ZELAPAR o Rasagiline AZILECT o Ropinirole REQUIP o Rotigotine NEUPRO (dopamine agonist) ❑ Treatment depends on the following: A) Increasing DA content by: a. Increasing the synthesis by the use of L-dopa/ carbidopa. b. Decreasing the degradation of DA by selegiline. c. Increasing DA- receptor activity by bromocriptine, ropenirol and pramipexol. d. Drugs that release dopamine e.g. amantadine. B) Reduction of cholinergic activity by anticholinergic drugs e.g. benzatropine. A-LevoDOPA/Carbidopa o It is a metabolic precursor of dopamine o It restores dopaminergic neurotransmission in the neostriatum by enhancing the synthesis of dopamine in the surviving neurons of the substantia nigra. o It is the first line treatment for PD 6  o It is always combined with a peripheral dopa decarboxylase inhibitor either carbidopa or benserazide which reduces the dose needed by about 10 fold and diminishes the peripheral side effects. o Dopamine can’t pass the BBB but L-dopa can. o Decarboxylation occurs rapidly in the brain ‘since the decarboxylase inhibitors can not pass BBB. Synthesis of dopamine from levodopa in the absence and presence of carbidopa, an inhibitor of dopamine decarboxylase in the peripheral tissues. GI=gastrointestinal o In early disease, the number of residual dopaminergic neurons in the substantia nigra (typically about 20% of normal) is adequate for conversion of levodopa to dopamine.Thus, in new patients, the therapeutic response to levodopa is consistent, and the patient rarely complains that the drug effects “wear off.” o Unfortunately, with time, the number of neurons decreases and fewer cells are capable of converting exogenously administered levodopa to dopamine. o Consequently, motor control fluctuation develops. Relief provided by levodopa is only symptomatic, and it lasts only while the drug is present in the body. o Combination of L-dopa with COMT-inhibitor e.g. entacapone in order to inhibit its degradation improves its clinical response. ❑ Therapeutic uses: o It decreases rigidity, tremors, and other symptoms of parkinsonism. o Patients typically experience a decline in response during the 3rd to 5th year of therapy. Withdrawal from the drug must be gradual. ❑ Absorption and metabolism: o The drug is absorbed rapidly from the small intestine (when empty of food). o Levodopa has an extremely short half-life (1 to 2 hours), which causes fluctuations in plasma concentration. This may produce fluctuations in motor response. o Motor fluctuations may cause the patient to suddenly lose normal mobility and experience tremors, cramps, and immobility. 7  o Ingestion of meals, particularly if high in protein, interferes with the transport of levodopa into the CNS. Thus, levodopa should be taken on an empty stomach, typically 30 minutes before a meal. ❑ Adverse effects: a) Peripheral effects: o Tachycardia result from dopaminergic action on the heart. o Hypotension may also develop. Adrenergic action on the iris causes mydriasis. o Saliva and urine have brownish color because of the melanin pigment produced from catecholamine oxidation. b) CNS effects: o Anorexia and nausea occur because of stimulation of the chemoreceptor trigger zone. o Visual and auditory hallucinations and abnormal involuntary movements (dyskinesias). o These effects are the opposite of Parkinsonian symptoms and reflect over-activity of dopamine in the basal ganglia. o Levodopa can also cause mood changes, depression, psychosis, and anxiety. ❑ Interactions: o The vitamin pyridoxine (B6) increases the peripheral breakdown of levodopa and diminishes its effectiveness. o Concomitant administration of levodopa and ), such as phenelzine, can produce a hypertensive crisis caused by enhanced catecholamine production. o Cardiac patients should be carefully monitored for the possible development of arrhythmias. o Antipsychotic drugs are generally contraindicated in Parkinson’s disease, because they potently block dopamine receptors and may augment parkinsonian symptoms. However, Some drug interactions observed with low doses of atypical antipsychotics are sometimes used to Levodopa. MAO=monoamine oxidase treat levodopa-induced psychotic symptoms. B. Selegiline(deprenyl) and rasagiline ❑ Selegiline selectively inhibits monoamine oxidase (MAO) type B (metabolizes dopamine) at low to moderate doses. It does not inhibit MAO type A (metabolizes norepinephrine and serotonin) unless given above recommended doses, where it loses its selectivity. ❑ By decreasing the metabolism of dopamine, selegiline increases dopamine levels in the brain. ❑ When selegiline is administered with levodopa, it enhances the actions of levodopa and hence reduces the required dose. ❑ Unlike nonselective MAOIs, selegiline at recommended doses has little potential for causing hypertensive crises. ❑ Selegiline is metabolized to methamphetamine and amphetamine, whose stimulating properties may produce insomnia if the drug is administered later than mid-afternoon. ❑ Rasagiline, an irreversible and selective inhibitor of brain MAO type B, has five times the potency of selegiline. ❑ Unlike selegiline, rasagiline is not metabolized to an amphetamine-like substance. 8 C. Catechol-O-methyltransferase inhibitors ❑ Normally, the methylation of levodopa by (COMT) to 3-O-methyldopa is a minor pathway for levodopa metabolism. ❑ However, when peripheral dopamine decarboxylase activity is inhibited by carbidopa, a significant concentration of 3-O-methyldopa is formed that competes with levodopa for active transport into the CNS. Entacapone and tolcapone selectively and reversibly inhibit COMT. ❑ Inhibition of COMT by these agents leads to decreased plasma concentrations of 3-O-methyldopa, increased central uptake of levodopa, and greater concentrations of brain dopamine. Both of these agents reduce the symptoms of “wearing-off” phenomena seen in patients on levodopa−carbidopa. Effect of entacapone on dopa concentration in the CNS. COMT = catechol-O- methyltransferase. ❑ Adverse effects: o Diarrhea, postural hypotension, nausea, anorexia, dyskinesias, hallucinations o Most seriously, fulminating hepatic necrosis is associated with tolcapone use. Therefore, it should be used, along with appropriate hepatic function monitoring, only in patients in whom other modalities have failed. Entacapone does not exhibit this toxicity and has largely replaced tolcapone. D- Dopamine receptor agonists ❑ This group of antiparkinsonian compounds includes bromocriptine, an ergot derivative, the nonergot drugs, ropinirole, pramipexole, rotigotine, and the newer agent, apomorphine. ❑ They have a longer duration of action than that of levodopa and are effective in patients exhibiting fluctuations in response to levodopa. Initial therapy with these drugs is associated with less risk of developing dyskinesias and motor fluctuations as compared to patients started on levodopa. ❑ However, these drugs are ineffective in patients who have not responded to levodopa. ❑ Apomorphine is an injectable dopamine agonist that is used in severe and advanced stages of the disease “e.g. acute management of the hypomobility “off” phenomenon”. ❑ Bromocriptine: Its actions are similar to those of levodopa, except that hallucinations, confusion, delirium, nausea, and orthostatic hypotension are more common, whereas dyskinesia is less prominent. ❑ In psychiatric illness, bromocriptine may cause the mental condition to worsen. 9 ❑ It should be used with caution in patients with a history of myocardial infarction or peripheral vascular disease. ❑ Because bromocriptine is an ergot derivative, it has the potential to cause pulmonary and retroperitoneal fibrosis. ( the presence of inflammation and fibrosis in the retroperitoneal space) ❑ Rotigotine is administered as a once-daily transdermal patch that provides even drug levels over 24 hours. These agents alleviate the motor deficits in patients who have never taken levodopa and also in patients with advanced Parkinson’s disease who are treated with levodopa. ❑ Adverse Effect and Drug Interaction ❑ Side effects severely limit the utility of the dopamine agonists. o Pramipexole is excreted unchanged in urine; dosage adjustments are needed in renal disease. o The fluoroquinolone antibiotics and other inhibitors of the cytochrome P450 (CYP450) 1A2 isoenzyme (for example, fluoxetine) may inhibit the metabolism of ropinirole, requiring an adjustment in ropinirole dosage. E. Amantadine ❑ It was accidentally discovered that the antiviral drug amantadine, used to treat influenza, has an antiparkinsonian action. ❑ Amantadine has several effects on a number of neurotransmitters implicated in Parkinsonism, including increasing the release of dopamine, blocking cholinergic receptors, and inhibiting the N- methyl d- aspartate (NMDA) type of glutamate receptors “main mechanism”. ❑ The drug may cause restlessness, confusion, and hallucinations, and, at high doses, it may induce acute toxic psychosis, orthostatic hypotension, urinary retention, peripheral edema, and dry mouth. ❑ Amantadine is less efficacious than levodopa, and tolerance develops more readily. However, amantadine has fewer side effects. F. Anticholinergic agents ❑ Antimuscarinics are much less efficacious than levodopa and play only an adjuvant role in therapy. ❑ The action of benztropine, trihexyphenidyl, procyclidine, and biperiden are similar, although individual patients may respond more favorably to one drug. ❑ Adverse Effects o These agents can induce mood changes and produce dryness of the mouth, constipation, and visual problems typical of muscarinic blockers. o They interfere with gastrointestinal peristalsis and are contraindicated in patients with glaucoma, prostatic hyperplasia, or pyloric stenosis. 10