Pharmacology-2 Past Paper PDF (BUE 2024-2025)

Pharmacology-2, BUE, 2024-2025, Prof. Dr. Marwa Safar Drugs affecting the Central Nervous System Drugs used in the management of Neurodegenerative diseases Learning Objectives: 1- Demonstrate understanding of dopaminergic neural pathways. 2- Classify antiparkinsonian drugs. 3- Compare the mechanism of action and side effects of antiparkinsonian drugs. Neurodegenerative diseases: neuronal damage in certain brain areas. Causes of neuronal damage: 1. Excessive excitotoxicity (excess glutamate → acts on N methyl aspartate receptors NMDA). 2. Stroke, head trauma. 3. Oxidative stress →  reactive oxygen species (ROS) →  free radical as OH.. 4. Apoptosis (programmed cell death). Q. Why is it difficult to treat neurodegenerative diseases? As CNS neurons CANNOT divide or regenerate once they are damaged, they cannot be regenerated → so treatment is symptomatic not alter progression of disease. Examples of neurodegenerative diseases: Parkinson’s disease, Alzheimer, Huntington, Multiple sclerosis. Dopaminergic neurons pathways: In the CNS, dopamine (DA) is a precursor to NE in noradrenergic pathways and is a neurotransmitter in the following major dopaminergic pathways: ❖ Nigrostriatal tract: cell bodies in the substantia nigra project to the stratium, where they release DA, which inhibits GABA-ergic and cholinergic neurons → regulates kinesis (movement). ❖ Mesolimbic-mesocortical tracts: Cell bodies in midbrain project to cerebrocortical and limbic structures and release dopamine. Regulates cognitive functions, sensory perception, psychomotor functions. ❖ Tuberoinfundubular: Cell bodies in hypothalamus project to anterior pituitary and release dopamine →  prolactin. ❖ Chemoreceptor trigger zone: in medulla activation of DA receptors →  emesis 1 Pharmacology-2, BUE, 2024-2025, Prof. Dr. Marwa Safar PARKINSON'S DISEASE "Paralysis Agitans" Management Overview of Parkinson’s disease The second common neurodegenerative disease after Alzheimer’s disease. Definition: It is a progressive neurological disorder of muscle movement, characterized by the 4 cardinal motor features: Resting Tremors (involuntary trembling when a limb is at rest), Muscular rigidity (inability to initiate movements), Bradykinesia (slowness in initiating & carrying out voluntary movement), Abnormal posture and gait (shuffling gait). In late-stage disease, the patient may be physically disabled, wheelchair bound, or bedridden. It occurs mainly in elderly people over the age of 65. It was first described by James Parkinson. Non motor symptoms: depression, dementia, sleep disturbances. Etiology: neurodegeneration in the inhibitory dopaminergic (DA) neurons relative to excitatory cholinergic (Ach) neurons in the nigrostriatal tract (Dopamine is formed in the substantia nigra, dopaminergic neurons are connected to the striatum; a cluster of neurons in the basal ganglia which contains cholinergic neurons and control movement). 2 Pharmacology-2, BUE, 2024-2025, Prof. Dr. Marwa Safar Classification: Primary (Idiopathic) Parkinson’s disease (PD): due to degeneration of > 80% of dopaminergic neurons secreting dopamine in the substantia nigra → imbalance between the excitatory cholinergic neurons (Ach) & the inhibitory dopaminergic neurons (DA) i.e  DA &  Ach. N.B. Oxidative stress  formation of free radicals in the substantia nigra  degeneration of dopaminergic neurons. Aging also leads to gradual loss of DA neurons. Secondary Parkinsonism “Atypical Parkinsonism”: The imbalance between Ach & DA ( DA &  Ach) is due to: Vascular Parkinsonism – Resulting from multiple small strokes affecting parts of the brain related to movement control (small vessel cerebral ischemia). Post-Traumatic Parkinsonism – Caused by repeated head trauma, as seen in some athletes. Toxin-Induced Parkinsonism – Resulting from exposure to certain toxins (e.g., carbon monoxide, manganese, or pesticides). Infectious Parkinsonism – Linked to infections like encephalitis that damage the brain's motor regions. Drug-induced → Dopamine blockers (e.g: antipsychotics). 3 Pharmacology-2, BUE, 2024-2025, Prof. Dr. Marwa Safar Treatment Treatment goal: restoring the balance between Ach & DA in the basal ganglia   DA &  Ach. Treatment leads to temporary relief of symptoms and slow but not prevent progression of disease (symptomatic treatment). Anti-Parkinsonian drugs  DA  Ach 1. Dopaminergic drugs e.g. l-dopa. - Anticholinergic drugs. 2. Dopamine receptor agonists. 3. Dopamine releasers. 4. Selective MAOB inhibitors. I. Dopaminergic drugs 1. Levodopa (l-dopa): Mechanism of action: Dopamine itself does not cross the BBB (not lipid soluble), but its precursor levodopa is readily transported into the CNS and is converted to dopamine in the brain by the enzyme dopa decarboxylase→ thus restoring DA & Ach balance. Number of surviving DA neurons in the substantia nigra should be adequate for conversion of l-dopa to DA (80% of the Dopaminergic neurons are degenerated so the remained 20% should be intact to convert l-dopa to DA so that drug gives effect). Required CNS=Basal ganglia L-dopa Dopa decarboxylase Dopamine  DA NOT required Peripherally Q: Large doses of levodopa (l-dopa) are required why? Because most of the drug (>90%) is decarboxylated to dopamine in the periphery (gut, blood, liver) resulting in peripheral adverse effects. Peripheral dopa decarboxylase inhibitors: Carbidopa or Benserazide: Selective peripheral (extra-cerebral) dopa decarboxylase inhibitor that does not cross the blood-brain barrier. l-dopa + carbidopa (Sinemet® or benserazide)  Availability of l-dopa to the CNS.  Dose of l-dopa to 1/5.  S.Es of the peripheral formed DA. Levodopa/Carbidopa combination produces good control on disease symptoms but this effect starts to decline from the 3rd to 5th year. dopamine L-dopa Dopa decarboxylase Carbidopa Peripherally Inhibited by Or Benserazide L-dopa Dopa decarboxylase dopamine Centrally 4 Pharmacology-2, BUE, 2024-2025, Prof. Dr. Marwa Safar COMT inhibitors: Entacapone & Tolcapone: L-dopa undergoes O-methylation by COMT to inactive metabolite (3-O-methyldopa); minor pathway for levodopa metabolism. However, when peripheral dopamine decarboxylase is inhibited by carbidopa, a significant concentration of 3-O-methyldopa (partial agonist at dopamine receptors) is formed that competes with l-dopa for active transport into the CNS. A peripheral COMT inhibitor is given together with L-dopa to protect it from destruction by COMT. l-dopa + Entacapone or Tolcapone  degradation of L-dopa  side effects  doses required.  availability of L-dopa to the CNS. Treatment= L-dopa + Carbidopa + Entacapone (Stalevo®) Carbidopa: peripheral dopa decarboxylase inhibitor. Entacapone: peripheral COMT inhibitor  Availability of L-dopa in CNS Greater more L-dopa crosses the BBB  More constant (sustained) Dopaminergic stimulation in the brain  symptoms of the disease. S.Es of the peripherally formed dopamine. Central COMT inhibitor  overcomes short half life N.B. Tolcapone causes hepatotoxicity. only be used in patients in whom other modalities have failed. Pharmacokinetics: 1. Short t½ (1-2 hrs) → fluctuations in plasma concentration. 5 Pharmacology-2, BUE, 2024-2025, Prof. Dr. Marwa Safar Fluctuations in plasma & hence brain concentration that rise and fall several times over a day→ "on-off phenomenon" due to short half-life of L-dopa→ fluctuations in motor respone. i.e the patient’s response to each dose consists of swinging between a. ON → no symptoms of parkinson’s i.e parkinson’s free period (mobility). b. OFF→ parkinson’s symptoms appear (immobility, freezing) How to overcome the on-off phenomenon? 1- Giving more small frequent doses of levodopa or a sustained-release preparation 2- Combined treatment with a direct dopamine receptor agonist. 3- COMT inhibitor Wear-off phenomenon “End of dose deterioration” → improvement gained from a dose of levodopa medication gradually fades off and does not last until the time that the next dose of levodopa is due or begins to work, i.e the duration of clinical response shortens with chronicity of treatment. Therefore, the patient may want to take the next dose sooner Why? because with time most dopaminergic neurons are degenerated and fewer cells are capable of converting exogenously administered levodopa to dopamine. Food (high protein diet; amino acids) →  Absorption of L-dopa from small intestine→ so take 30 minutes before a meal. L-dopa is absorbed from the upper small intestine by active amino acid transport and crosses the blood brain barrier by a similar amino acid transporter that normally transports amino acids into the brain, so if protein is taken  compete with L-dopa → absorption of L-dopa. Adverse effects of l-dopa:  DA centrally & peripherally 1. Central side effects a.  DA in the striatum → Dyskinesia: Excessive abnormal involuntary purposeless movements develop usually within 4-10 years of starting l-dopa therapy (oral and facial musculature, patients can appear as if they are chewing on large pieces of food while protruding their lips, writhing and flinging movements of the arms and legs) WHY? due to Long-term use of levodopa leads to the overstimulation of dopamine receptors (specifically D1 and D2 receptors) in certain parts of the brain, such as the basal ganglia, which controls movement. This overstimulation is linked to the abnormal movements seen in dyskinesia. The supersensitivity of these receptors to levodopa occur because the brain compensates for the progressive loss of dopamine-producing neurons by becoming more sensitive to the dopamine provided by levodopa. b. DA in the mesolimbic and mesocortical pathways  Delusions, Hallucinations & psychosis, mood changes, anxiety & depression (CI in psychosis). Low doses of atypical antipsychotics (with weak dopamine antagonism), such as quetiapine are used to treat levodopa induced psychosis. 2. Peripheral side effects 1.  dopamine in CTZ in medulla → nausea, vomiting & anorexia (loss of appetite). Most common side effect. How to overcome? D2 blocker that acts only peripherally (Domperidone). Why not metoclopramide? As it crosses BBB. 6 Pharmacology-2, BUE, 2024-2025, Prof. Dr. Marwa Safar 2.  β1→ tachycardia and arrhythmia. 3. Postural hypotension due to a. Dopamine is a vasodilator. b. V.D. of renal blood vessels (D 1 receptor)renal blood flow  sodium excretion (natriuresis) which can reduce blood volume and lead to lower blood pressure. 4. Catecholamine oxidation →  melanin pigment, homovanellic acid → Brown saliva, sweat and urine. 5. Mydriasis → stimulate -receptor on radial muscle in high doses only (CI in acute angle closure glaucoma). Drug interactions: 1. Vit B6 (pyridoxine)  peripheral decarboxylation of l-dopa to dopamine  efficacy of l-dopa. 2. Levodopa + nonselective MAO inhibitors (eg Phenelzine, antidepressants) → dopamine formed from levodopa is not destructed and is converted to noradrenaline → →  catecholamine accumulation →  BP (hypertensive crisis). 3. Anti-psychotics (D2-blockers) → cause parkinsonian syndrome, decrease effect of L- dopa so better avoided in PD patients. 4. Cardiac patients should be monitored because of the risk of cardiac arrhythmias. II. Dopamine receptor agonists Stimulate D2 receptors in the striatum, act like dopamine. These drugs are ineffective in patients who have not responded to levodopa Their main advantage over levodopa: they don’t result in significant motor fluctuations or dyskinesias Why? As they have longer duration of action (t1/2) and they are not dependent on presynaptic conversion to dopamine by dopa decarboxylase. Used as initial therapy in patients who have mild PD and a younger age of onset or as adjuncts to levodopa in patients with severe motor fluctuations (on–off phenomena, wearing off). They decrease the dose of L-dopa in advanced PD. Adverse effects: Like L-dopa 1-  dopamine in CTZ in medulla → nausea, vomiting. 2- Confusion, psychomotor excitation, hallucination (N.B. Neuropsychiatric disorders are more frequent than with levodopa monotherapy). 3- Orthostatic hypotension. 1. Bromocriptine (Ergotamine derivative; Parlodel®) Drug–disease interactions: 1. Worsening of patient with peripheral vascular disease (due to vasoconstriction as it is ergotamine derivative which stimulates alpha receptors and serotonin receptors) 2. Serious cardiac problems in patients with history of myocardial infarction due to vasospasm risk. 7 Pharmacology-2, BUE, 2024-2025, Prof. Dr. Marwa Safar 3. In psychiatric illness, bromocriptine and l-dopa may cause mental condition to worsen. N.B. Prolonged use cause pulmonary fibrosis 2. Non ergot drugs: Apomorphine, Pramipexole, Ropinirole, Rotigotine Apomorphine as s.c injection is used for acute management of ‘off’ periods (patients may be stuck or frozen in one position), but it causes severe nausea → must be preceded by antiemetic. Pramipexole, Ropinirole taken orally Rotigotine once daily transdermal patch III. Drugs inducing dopamine release Amantadine: "Antiviral against influenza A virus" -  Release and  reuptake of dopamine in surviving neurons. - Anticholinergic action (block M)  Ach. It’s less effective than L-dopa, its actions  with time and tolerance develops rapidly to its use. Used in early disease, especially in younger patients and as an adjunct to L-dopa to reduce dyskinesias. S.Es: those of L-dopa + urinary retention & dry mouth (atropine like)+ Skin discoloration (Levido reticularis; mottled skin due to dilatation of blood vessels; harmless). About 95% is eliminated by the kidneys and it should not be used in patients with renal failure IV. Monoamine oxidase B inhibitors (MAOB inhibitors) 1. Selegiline (Deprenyl) - Irreversible selective inhibitor of MAOB →inhibit dopamine breakdown→ DA in brain (No effect on MAOA which metabolizes NE and 5-HT) - Uses: single drug in early or mild PD, combined (adjunct) with L-dopa → L-dopa action,  L-dopa required dose, improve motor function in patients who experience wearing off and on-off difficulties with levodopa. S.Es: Deprenyl is metabolized into amphetamine & methamphetamine  insomnia, & anxiety if the drug is administered later than midafternoon. Contraindications: - Unlike nonselective MAO inhibitors  NO hypertension crisis when combined tyramine-containing food as MAOA in the liver and sympathetic nerve endings can metabolize tyramine. BUT at high doses (six times the therapeutic dose), selectivity is lost, inhibit both MAOA & MAOB  hypertensive crisis. 8 Pharmacology-2, BUE, 2024-2025, Prof. Dr. Marwa Safar 2. Rasagiline: Irreversible selective inhibitor of MAOB, 5 times more potent than selegiline. Can be used as monotherapy in early stages or combined with L- dopa. It is not metabolized to an amphetamine like substance. V. Anticholinergics e.g. Benztropine, Trihexyphenidyl, Procyclidine, & Biperiden - Restore the balance between dopamine and ACh in the Neostriatum. - Pharmacological actions:  Tremors, Rigidity only (but not bradykinesia) so used as adjuvant therapy (effect l-dopa). Drug of choice for PD caused by D2 blockers Why?? Anti psychotics decrease dopamine so it's essential to give d2 blocker to avoid extra hallucinations - Improve sialorrhea - Side effects: Atropine like side effects: mydriasis, blurred vision, urinary retention, xerostomia (dry mouth), decreased GIT motility (constipation) & decreased memory and concentration, confusion with visual hallucination. - Contraindications: glaucoma, prostatic hypertrophy.  DA level or effect in the Striatum  Ach level or effect in the Striatum Adv: treat all signs & symptoms including Adv:  Tremors & Rigidity only (adjuvant bradykinesia only) S.Es: Nausea, Vomiting, Anorexia S.Es: Atropine S.Es Tachycardia=arrhythmia. due to b1 Postural hypotension.due to d1 Psychosis (centrally). e.g. l-dopa, Bromocriptine, Amantadine, e.g. Benztropine, Trihexyphenidyl & Deprenyl. Biperiden Adverse effects of: levodopa dopamine agonists 9 Pharmacology-2, BUE, 2024-2025, Prof. Dr. Marwa Safar Video Links: Parkinson’s disease Parkinson’s symptoms https://www.youtube.com/watch?v=TNB2oAAMEyg https://www.youtube.com/watch?v=j86omOwx0Hk Parkinson’s disease and dopamine https://www.youtube.com/watch?v=7upHDhAmkqU Parkinson’s disease treatment https://www.youtube.com/watch?v=5hM8xUB07Y0 Ways to increase your dopamine (motivational video) https://www.youtube.com/watch?v=4p3X0DrTehI 10 Pharmacology-2, BUE, 2024-2025, Prof. Dr. Marwa Safar ANTIPSYCHOTICS “Antischizophrenics” Learning Objectives: - Demonstrate understanding of Schizophrenia. - Classify antipsychotic drugs. - Compare and contrast the mechanism of action and side effects for drugs used in Parkinson’s disease with antipsychotic drugs. Schizophrenia (Schizen = to split, phrenia = mind): a type of chronic psychosis. The disease is usually characterized by recurrent acute episodes which develops into chronic disease. It is characterized by the following symptoms. N.B. In psychosis patient is not aware of his illness (absent insight), Opposite to neurosis. Pathophysiology:  Dopamine,  5-HT in the brain cortex and limbic system. Positive (+ve) symptomsNegative (–ve) symptoms - Excess or distortion of - Reduction or lack of normal normal functions functions. Onset - Acute schizophrenia - Chronic schizophrenia (early stage of disease)(late stage of disease) Delusions (false beliefs, a. Alogia (Poverty of speech). Paranoia). b. Anhedonia (Lack of interest a. Hallucinations (false perception, in life activities). often auditory) c. Apathy (Loss of motivation Description b. Thought disturbance. & energy). c. Speech disturbance. d. Cognitive and attention d. Bizarre behavior impairment. e. Social withdrawal f. Emotional blunting. Due to over activity of Due to  serotonin (5-HT) in Pathogenesis dopamine (DA) in the the mesolimbic system mesolimbic system. Etiology: Strong evidence for the genetic hereditary factors. The onset of illness is often during late adolescence or early adulthood. It occurs in about 1% of the population. Schizophrenia has a strong genetic component Treatment Antipsychotic drugs are not curative and do not eliminate chronic thought disorders, but they decrease the intensity of bizarre behavior, hallucinations and delusions and permit the patient to function in a supportive environment. Pharmacology-2, BUE, 2024-2025, Prof. Dr. Marwa Safar A- First Generation “Typical= conventional=traditional=classical" Antipsychotics “historically called neuroleptics, and major tranquilizers” : mainly block D2 in the mesolimbic system more than 5-HT2A a- Phenothiazines: Chlorpromazine (CPZ), Fluphenazine, Prochlorperazine,, Trifluoperazine b- Thioxanthenes: Thiothixene, Flupenthixol (Flupentixol) c- Butyrophenones: Haloperidol d- Substituted benzamide: Sulpiride B- Second Generation “Atypical = non-classical" Antipsychotics: block mainly 5-HT2A than D2 in the mesolimbic system Risperidone - Ziprasidone- Aripiprazole- Brexpiprazole- Clozapine – Olanzapine– Quetiapine - Pimavanserin. Mechanism of action, pharmacological actions & adverse effects: They have many actions as they block many receptors with variable affinities: a. DA receptors (D2 most important, D1, D4). b. 5-HT receptors (especially 5-HT2A). c. Adrenergic receptors (α1). d. Cholinergic receptors (M) specially clozapine and olanzapine. e. Histamine receptors (H1). 1. Antipsychotic action: a. Competitive Blocking of D2 receptor in the mesolimbic system. All antipsychotics (both first & second generation) block D2 receptors in the mesolimbic system of brain → antipsychotic. The stronger the blocking D2 activity  the greater the antipsychotic effect (e.g. Haloperidol). b. Blocking of 5-HT2A receptor in the mesolimbic system. Mainly Second generation blocks 5-HT2A+ D2 receptors → antipsychotic. The +ve symptoms are relieved by typical, atypical antipsychotics, while the –ve symptoms are relieved by the atypical agents only. The antipsychotic effect takes several weeks to fully develop, suggesting that the therapeutic effects are due to 2ry changes in the brain, rather than only receptor blockade. 2. Extrapyramidal symptoms “EPS” = Motor disturbances=Dyskinesias: Due to blocking of D2 in nigrostriatal pathway (basal ganglia)→  ACh relative to DA. Movement disorders is time and dose dependent as follows: a- Dystonia  sustained muscle contraction often affects neck and facial muscles (facial grimacing) accompanied by twisting and distorted posture. It occurs within few hours to days of the treatment Pharmacology-2, BUE, 2024-2025, Prof. Dr. Marwa Safar b- Akathisia  inability to sit still, motor restlessness, foot tapping, moving of legs repetitively. Occurs within days to weeks. c- Parkinson’s like symptoms (pseudoparkinsonism) bradykinesia, tremors, rigidity. Occurs within weeks to months. d- Tardive dyskinesia: Involuntary repetitive movements of facial jaw (chewing), tongue (fly catching, tongue may be injured), puffing of cheeks, trunk, neck, lip smacking, and limbs. * It occurs lately after chronic treatment (months to years) WHY?? Due to increased number of dopamine receptors that are synthesized as a compensatory response to long- term dopamine receptor blockade (upregulation). Thus the neuron are supersensitive to the actions of dopamine. N.B. Dystonia, akathisia, and pseudoparkinsonism are considered acute EPS while tardive dyskinesia is considered chronic EPS. Treatment: 1. Anticholinergics (e.g. benztropine, procyclidine, orphenadrine): Blocking both D and Ach receptors restores the balance between them and improves extrapyramidal effects. 2. Antipsychotics with strong anticholinergic activity (e.g. clozapine) i.e. D2 Blockers with strong M-blocking activity. 3. Akathisia is managed by β blockers (e.g. propranolol, Nadolol) or benzodiazepines, better than anticholinergics. 4. Reducing the dose N.B. Tardive dyskinesia is irreversible and resistant to treatment. Anticholinergic drugs may worsen tardive dyskinesia. A prolonged holiday from antipsychotics may cause the symptoms to diminish or disappear within a few months. However, in many individuals, tardive dyskinesia is irreversible and persists after discontinuation of therapy.. Atypical antipsychotics produce less motor disturbances than typical agents, why? Because atypical are more selective D2-blockers in the mesolombic system than for the nigrostriatal system (basal ganglia). 3. Antiemetic effect: Blocking of D2 receptors in the chemoreceptor trigger zone (CTZ) in the medulla. Pharmacology-2, BUE, 2024-2025, Prof. Dr. Marwa Safar 4. Endocrine effect: “Hyperprolactinemia” Blocking of D2 in anterior pituitary (tuberoinfundibular pathway) removing the inhibitory effect of dopamine on prolactin) → hyperprolactinemia =  Prolactin causing: a. In Females: galactorrhea (inappropriate milk secretion without childbirth), menstrual abnormalities including amenorrhea (absence of menstruation) and infertility. b. In males: gynecomastia (enlarged male breast) & impotence. Second generation are less likely to produce prolactin elevation. Bromocritpine and amantadine that reduce prolactin secretion may help. 5. CVS actions: a. Postural hypotension (due to blocking of α1 receptors). N.B. blocking of α1 receptors leads to failure of ejaculation which leads to patient non- compliance. b. Tachycardia as a reflex action to hypotension and due to anticholinergic effect (M-blocking activity). N.B. Thioridazine was withdrawn from market due to arrhythmia. 6. Antimuscarinic effects: Atropine-like side effects: include blurred vision, dry mouth, confusion, inhibition of gastrointestinal and urinary tract smooth muscles leading to constipation and urinary retention This may be beneficial to counteract the EPS. 7. Sedative action: with agents that blocks H1 receptors in CNS e.g. chlorpromazine, olanzapine, quetiapine, and clozapine. 8. Weight gain:  appetite due to blocking of 5-HT2 receptors and is more with atypical ones (reason for non-compliance), and due to blocking H1 receptors. 9. Effect on body temperature: Alter body temperature regulating mechanisms → may produce poikilothermia (body temperature varies with the environment). 10. Second generation agents cause elevation of glucose and lipids ( appetite ) monitor blood glucose and lipid profile (exacerbation of preexisting diabetes or hyperlipidemia). 11. All antipsychotics  the seizure threshold and should be used cautiously in patients with seizure disorders. 12. Antipsychotic/Neuroleptic malignant syndrome: “Rare, fatal”:  body temperature + muscle rigidity + catatonia (patient appears frozen in position) in addition altered consciousness, autonomic disturbance leading to blood pressure swings, excessive sweating, excessive saliva. Pharmacology-2, BUE, 2024-2025, Prof. Dr. Marwa Safar The drug must be discontinued. Treated with Dantrolene (muscle relaxant) or dopamine agonists (Bromocriptine) + Cooling. Mostly caused by haloperidol (Typical antipsychotics) Therapeutic uses: 1. Treatment of Schizophrenia; Second-generation agents are generallyused as first-line therapy for schizophrenia to minimize the risk of EPS. N.B. - Clozapine is used only for patients who are resistant to other first or second generation therapy (refractory patients) or patients with substantial risk of suicide or history of suicide attempts as it has serious adverse effects: constipation that can progress to serious bowel complications, CVS effects (hypotensive effect), seizures, bone marrow suppression, neutropenia & agranulocytosis (low WBC count; leukopenia therefore increase infections) therefore blood monitoring is essential as well as blood pressure checking. It has a relatively higher affinity to D1 as well as D2 - Pimavanserin acts as antagonist at the 5-HT2A receptor, with no appreciableaffinity for dopamine receptors. Pimavanserin is only indicated for psychosis associated with Parkinson disease. 2. Antiemetic mainly in drug induced nausea (e.g. Prochlorperazine, Olanzapine). 3. Chlorpromazine is used to treat intractable (IM injection). 4. Risperidone and Aripiprazole are approved for the management of disruptive behavior and irritability secondary to autism. 5. Aripiprazole and Quetiapine are used as adjunctive agents with antidepressants for treatment of refractory depression and in bipolar depression. Drug Interactions: with anticholinergics, alpha blockers, antihistaminics, and CNS depressants. Remark: Long acting injectable formulations. There is slow absorption into the systemic circulation. Given once every two to four weeks For non adherent patients Pharmacology-2, BUE, 2024-2025, Prof. Dr. Marwa Safar Some video links: Schizophrenia - causes, symptoms and diagnosis https://www.youtube.com/watch?v=-xrv6wDNNvE Treatment of schizophrenia https://www.youtube.com/watch?v=stSvcwY0RWI https://www.youtube.com/watch?v=FUfL0rWCGCU Extrapyramidal symptoms and their treatments https://www.youtube.com/watch?v=nbYylG19y6g https://www.youtube.com/watch?v=ztRK2dbglpY Common adverse effects of antipsychotics Alzheimer’s Disease Alzheimer's disease is a common age-related dementia. Symptoms: loss of intellectual ability & learning deficit. Etiology: 1. Plaques (β-amyloid), neurofibrillary tangles (Tau protein accumulation) mainly in hippocampus. 2. Degeneration of cholinergic neurons ( Ach) in the cortex. Treatment: No effective therapy is available. Provides modest short-term benefits by lessening or stabilizing symptoms. Pharmacology-2, BUE, 2024-2025, Prof. Dr. Marwa Safar 1. Acetylcholinesterase inhibitors: Donepezil (Aricept®), Galantamine, and Rivastigmine They prevent breakdown of Ach in the neurons that are still functioning which supports communication among nerve cells. They have some selectivity for AChE in the CNS, as compared to the periphery. Used in mild to moderate cases. Donepezil is generally preferred since it can be given once daily. Rivastigmine The only agent approved for the management of dementia associated with Parkinson’s disease without generally worsening the patient’s motor symptoms (Because the basal ganglia also participate in procedural memory and other cognitive functions, patients with PD may have difficulty remember how to perform learned motor skills, such as driving a car). The only AChE inhibitor available as a transdermal formulation (Exelon®). It has no interactions with drugs that alter the activity of CYP450 enzymes. The other agents are substrates for CYP450 and have a potential for such interactions. Adverse effects: nausea, vomiting, diarrhea, anorexia, tremors, bradycardia, and muscle cramps. Treatment of overdose: Atropine 2. NMDA receptor antagonist (used in moderate to severe cases) Stimulation of glutamate receptors in the CNS is critical for memory. However, overstimulation of glutamate receptors, particularly of the NMDA type, assists in the opening of an ion channel that allows Ca2+ to enter the neuron. Excess intracellular Ca2+ results in excitotoxic effects on neurons, which in turn results in neurodegenerative or apoptotic (programmed cell death) processes. Memantine is an NMDA receptor antagonist indicated for moderate to severe Alzheimer’s disease. It blocks the NMDA receptor and limits Ca2+ influx into the neuron. It is often given in combination with an AChE inhibitor. 3. Aducanumab Aducanumab is an amyloid beta–directed monoclonal antibody. Administered intravenously. Aducanumab reduces amyloid beta plaques inthe brain, although it is uncertain if it delays disease progression. Adverse effects: amyloid-related imaging abnormalities such as brain edema or microhemorrhage, headache, and diarrhea. Pharmacology-2, BUE, 2024-2025, Prof. Dr. Marwa Safar Video Links: Alzheimer disease Alzheimer disease pathophysiology https://www.youtube.com/watch?v=dj3GGDuu15I Alzheimer's disease - Causes and Symptoms https://www.youtube.com/watch?v=OJp0BM5ujj0 https://www.youtube.com/watch?v=v5gdH_Hydes Alzheimer disease treatment https://www.youtube.com/watch?v=durV0mnzPo4 Adverse effects of ACHE inhibitors Pharmacology 2, 2024-2025, Prof. Dr. Marwa Safar DRUGS USED IN TREATMENT OF AFFECTIVE DISORDERS (MOOD DISORDERS) Learning Objectives: Demonstrate understanding of the pathophysiology of depression and mania. Classify antidepressants according to their mechanism of action. Enumerate clinical uses of antidepressants. Compare side effects of various antidepressants. The affective disorders include depression & mania. 1. Uni-polar depression → patient is always in depressed mood; most common. Signs of depression: Emotional symptoms: sadness, hopelessness, frustration, apathy, feeling of low self-esteem, and loss of motivation and interest in usual activities (anhedonia), feeling of guilt and suicidal thoughts. Biological symptoms (psychosomatic): loss of libido, sleep disturbances, anorexia, chronic pain. 2. Bipolar depression (manic depressive illness) → it is characterized by occurring episodes of elevated & depressed mood. Signs of mania: enthusiasm,  self-confidence, anger, rapid thought and speech patterns (non-stop talk), impaired judgment. Pathophysiology of Depression “Biogenic amine theory; monoamine theory of mental depression” Depression is due to  of monoamines especially NE and/or 5-HT in brain, whereas mania is due to  monoamines in brain.  expression of brain receptors 5HT2A, 5HT2C Neurotrophic and cytokines theory:  brain neurotrophic factor (BDNF), hypothalamus- pituitary axis dysregulation,  proinflammatory cytokines e.g: IL-1; IL-6; TNF-α Genetic (endogenous; major depressive disorder MDD; may not be associated with easily recognized causes) and social factors (exogenous or reactive depression) are involved. Episodes of MDD may occur at intervals throughout one’s lifetime. Pharmacology 2, 2024-2025, Prof. Dr. Marwa Safar ANTIDEPRESSANT DRUGS Treatment goal = NA and /or  5-HT in brain. Typical antidepressants: NA and /or  5-HT in brain. Atypical antidepressants: work by other mechanisms. 1. MONOAMINE OXIDASE INHIBITORS (MAOIs) Non-selective irreversible MAO inhibitors (blocks MAOA& MAOB) (Phenelzine, Isocarboxazid, Tranylcypromine). Selective MAOB inhibitors: Selegiline (Only antidepressant available as transdermal patch) MOA: MAOIs  inactivate MAO (reversible or irreversible) metabolism of NA, 5-HT, dopamine →  NA & 5-HT & dopamine leakage of greater amounts into synaptic space → activation of NE and 5-HT receptors → antidepressant effect. N.B. Their antidepressant effect is delayed for 2 weeks or more, and it persists for 2-3 weeks after stopping the drug [time taken for regeneration of a new enzyme]. Contraindications and precautions on use: MAOIs should not be taken with indirect acting sympathomimetics including tyramine that is present in aged cheese, yeast products, smoked fish, herring, chicken liver and red wine Why?? Tyramine (Metabolized by MAO in gut and liver)→ release NE→  blood pressure MAOIs →  NE release  blood pressure Tyramine + MAOIs hypertensive crisis Symptoms of hypertensive crisis: occipital headache, stiff neck, tachycardia, nausea, hypertension, cardiac arrhythmias, seizures, and possibly stroke Management of hypertensive crisis: −blockers e.g. phentolamine Certain sympathetic drugs used in the treatment of cold symptoms (decongestants) interact with MAO inhibitors causing the potentiation of the effect of sympathetic agents. Uses: Last line antidepressants in unresponsive patients The use of MAOI is now limited due to dietary restrictions. Pharmacology 2, 2024-2025, Prof. Dr. Marwa Safar 2. TRICYCLIC ANTI DEPRESSANTS (TCAs); named after their 3 ringed structure Amitriptyline, Clomipramine, Trimipramine, Nortriptyline, Protriptyline, Imipramine, Desipramine, Doxepin MOA TCAs inhibit the neuronal re-uptake of NE and 5-HT→  NE and 5-HT in the Brain.1 → antidepressant action (elevates mood). Effect is delayed for 2-3 weeks. maximum benefit may require up to 12 weeks or more. 2. Muscarinic antagonists, Have strong Anticholinergic activity “Strong Atropine actions”. 3. H1-blocker “Anti-histaminic” Sedative. 4. α1 blocker USES 1. Depression 2. Nocturnal enuresis (especially IMIPRAMINE due to Anticholinergic=Atropine like actions). 3. Panic disorder. 4. Severe chronic pain as diabetic peripheral neuropathy, trigeminal neuralgia. 5. Insomnia. 6. Prevent migraine (particularly Amitriptyline) Adverse effects: 1. Anticholinergic (Atropine) adverse effects; dry mouth, constipation, urine retention (C.I. in Prostatic patients), tachycardia, blurred vision, aggravating glaucoma,..etc. 2. Sedation due to H1 blocking activity (given at night) 3. Orthostatic (postural) hypotension and reflex tachycardia due to 1 blocking activity. 4. Weight gain. Over dose: 3Cs: Coma (excessive sedation), Convulsions, Cardiac arrhythmias (depress cardiac conduction) N.B. Because depressed patients might attempt suicide, the safety of an antidepressant in overdose is an important consideration when selecting a drug for a particular patient. Treatment of Adverse Effects: arrhythmia can be treated by the intravenous administration of sodium bicarbonate. Sodium bicarbonate increases the ratio of nonionized TCA to ionized TCA and thereby decreases the binding to the sodium channel in cardiac membranes. N.B. 1. Tolerance to the Anticholinergic properties and autonomic effects of the TCAs develops within a short time BUT NO tolerance to the antidepressant effect. 2. Therapeutic index: narrow, Monitoring is essential Pharmacology 2, 2024-2025, Prof. Dr. Marwa Safar 2. SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs) Fluoxetine [prototype], Paroxetine, Sertraline, Fluvoxamine, Citalopram, Escitalopram (S-enantiomer of citalopram) Mechanism of action: SSRIs  U1 of 5-HT mainly  selectively inhibit the neuronal reuptake of 5-HT → 5-HT level in the synapse → antidepressant effect after 2-3 weeks, maximum benefit may require up to 12 weeks or more. Little blocking of muscarinic, α-adrenergic, and histamine H1 receptors → less side effects than TCAs. Clinical uses: 1. Depression (Expensive drugs opposite to TCAs), Drug of Choice 2. Generalized anxiety disorder (GAD). 3. Eating disorders “Bulimia nervosa and anorexia nervosa”. Fluoxetine is FDA-approved for treating bulimia. 4. Premenstrual dysphoric disorder (PMDD). 5. Panic disorder. 6. Obsessive compulsive disorder (OCD). 7. Posttraumatic stress disorder (PTSD). 8. Social anxiety disorder Adverse effects: 1. Gastrointestinal side effects (nausea, diarrhea), take after food. 2. Agitation & Insomnia (given at day time) 3. Sexual dysfunction. 4. Changes in weight Advantages over TCAs: NO anticholinergic side effects, NO sedation, Less weight gain. Dapoxetine Increase blood pressure Drug interactions: 1. Most SSRIs inhibit HME (hepatic microsomal enzymes=CytP450)  activity of drugs that are metabolized by CytP450 Toxicity e.g. TCAs, -blockers. SSRIs (inhibit reuptake of 5-HT) + MAOIs (inhibit destruction of 5-HT)  5-.3 HT life threatening serotonin syndrome (agitation, restlessness, confusion, insomnia, hypertension, and gastrointestinal symptoms and if severe may cause hyperthermia, muscle rigidity, sweating, seizures and changes in mental status Pharmacology 2, 2024-2025, Prof. Dr. Marwa Safar and vital signs). Both types of drugs require at least 2 weeks washout period before the other type starts. N.B. Serotonin syndrome also occurs due to over dose of SSRIs. Discontinuation syndrome: Occurs after abrupt withdrawal, Symptoms: headache, malaise, and flu-like symptoms, agitation and irritability, nervousness, and changes in sleep pattern. Gradual tapering of the SSRIs is recommended to preventor reduce symptoms of discontinuation syndrome 4. Serotonin/Norepinephrine reuptake inhibitors (SNRIs) Venlafaxine, Desvenlafaxine (demethylated venlafaxine; active metabolite of venlafaxine), Duloxetine, Milnacipran, Levomilnacipran MOA: inhibit the reuptake of both 5-HT and NE. SNRIs, unlike the TCAs, have little activity at α, M, H receptors →  adverse effects than the TCAs. Uses: 1- Depression in patients in whom SSRIs are ineffective 2- Chronic painful symptoms accompanying depression (e.g. back and muscle aches). This pain is modulated by both 5-HT and NE pathways therefore SSRIs are relatively ineffective 3- Chronic neuropathic pain (diabetic peripheral neuropathy, fibromyalgia, postherpetic neuralgia, low back pain). 4- Generalized anxiety disorder. Adverse effects: Gastrointestinal issues: Nausea, constipation, dry mouth. Central Nervous System effects: Headache, dizziness, insomnia. Cardiovascular effects: Increased blood pressure and heart rate. Sexual dysfunction: Decreased libido, erectile dysfunction. Other: Sweating, weight changes. May precipitate a discontinuation syndrome if abruptly stopped. Pharmacology 2, 2024-2025, Prof. Dr. Marwa Safar ATYPICAL ANTIDEPRESSANTS Mixed group of agents that have actions at several different sites. 5. Serotonin Receptor Antagonists Nefazodone, Trazodone Mirtazepine - Block the 5-HT2A receptor, a G-protein coupled receptor located in several brain regions. It is believed that post-synaptic 5-HT2A overdensity is involved in the pathogenesis of depression. - Mirtazapine blocks presynaptic 2 autooceptor (responsible for negative feedback of transmission release)→  NE & 5HT release - Nefazodone, Trazodone block 1 receptor → postural hypotension - They are sedatives, because of their potent histamine H1-blocking activity (Useful in depressed patients having difficulty sleeping). Side effects: Sedation, dizziness, dry mouth, Increased appetite, and weight gain. Nefazodone is hepatotoxic therefore was withdrawn from some countries. Trazodone causes priapism (sustained and painful erection in males). 6. Vortioxetine ❑ Vortioxetine increases serotonin concentrations in the brain → utilizes a combination of serotonin reuptake inhibition, 5-HT1a agonism, and 5-HT3 and 5- HT7 antagonism as its suggested mechanisms of action to treat depression. ❑ The common adverse effects include nausea, constipation, and sexual dysfunction (serotonergic mechanisms) 7. Bupropion Weak Norepinephrine and dopamine reuptake inhibitor (NDRI). Nicotinic receptor antagonist. Useful for decreasing cravings and attenuating withdrawal symptoms of nicotine in patients trying to quit smoking. Remember: Varenicline is a partial agonist of nicotinic receptors used in smoking cessation. Very low incidence of sexual dysfunction as it doesn’t or weak inhibitor of serotonin reuptake. May be used in patients who are concerned about the risk of antidepressant-related sexual dysfunction. 8. SEROTONIN–DOPAMINEANTAGONISTS The second-generation antipsychotics block serotonin (5-HT2) and dopamine (D2) receptors. Used as an adjunctive treatment in patients without complete response to antidepressant therapy. E.g: Aripiprazole, olanzapine e, and quetiapine Pharmacology 2, 2024-2025, Prof. Dr. Marwa Safar Extracts of the plant St. John’s wort (Hypericum perforatum) The extracts contain a substance called hypericin and several flavones. Some of these compounds inhibit MAO, whereas others appear to block the neuronal reuptake of serotonin. Hypericum extracts appear to cause fewer adverse effects than other antidepressants but are not as effective as prescription antidepressants. Electroconvulsive therapy (ECT) is a successful physical tool to treat depression that usually acts more rapidly than drugs, and can be used in combination with drugs. N.B. All antidepressant are with delayed onset (2-4 weeks), although their effect on NA, 5- HT level doesn’t require such a long time  this suggest 2ry effects in brain that may be involved in their antidepressant. Treatment of Mania and Bipolar Manic Depression Mood stabilizer 1. Lithium It remains the drug of choice (DOC) for bipolar disorders. MOA: Not fully understood i. Lithium decreases central cAMP, IP3 formation (2nd messengers)→ neuronal response to serotonin and NE. ii. Lithium is a monovalent cation that mimics the role of Na+ in the excitable tissue. It can enter the neuron through the Na+ channel but unlike Na+ it is not pumped out by Na+/K+ ATPase pump  partial loss of intracellular K+ Conc. gradient of K+ form inside to outside  K+ efflux excitation of neurons partial depolarization &  in excitability of nerve tissue. N.B. Narrow therapeutic index so monitoring is essential. Side effects: Polyuira, polydepsia, polyphagia (Diabetes insipidus, it interferes with the action of antidiuretic hormone and thereby inhibits the kidney’s ability to concentrate the urine; manage with amiloride), fine hand tremors (can usually be controlled by β-adrenoceptor antagonist), thyroid function (blocking thyroid hormone synthesis and release). Lithium is renally eliminated and should be used cautiously in renally impaired patients. Teratogenicity: Ebstein’s anomaly (malformed tricuspid valve) 2. Some antiepileptic drugs e.g. carbamazepine, valproic acid, lamotrigine. Pharmacology 2, 2024-2025, Prof. Dr. Marwa Safar 3. Some antipsychotics e.g. chlorpromazine, haloperidol, risperidone, olanzapine, ziprasidone, aripiprazole, quetiapine Some video links: Pathophysiology of Depression https://www.youtube.com/watch?v=QEjWLj5wAFM Unipolar depression https://www.youtube.com/watch?v=tvpVfXAC5Ow Bipolar disorder https://www.youtube.com/watch?v=RrWBhVlD1H8 ANTIDEPRESSANT DRUGS “SSRI” mechanism of action https://www.youtube.com/watch?v=T25jvLC6X0w ANTIDEPRESSANT DRUGS - SSRIs, SNRIs, TCAs, MAOIs, Lithium https://www.youtube.com/watch?v=-EMg12QBUx4 Fluoxetine as SSRI https://www.youtube.com/watch?v=kKDXqlSWovA SNRIs mechanism of action https://www.youtube.com/watch?v=l3N8ThFbBvs Serotonin & depression https://www.youtube.com/watch?v=4D3IlIcqny4 Atypical antidepressants https://www.youtube.com/watch?v=zfTNPKrnfTE Trade names for antidepressant drugs https://www.youtube.com/watch?v=JDaYDWEc15k Pharmacology-2, 2024-2025, Prof. Dr. Marwa Safar Sedative- Hypnotic- Anxiolytic Drugs Learning outcomes: - Compare between benzodiazepines and barbiturates. - Classify benzodiazepines and barbiturates. - Demonstrate knowledge and understanding of other drugs that can be used as Sedative- Hypnotic- Anxiolytic Drugs. Anxiolytics: drugs used to treat anxiety. Anxiety: is state of tension, apprehension, and fear that arises from either a known or unknown cause. It is a common mental disturbance. Anxiety disorders include panic disorder, social anxiety disorder, post-traumatic stress disorder (PTSD), acute stress disorder, generalized anxiety disorder (GAD), simple phobia, obsessive-compulsive disorder (OCD). Panic attacks: Episodes of severe anxiety accompanied by activation of sympathetic that leads to tachycardia, palpitation, sweating. Anxiolytic drugs are sedative, will assist sleep when given at night. Hypnotics: These are drugs used to treat insomnia (difficulty to induce and/or maintain sleep). Difficulty to induce sleep (>45`min) or Difficulty to maintain sleep (6 or more awakenings/night) is due to  activity of RAS (reticular activating system). Hypnotics in small doses reduce anxiety. Neither hypnotics nor anxiolytics are suitable for the long-term management of insomnia or anxiety, due to tolerance and dependence. Better not to exceed their use more than 2 weeks after 2 weeks , addiction may happen Normal sleep is divided into 2 phases: 1. Non-REM (Non-rapid eye movement sleep) = around 75% of total sleep; divided into 4 stages. Progression from stage 1 to stage 4 is characterized by deeper levels of sleep and usually takes 60-90 minutes. 2. REM (Rapid eye movement sleep) = around 25% of total sleep, after stage 4, individuals enter REM for approximately 20 minutes, dreams occur in this phase. In REM, daily events are reviewed and information is integrated into memory. After REM, individuals return to NREM and repeat the cycle. Most individuals go through 4-6 sleep cycles per night. Different stages of sleep produce brain waves that can be identified by electroencephalogram (EEG). With aging there is reduction In stage 3 & 4 (deep sleep). Elderly people suffer insomnia And problems with sleeping. Pharmacology-2, 2024-2025, Prof. Dr. Marwa Safar * GABAA-Cl- channel complex: the amino-acid GABA ( inhibitory neurotransmitter) binds to this ion channel→ it opens and Cl- enters→ hyperpolarization→ CNS depression. 1. BENZODIAZEPINES “BDZs” ZEPAM They are so named because they share the common chemical structure of a benzene ring (benzo) joined to a seven member ring containing two nitrogen molecules (diazepine). Mechanism of action: BDZs binds to BDZ site (receptors) on GABAA receptors potentiate the effect of GABA (main inhibitory transmitter in the CNS) on GABAA receptors →  the affinity of GABA on GABAA receptor→ frequency of Cl- channel opening by GABA  Cl- influx → hyperpolarization of the neuron and decreases neurotransmission by inhibiting the formation of action potentials. N.B. BDZ is not agonist on GABAA receptor (c.f. barbiturates) msh by7l makan el gaba They are classified according to their duration of action into: a- Long acting BDZs (1-3 days) e.g. Flurazepam, Chloradiazepoxide, Quazepam. USED AS ANXIOLYTICS b- Intermediate acting BDZs (10-20 hrs) e.g. Diazepam, Clonazepam, Chlorazepate Temazepam, Lorazepam, Oxazepam, Estazolam, Nitrazepam. USED AS HYPNOTICS c- Short-acting BDZs (3-8 hrs) e.g. Alprazolam, Triazolam, Midazolam. Used in sleep disorders d- Ultra-short acting BZDs (30 min): Remimazolam; used in I.V. induction of anesthesia. Pharmacology-2, 2024-2025, Prof. Dr. Marwa Safar Pharmacological actions: 1. Anxiolytic effect: by inhibiting neural circuits in the limbic system through enhancing the GABAergic transmission. 2. Sedative-hypnotic effect: by inhibiting the RAS (sedation in low doses & hypnosis in high doses). 3. Anterograde amnesia: Inability to create new memories (an individual will not remember what happens from the time that the drug is administered to the time that the drug effects dissipate. This is in contrast to retrograde amnesia, in which a person cannot remember what happened before a certain point in time; the amnesic property of benzodiazepines is often useful when patients are undergoing stressful procedures, such as endoscopy or outpatient surgery. When these drugs are used on a long-term basis, such as in treating anxiety, the amnesic properties can have an adverse effect on the patient’s ability to function). 4. Anticonvulsant effect: especially Diazepam and Clonazepam. becaus 5. Skeletal muscle relaxant: At high doses, by increasing pre-synaptic inhibition e they in the spinal cord especially Diazepam. make hyperpo larizatio Clinical uses: n : no action 1. Anxiety disorders potentia 2. Sedative/Hypnotic in treatment of sleep disorders or insomnia. The l antianxiety effects of the benzodiazepines are less subject to tolerance than the sedative and hypnotic effects [Note: Tolerance that is, decreased responsiveness to repeated doses of the drug occurs when used for more than 1 to 2 weeks WHY? Tolerance is due to a decrease in GABA receptor density &/or sensitivity + increase sensitivity of excitatory transmitters such as NMDA glutamate receptors 3. Alcohol withdrawal: help reduce withdrawal symptoms such as anxiety, agitation, and sleep disturbances and prevent complications, such as seizures 4. Seizures: e.g. Diazepam, Lorazepam, Clonazepam. 5. Skeletal muscle relaxants especially diazepam to reduce muscle strain and muscle spasticity accompanying neurodegenerative disorders such as multiple sclerosis. 6. Amnesia and Induction of Anesthesia. The shorter-acting agents are often employed as premedication for anxiety-provoking surgeries and procedures. These agents cause a form of conscious sedation, allowing the patient to be receptive to instructions and follow commands during the procedure. Midazolam is the most used benzodiazepine to provide this level of sedation, and its use results in anterograde amnesia that renders the patient without memory of the event. Deeper levels of sedation occur 7. epileplsy with escalating doses of benzodiazepines, and in higher doses these agents can produce a state of general anesthesia. Adverse effects: 1. CNS depression: drowsiness, dizziness. 2. Ataxia at high doses (inability to coordinate voluntary muscle movements). Pharmacology-2, 2024-2025, Prof. Dr. Marwa Safar Activities that require fine motor co-ordination like car driving are affected. 3. Psychological and physical dependence (the severity of which is proportional to dosage and duration of administration). Withdrawal symptoms confusion, anxiety, agitation, restlessness, insomnia, tension, and (rarely) seizures especially with short acting BDZs. 4. Hangover: residual day time sedation that may occur upon awakening specially with long-acting drugs 5. Cognitive impairment (decreased recall and retention of new knowledge), lack of concentration, memory disturbance. 6. Used with caution in liver diseases as BDZs is metabolized in liver. 7. Used with caution when combined with other CNS depressants due to additive effect. N.B. Benzodiazepines are relatively safe, because the lethal dose is over 1000-fold greater than the typical therapeutic dose. and antagonist is availiable flumanzeil and they do not induce liver microsomal enzymes 2. Benzodiazepine antagonist: e.g. Flumazenil (I.V.) Mechanism: competitive blocker of BDZ receptor which is present on GABAA receptor. Uses: Treatment “Reversal” of benzodiazepines toxicity (Specific antidote) Reversal of benzodiazepine sedation after endoscopy, dentistry. Half-life is approximately 1 hr (shorter than most benzodiazepines) and may require repeated administration. 3. BARBITURATES (Derivatives of barbituric acid, Acidic in nature) MOA: Barbiturates  RAS  Hypnosis. 1- Act on modulatory site on GABAA receptor  facilitate and prolong the inhibitory action of GABA on GABAA receptor (enhance GABAergic transmission, increase the length of time that the channel remains open)→  Cl- influx→ hyperpolarization & inhibition. N.B. This biding site is distinct from that of benzodiazepines. 2- In high doses direct agonist on GABAA (GABA mimetic) →  Cl- influx. Act independent of GABA; that is why they cause greater CNS depression and toxicity than the benzodiazepines. 3- Barbiturates can inhibit the release of the excitatory neurotransmitter glutamate and block glutamate receptors. Pharmacology-2, 2024-2025, Prof. Dr. Marwa Safar They are classified according to their duration of action into: a. Long-acting barbiturates: Phenobarbital (duration 12-24 hrs): anticonvulsant. b. Intermediate and Short-acting barbiturates: Pentobarbital, Amobarbital, Secobarbital (3-8 hrs): sedative hypnotic but not anxiolytics. c. Ultrashort acting barbiturates: Thiopental (duration  20 minutes): used in I.V. induction of anesthesia. Pharmacological actions: 1. CNS Depression CNS (sedation, hypnosis, anesthesia & anticonvulsant) Small dose: Sedation, Normal dose: Hypnosis, High doses:  loss of feelings & sensationAnesthesia coma death. 2. Respiration: High doses  Respiratory center (R.C.) at the medulla Respiratory depression  Respiratory failure  death. As in high doses barbiturates  the respiratory center &  the hypoxic response to CO2 → respiratory failure. (This is the main cause of death in acute barbiturate toxicity). 3. Liver: Barbiturates are liver microsomal enzyme inducersP450  Metabolism of other drugs+  Metabolism of itself (barbiturates)  “Tolerance”. N.B. Benzodiazepines don’t cause enzyme induction of microsomal metabolizing enzymes. 4. Skeletal muscle relaxation 5. Anticonvulsant effect: 6. Hypotension due to myocardial depression and depression of VMC. Pharmacology-2, 2024-2025, Prof. Dr. Marwa Safar Clinical uses: 1. Anesthesia: Ultrashort acting (I.V.) for induction of anesthesia. 2. Anticonvulsant especially Phenobarbital Hypnotic (but now OBSLETE due to S.E. & replaced by Benzodiazepines BDZ)..B. Benzodiazepines are Superior to Barbiturates as hynotics due to less addictive1, less tolerance2, less respiratory depression3, high therapeutic index4, less hang over5, No night mares6, No effect on REM7. Adverse effects: 1. Physical dependence = Addiction after prolonged use Sudden (abrupt) withdrawal → withdrawal symptoms (Sweating tremors, delirium, anxiety, restlessness, insomnia & convulsions). Treatment of barbiturates addiction. a. Gradual withdrawal. b. Substitute with less addictive drugs as Benzodiazepines. e.g. Flurazepam 2. Impaired concentration, Drowsiness. 3. Mental and physical sluggishness (depress cognitive performance). 4. Drug hangover (hypnotic doses after wakening feeling of tiredness, nausea & dizziness) especially with long-acting drugs. 5. Increased porphyrin (Hemoglobin precursor) synthesis so C.I. in patient with acute intermittent porphyria condition (hereditary defect causes excessive porphyrin synthesis and excretion, with neurologic and cutaneous manifestations). 6. Tolerance that may be explained in part by the stimulant effect of barbiturates on hepatic microsomal enzyme (HME) →  their own rate of metabolism (self tolerance) and  the metabolism of other drugs concomitant used. Toxicity: Respiratory depression (cynosois) & Cardiovascular depression ( B.P & shock) Due to depression of respiratory centers & vasomotor center which is responsible for sympathetic control over blood vessels in medulla oblongata Treatment of toxicity: 1. Artificial respiration (Mechanical ventilation). 2. Purging and Gastric lavage for cleaning stomach of its contents. 3. Hemodialysis if large quantity has been taken. 4. Alkalinization of urine aids in its elimination. 5. Sympathomimetics and IV fluids to elevate blood pressure. N.B. No specific barbiturate antagonist is available. Pharmacology-2, 2024-2025, Prof. Dr. Marwa Safar 4- OTHER ANXIOLYTICS a) Buspirone: a. Anxiolytic b. NO skeletal muscle relaxant or NO anticonvulsant activity, NO effect on car driving & has minimal sedation effect. a. 5-HT1A partial agonist → serotonergic activity is suppressed. b. Slow onset of action (2 weeks, not suitable for acute anxiety states) b) Antidepressants SSRIs (e.g. escitalopram, paroxetine) and SNRIs (e.g. venlafaxine or duloxetine) have a low potential for physical dependence than the benzodiazepines and have become first-line treatment for GAD (generalized anxiety disorder). May be used alone or prescribed in combination with a low dose of a benzodiazepine during the first weeks of treatment. After 4 to 6 weeks, when the antidepressant begins to produce an anxiolytic effect, the benzodiazepine dose can be tapered. c) β- Blockers Reduce effects of increases sympathetic activity e.g. propranolol (taken an hour before the anticipated anxiety provoking event, propranolol prevents tachycardia and other signs and symptoms of acute anxiety caused by sympathetic stimulation). Less dependence and abuse 5- Other hypnotics a) Zolpidem, Zopiclone, Eszopiclone, Zaleplon (Z-hypnotics) They are not BDZ but acts selectively on a subunit of BDZs receptors → facilitate GABA → hypnotic Because of selectivity NO anticonvulsant activity, NO muscle relaxant activity, NO antianxiety, Less tolerance & dependence. Few withdrawal symptoms =Minimal rebound insomnia. N.B. Their sedative effect is antagonized by flumazenil. b) Antihistamincs (H1-blocker): Diphenhydramine, Doxylamine, Hydroxyzine, Promethazine. Have sedative effect and can be used as sleeping aids in mild insomnia. Side effects: Anticholinergic effects. c) Melatonin and Ramelteon - Selective agonist at the MT1 and MT2 subtypes of melatonin receptors→ induce sleep. - Used mainly for jetlag, insomnia in shift-change workers (If taken at bedtime for a few nights, it may accelerate the resetting of the biologic clock in these persons). Pharmacology-2, 2024-2025, Prof. Dr. Marwa Safar - Doesn’t cause dependence. N.B. Melatonin is a hormone secreted by the pineal gland in response to decreased sunlight (released at night) that helps to maintain the circadian rhythm underlying the normal sleep–wake cycle. d) Antipsychotics: due to 5HT2 antagonism, α1 antagonism, H1 antagonism e.g. Quetiapine e) Antidepressants Sedating antidepressants with strong antihistamine actions e.g. TCAs (e.g. Doxepin), Mirtazepine Some video links: GABA and neurotransmitters https://www.youtube.com/watch?v=bQIU2KDtHTI https://www.youtube.com/watch?v=M_QQD9NdJcU Sedative & Hypnotic Drug classes https://www.youtube.com/watch?v=fTR9JGtshLo GABA Receptor, hyperpolarization and GABA acting drugs https://www.youtube.com/watch?v=-eBUJ-1vcjk https://www.youtube.com/watch?v=hB-BxvUJTTM GABA Receptor and drugs acting on them https://www.youtube.com/watch?v=MRr6Ov2Uyc4 https://www.youtube.com/watch?v=pakPcZs-Esk Anterograde amnesia https://www.youtube.com/watch?v=2GdxiB7FU04 BDZs side effects https://www.youtube.com/watch?v=8TSUS8IF8Hw BDZs vs. Barbiturates https://www.youtube.com/watch?v=EfwJlv5TVAg Uses & mechanism of action of barbiturates https://www.youtube.com/watch?v=BGsfP_0NZLs Pharmacology- 2, 2024-2025, Prof. Dr. Marwa Safar ANTIEPILEPTIC DRUGS Learning Outcomes: - Classify seizure types. - Describe the mechanism of action and unique features of the commonly used anticonvulsants. - Provide an overview of which anticonvulsants are used for which types of seizures. - Demonstrate understanding of local anesthetics as regards to the mechanism of action and side effects. Globally, epilepsy is the 4th most common neurologic disorder after migraine, cerebrovascular disease (stroke), and Alzheimer’s disease. The term EPILEPSY refers to sudden, excessive, episodic, and abnormal electrical discharge of cerebral neurons that can be observed on an ElectroEncephaloGram (EEG). Instead of firing a single action potential, these neurons stay depolarized too long firing a train of many action potentials. The characteristic depolarizng recurrent event in epilepsy is seizure. SEIZURES: The variety of events (clinical symptoms or signs) which occur because of abnormal electrical activity of a group of hyperexcitable neurons, called a FOCUS. These include abnormal motor and/or sensory behavior of short duration usually followed by periods of inactivity (e.g. loss of consciousness, abnormal movements, odd behavior, and/or distorted perceptions). Seizures tend to recur (recurrent, episodic). The terms seizure and convulsion are not synonymous. Seizure is a general term that applies to all types of epileptic events. In contrast, convulsion has a more limited meaning applying only to abnormal motor phenomena (spasmodic contractions of skeletal muscles). Focal areas that are functionally abnormal may be triggered into activity by changes in physiologic factors, such as an alteration in blood gases, pH, electrolytes, and blood glucose and changes in environmental factors, such as sleep deprivation, seizure threshold = low-> easily triggered alcohol intake, and stress. The brain region of the abnormal neuronal firing determines the symptoms that are produced during the seizure e.g.: If motor cortex is involved → convulsions (abnormal movements). Pharmacology- 2, 2024-2025, Prof. Dr. Marwa Safar If parietal or occipital lobes (parts of the cerebral cortex) are involved → visual, auditory, olfactory hallucinations. If RAS is involved → loss of consciousness. If hypothalamus  increased autonomic discharge. urination, salivation Classification of epilepsy according to cause: 1. Primary (idiopathic) epilepsy: NO specific anatomic cause for the seizure. May be inherited (genetic basis). Antiepileptic drugs are given chronically. Often leads to generalized seizures. 2. Secondary epilepsy: Secondary to 1ry cause. May be head trauma, stroke, meningitis, hypoglycemia, tumors, hypoxia, fever, rapid alcohol withdrawal, or drug toxicity. Often leads to partial seizures. birth hypoxia N.B. Intrauterine or neonatal complications (e.g. birth hypoxia) result in epilepsy. Etiology: depends upon the age of the patient: Young infants: hypoxia - birth asphyxia – infection - congenital malformations in brain. Adults: head injury (trauma)– alcohol abuse - brain tumor- Stroke Elderly: (>50 y): cerebrovascular disease ischemia CLASSIFICATION OF SEIZURES: according to the International League Against Epilepsy (ILAE) Seizures can be divided into two broad categories: partial or 1. Focal seizures: the discharge begins locally and remains often localized. Focal seizures involve only a portion of one hemisphere. This type of seizures is further classified to: simple partial 1.1. Focal with preserved awareness: involve limited area of the brain, cause relatively simple symptoms without loss of consciousness. Often manifested by a sensory change (numbness) or muscular twitch that is confined to one body part (single limb jerking). Pharmacology- 2, 2024-2025, Prof. Dr. Marwa Safar 1.2. Focal with impaired awareness: characterized by loss of consciousness (blackout) at the onset of attack or somewhat later usually not longer than a minute or 2 and are accompanied by some type of characteristic movement. These movements are described as purposeless because they are not goal directed and involve such things as lip smacking or other repetitive movements. Following the attack, the individual has no memory of what occurred. 1.3. Focal with 2ry generalization: focal seizures can propagate quickly to become secondary generalized seizures. 2. Generalized seizures: the whole brain (both hemispheres) is involved. It is characterized by immediate loss of consciousness, no memory. Primary generalized seizures may be convulsive or nonconvulsive. Generalized seizures are further subdivided into five main subtypes: 2.1. Tonic–clonic: These seizures result in loss of consciousness, they start by tonic grand mal (sustained contraction and muscle rigidity, stiff) followed by clonic (rapid contraction and relaxation, muscle jerks) phases. The individual appears to jerk around due to the alternating muscle contractions and relaxations. Increases in blood pressure, heart rate, urination, defecation, and tongue biting are common. A seizure usually lasts several minutes. The seizure may be followed by a period of confusion and exhaustion due to the depletion of glucose and energy stores. It is usually preceded by a warning sign, usually a sound (aura). t mal 2.2. Absence: These seizures involve a brief, abrupt, and self-limiting loss of consciousness without motor convulsions. The onset generally occurs in patients at 3 to 5 years of age and lasts until puberty or beyond. The patient abruptly ceases whatever he was doing, and exhibits abnormal motor activity varying from stares, rapid eye-blinking and jerking of entire body which lasts for 5-30 seconds. The patient is unaware of the surroundings and recovers with no after-effects. After a seizure, activity continues as if nothing had happened. An absence seizure has a very distinct 3 per second spike and wave discharges seen on ECG. 2.3. Myoclonic: short episodes of muscle contractions that may recur for several minutes. They generally occur after waking and exhibit as brief random jerks of the limbs often confined to one part of the body. Myoclonic seizures occur at any age but usually begin Pharmacology- 2, 2024-2025, Prof. Dr. Marwa Safar around puberty or early adulthood. Patients may not lose consciousness due to seizures lasting less than 3 to 4 seconds. 2.4. Clonic: These seizures consist of short episodes of muscle contractions that may closely resemble myoclonic seizures. Consciousness is more impaired with clonic seizures as compared to myoclonic. 2.5. Tonic: These seizures involve increased tone in the extension muscles and are generally less than 60 seconds long. 2.6. Atonic: Sudden loss of consciousness and muscle tone; No muscle movements, patients fall if not lying down or sitting and can suffer head and other body injury, described as “falling out” or “drop attacks”. Clinical course of generalized seizures: Pre-ictal phase (aura), Ictal Phase, Post-ictal phase Febrile seizures: occur in young children (6 months-5 years) who develop high fever and consist of generalized tonic-clonic convulsions of short duration. These seizures do not cause neurological damage and don’t require antiepileptic medication. Status epilepticus: repetitive episodes, 2 or more seizures without recovery of full consciousness between them. These seizures may be focal or generalized, convulsive or nonconvulsive. Life threatening and requires emergency treatment. It often arises in patients who have inappropriately withdrawn or not taking the drug. It can be the first presentation of epilepsy due to an acquired brain insult e.g. viral encephalitis. Possible Mechanisms Underlying Epilepsy: 1- Exaggerated action of an excitatory transmitter (glutamate) and activation of N-methyl D-aspartate (NMDA) receptors. 2- Deficiency in GABA-mediated inhibition of transmission. 3- Disturbances of Na+/K+ pump through disturbance of energy such as in cases of hypoglycemia and hypoxia. sodium influx= depolraiztion Pharmacology- 2, 2024-2025, Prof. Dr. Marwa Safar Anti-epileptic drugs act through basic mechanisms: ( inhibitory effect and/or  excitatory) 1- Na+ channels blocking ( depolarization of the electric focus   membrane excitability): Phenytoin, Fosphenytoin (a prodrug that is rapidly converted to phenytoin), Carbamazepine, Eslicarbazepine, Oxacarbazepine (prodrug), Valproic acid, Felbamate, Lamotrigine, Topiramate, Zonisamide, Lacosamide, Rufinamide 2- Ca2+channel blocking ( release of excitatory neurotransmitters;  synaptic transmission): Ethosuximide, Felbamate, Lamotrigine, Pregabalin, Topiramate, Zonisamide (sulfonamide derivative), Gabapentin, Valproate. 3- Glutamate receptors blocking (Glutamate is an excitatory neurotransmitter. It acts on N-methyl-D-aspartate (NMDA) receptor leading to Ca2+, Na+ influx & depolarization and leads to the genesis and propagation of high-frequency discharges): Felbamate, Topiramate, Valproate 4- Enhancing GABA effect: (GABA acts as an inhibitory neurotransmitter by opening chloride channels that lead to hyperpolarization and suppression of epileptic discharges) a. Enhancing affinity of receptors toward GABA: Phenobarbital, Benzodiazepines (Clonazepam, Diazepam, Chlorazepate), Felbamate, Topiramate. b. Inhibiting reuptake of GABA: Tiagabine c. GABA degradation by inhibiting GABA transaminase: Valproic acid, Vigabatrin d. ↑ release of GABA: Phenytoin 5-  release of glutamate: Phenobarbital, Phenytoin, Gabapentin, Lamotrigine Pharmacology- 2, 2024-2025, Prof. Dr. Marwa Safar Remarks: 1- Antiepileptic drugs results in either blocking the initiation of the abnormal electrical discharge from the focal area or preventing the spread of the abnormal electrical discharge to adjacent brain areas. i.e. antiepileptic drugs suppress seizures but don’t cure epilepsy. N.B. They don’t block normal neuronal signaling only the excessively rapid firing neurons hence don’t affect normal brain function (physiological neural activity). 2- Some antiepileptics have multiple targets within the CNS e.g. Felbamate, whereas the mechanism of action for some agents is poorly defined e.g. Levetiracetam 3- Divalproex is a combination of sodium valproate and valproic acid that is converted to valproate when it reaches the gastrointestinal tract. Divalproex sodium is absorbed more slowly, and it usually causes fewer adverse gastrointestinal side effects. 4- Avoid abrupt withdrawal may precipitate seizures (status epilepticus which can be fetal). 5- Antiepileptics are additive with other CNS depressants. 6- Primidone: Chemically related to barbiturates. Most of the drug is metabolized and converted in the body into phenobarbital which is believed to account for most of its antiepileptic effects i.e prodrug 7- Topiramate and Zonisamide are carbonic anhydrase inhibitors. Treatment Strategies: Start using one drug (Monotherapy) to control seizures. seizures can be controlled with one medication in approximately 75% of patients After trying three or so monotherapy and still seizures are not controlled, or toxic signs occur start using two drugs (Combination therapy =1st choice drug + 2nd choice drug) Focal Tonic-Clonic Absence Myoclonic First Lamotrigine Lamotrigine Ethosuximide Divalproex Topiramate Topiramate choice Divalproex Levetiracetam Levetiracetam Levetiracetam Lamotrigine Valproate has the broadest spectrum of activity WHY? Due to its multiple mechanisms of action. Pharmacology- 2, 2024-2025, Prof. Dr. Marwa Safar cpoptg In absence and myoclonic seizures: Carbamazepine, Phenytoin, Oxcarbazepine, Pregabalin, Tiagabine, and Gabapentin are avoided as they can exacerbate seizures. Status Epilepticus is treated by BZDS (Lorazepam,diazepam IV or IM) or phenytoin (IV). If not effective, then phenobarbital i.v is used. Once status epilepticus is under control, other antiepileptic drugs are used in the chronic treatment of epilepsy orally to prevent further seizures. Other Therapeutic Uses of Certain Antiepileptic Drugs: 1. Cardiac arrhythmias: Phenytoin (Epanutin®). 2. Bipolar illness: Lamotrigine, Carbamazepine, Valproate 3. Neuropathic pain: Gabapentin, Carbamazepine, Pregabalin (Lyrica®). 4. Migraine: Gabapentin (Neurontin®), Topiramate, Valproate 5. Trigeminal neuralgia: Carbamazepine (Tegretol®; Drug of Choice; DOC) as it possesses analgesic properties. Adverse Effects: Two types: Concentration related: Sedation, ataxia, diplopia Idiosyncratic (rare): Rash, fever, systemic organ involvement (Drug must be discontinued) Most AEDs Most have central, GIT side effects. They increase the risk of suicidal thoughts. Benzodiazepines: are reserved for emergency or acute seizure treatment due to tolerance. N.B. Diazepam is also available for rectal and intranasal administration to avoid or interrupt prolonged generalized tonic–clonic seizures when oral administration is not possible. Carbamazepine, Oxcarbazepine: Hyponatremia especially in elderly ( ADH secretion) N.B. Oxcarbazepine has less adverse effects than carbamazepine because it isn’t metabolized into epoxide. Felbamate: aplastic anemia and hepatic failure; Therefore, it is reserved for use in refractory epilepsies Gabapentin: Sedation, headache, dizziness, ataxia, tremor, tiredness. Lamotrigine: rash, which may progress to a serious life-threatening reaction. The risk of rash decreases if treatment begins with a low dose and increases slowly. Whereas concomitant use of valproate which inhibits Lamotrigine metabolism increases the risk of rash. Levetiracetam: mood alterations. Phenytoin: nystagmus and ataxia especially in elderly, cognitive impairment, gingival hyperplasia (gums grow over the teeth), hirsutism, induces folate Pharmacology- 2, 2024-2025, Prof. Dr. Marwa Safar metabolism and this can lead to megaloblastic anemia, long-term use may lead to development of peripheral neuropathies and osteoporosis (induces metabolism of vitamin D). Teratogenic: fetal hydantoin syndrome (cardiac defects; malformation of ears and limbs, cleft lip and palate, mental retardation, and microcephaly). Pregabalin: Weight gain, dizziness. Topiramate: somnolence, weight loss, and paresthesias, renal stones, glaucoma, oligohidrosis (decreased sweating), and hyperthermia. Valproic acid: Teratogenic (neural tube defect: spina bifida), cognitive abnormalities, elevation of liver functions (rarely hepatotoxicity from toxic metabolite), weight gain, hair loss Vigabatrin: visual field defects (requires monitoring). Zonisamide: kidney stones, oligohidrosis, hyperthermia, contraindicated in patients with sulfonamide hypersensitivity, increased risk of metabolic acidosis, especially in younger patients (serum bicarbonate levels should be monitored before and during treatment). Lacosamide: dizziness, headache, and fatigue. Rufinamide: Short QT interval Carbamazepine, Oxcarbazepine, Phenytoin, Phenobarbital, Valproate: reduce bone mineral density even after only 6 month→ risk of osteoporosis due to chronic use→ supplement of calcium and vitamin D + monitor every 2 years. Important remarks regarding the Pharmacokinetics of some antiepileptic drugs: Phenytoin biotransformation shows saturation process thus as dose increases  metabolism of drug  plasma half-life t1/2  increase in plasma conc.  drug induced toxicity (Michaelis-Menten metabolism) i.e. phenytoin is hydroxylated in liver, a process that becomes saturated at about the doses needed for therapeutic effect (10-20 mg/L). Thus phenytoin at low doses exhibits first order kinetics but saturation or zero order kinetics develop as the therapeutic plasma concentration range is approached therefore dose increments of equal size produce a disproportional rise in steady- state plasma concentration. Thus dose increments should be smaller as the dose increases (which is why there is 25 mg capsule) and plasma concentration monitoring is advisable. Pharmacology- 2, 2024-2025, Prof. Dr. Marwa Safar Gabapentin is excreted unchanged in urine thus it must be used with care in patients with impaired renal function (dose reduction is needed). More than 90% of Pregabalin is eliminated renally. Dosage adjustments are needed in renal dysfunction. Phenytoin, Carbamazepine, Oxcarbazepine, Phenobarbital, Topiramate are hepatic microsomal enzyme inducers (induces cytochrome P450 system) therefore accelerate the metabolism of many drugs and may accelerate their own metabolism with chronic use (require dose adjustment). Valproic acid is a hepatic microsomal enzyme inhibitor. Therefore, patients taking valproate and starting second line therapy with other antiepileptic drugs including lamotrigine, phenytoin, carbamazepine should receive lower doses of the second drug. Pharmacology- 2, 2024-2025, Prof. Dr. Marwa Safar Some antiepileptic drugs such as phenytoin and valproic acid are highly plasma protein bound. They can displace and be displaced by other drugs that are also highly protein bound. This increases the free drug concentration (unbound fraction) of the drug displaced and produced greater pharmacologic effects. Vagal Nerve Stimulation (VNS): This treatment was approved in 1997. It includes a small pulse generator with a battery and lead wires. It is implanted and the lead wires are wrapped around the patient’s vagal (parasympathetic nerve). Its mechanism of action is not exactly known but it affects CNS neuronal circuits. It is used in cases who suffer from severe drug side effects or are resistant to treatment. It is a costly and invasive procedure. Epilepsy in Pregnancy Several antiepileptic medications increase the metabolism of hormonal contraceptives, potentially rendering them ineffective. These include phenytoin, phenobarbital, carbamazepine, topiramate, oxcarbazepine, rufinamide. Most AEDs are category C (not enough research has been done to determine if these drugs are safe) and D (Adverse reactions have been found in humans). Pregnant females should receive the lowest effective dose of the least teratogenic drug e.g. lamotrigine Valproic acid and barbiturates must be avoided. Folic acid supplements are needed to reduce the risk of teratogenic effects (neural tube defects). During pregnancy, liver enzymes become induced, therefore patients on lamotrigine before conception require gradually increased dose during pregnancy to cope with the enhanced catabolism which reduces lamotrigine plasma concentration. Some video links: Types of seizure https://www.youtube.com/watch?v=6zXFUIjY5xU https://www.youtube.com/watch?v=wi_IsPVFC8Y https://www.youtube.com/watch?v=jrYVudPCY0g What is epilepsy & how it occurs? https://www.youtube.com/watch?v=Z_V-CqvsQU4 Pharmacology- 2, 2024-2025, Prof. Dr. Marwa Safar Antiepileptic drugs https://www.youtube.com/watch?v=c-Cf1xkKofg https://www.youtube.com/watch?v=GMyCWup1Xqo Antiepileptic drugs mnemonics https://www.youtube.com/watch?v=VONUWO89n7Y https://www.youtube.com/watch?v=sQf78HVGvqU Vagal Nerve Stimulation (VNS) https://www.youtube.com/watch?v=Irz-NySXrrw Pharmacology- 2, 2024-2025, Prof. Dr. Marwa Safar OPIOID ANALGESICS AND ANTAGONISTS Pain is usually initiated by a harmful (tissue-damaging, noxious) stimulus. Although pain is an unpleasant sensory and emotional experience, it serves to alert an individual to tissue damage. It can be acute or chronic. Analgesics can be classified as opioid analgesics or non-opioid analgesics. Opioid analgesics act in the spinal cord and brain to inhibit the neurotransmission of pain. Non-opioid analgesics act in peripheral tissues to inhibit the formation of pain- producing substances such as prostaglandins. Because most of the non-opioid analgesics also exhibit significant anti-inflammatory activity, they are called nonsteroidal anti-inflammatory drugs (NSAIDs). Opioids: Natural (opiates), semisynthetic, or synthetic compounds that produce morphine- like effects. All opioids act by binding to specific opioid receptors in the central nervous system (CNS) to produce effects that mimic the action of endogenous peptide neurotransmitters (endorphins, enkephalins, and dynorphins). Endogenous occurring opioids → endorphins, enkephalins, dynorphins. Opioid act on three main classes of opioid receptors: G protein–coupled receptors; Gi; Activation of opioid receptors → inhibition of adenylyl cyclase →  in the concentration camp of cyclic adenosine monophosphate →  in Ca2+ influx from Ca2+ ion channels on presynaptic neurons → presynaptic inhibition of neurotransmitter release from afferent fibers such as acetylcholine, substance P, catecholamines and glutamate (excitatory neurotransmitter that sends the pain signal along the nerve) therefore  pain transmission +  in K+ efflux from K+ ion channel postsynaptically→ hyperpolarization and inhibition of membrane depolarization (the nerve can’t respond to pain signals and further transmission to the brain is interrupted) Receptor Role Mu  Responsible for producing analgesia, euphoria, sedation, nausea, bradycardia, vasodilation, higher affinity respiratory depression, miosis, urine retention, g protein constipation, dependence. Kappa  Responsible for producing analgesia, sedation, dysphoria, miosis Delta  Responsible for producing analgesia, dependence widely distributed outside the CNS, eg in GIT and urinary tract. 1 Pharmacology- 2, 2024-2025, Prof. Dr. Marwa Safar Chemical classes of opioid agonists: 1- Natural: Morphine, Codeine methyl morphone 2- Semisynthetic: Heroin, Hydromorphone, Hydrocodone, Oxycodone, Oxymorphone, Buprenorphine 3- Synthetic: Fentanyl, Meperidine, Methadone, Tapentadol, Tramadol Morphine (IV, PO, SC, IM, rectally, epidural, Intrathecal into the cerebrospinal fluid) protoype Alkaloid derived from the poppy plant, Papaver somniferum. Morphine shows strong affinity for  receptors and varying affinities for  and  receptors. Pharmacological actions of morphine: I) Central Nervous System Analgesia → most potent drugs available for relief of pain acts on opioid receptors, decreases the release of nociceptive (painful) stimuli e.g. substance P. Euphoria:  dopamine inhibit Gaba Depression of mental function (sedation). Cough Suppression ( cough reflex in medulla) codeine 2 Pharmacology- 2, 2024-2025, Prof. Dr. Marwa Safar Respiratory depression → respiratory rate and volume are  → CO2 is retained in the blood, mild retention of CO2 produces headache because increased CO2 levels can dilate cerebral vasculature and causes increased intracranial pressure, ICP (CI in head injury)  sensitivity of medullary respiratory center neurons to CO2 → death can occur at high doses. Nausea and Vomiting→ due to stimulation of chemoreceptor trigger zone (CTZ) in medulla. Eye: Miosis pinpoint pupil → stimulate 3rd cranial nerve (oculomotor nerve, parasympathetic nerve innervating the pupil). Vagus: Stimulation → bradycardia, hypotension, bronchoconstriction II) Peripheral Effects CVS:  local histamine release from mast cells → cutaneous vasodilatation resulting in flushing of the face, neck, and thorax, urticaria, itching, V.D &  PR →  BP → hypotension, bradycardia ( receptor). N.B. there is very little cardiovascular change at normal dosages therefore can be used to relieve the pain accompanying myocardial infarction without worsening the condition. Bronchi: direct spasmogenic effect on bronchial muscle +  Local histamine release → bronchoconstriction (Caution in asthmatics). GIT:  propulsive movement (motility) and ↑ tone of anal sphincter +  Ach release inhibit the parasympathetic stimulation of the intestine→ constipation. Sphincters: contraction of the smooth muscles of the sphincters in biliary tract as well cannot as the bladder and ureter → opioids can cause biliary colic and postoperative urinary be taking in labor retention. because Uterus: decrease uterine tone + spasm in cervix (Prolongation of labor) it closes the cervix Antidiuretic effect:  secretion of antidiuretic hormone (ADH) → Kidney reabsorbs water + spasmogenic activity on ureters and sphincter muscle inhibits urine from passing out of the bladder → oliguria Hormonal actions: Prolonged use may lead to opioid-induced androgen deficiency due to suppression of the hypothalamic–pituitary–gonadal axis. This results in decreased production of sex hormones, especially testosterone. Important remarks:  Tolerance: It is a gradual loss in effectiveness with frequently repeated administration, due to down regulation of receptors. to increase its effect  Miosis, dry mouth and constipation are not affected by tolerance and remain problems with long term use (therefore miosis is a diagnostic sign of opioid overdose+ patients are in continual need for laxatives + patients develop dental caries). because of dry mouth  Physical dependence: appearance of withdrawal symptoms upon cessation of administration (abstinence syndrome). It is characterized by lacrimation, hyperthermia, chills, muscular ache, sleeplessness, anxiety, ……………..etc.  Morphine can cross the placental barrier and cause respiratory depression and, with chronic used, dependency in fetus. Can morphine be used in pregnancy 3 Pharmacology- 2, 2024-2025, Prof. Dr. Marwa Safar or during labor?  Morphine 6-glucuronide (metabolite) has analgesic effect  morphine Adverse Effects: 1. a) Respiratory depression (Apnoea, bronchoconstriction) b) Depression of respiratory centers in the medulla oblangata in brain stem. c)  Responsiveness of respiratory centers to  CO2 (hypercarbia) and hypoxaemia. d) Occurs at low doses and increases in a dose-dependent manner. e) Death from overdose is always from respiratory arrest. 2. Reduced gut motility, constipation, reduced secretions including dry mouth which leads to dental caries 3. Nausea and Vomiting 4. Sedation 5. Pruritus, urticaria (itching) (due to histamine release) 6. Elevation of intracranial pressure 7. Miosis 8. Confusion, hallucinations 9. Euphoria followed by dysphoria 10. Reduction of the sympathetic tone (hypotension, bradycardia in high doses) Drug interactions: Morphine + antipsychotics, sedatives (e.g. TCAs, benzodiazepines), or MAO inhibitors → can lead to death from CNS suppression. Antidote: Treatment of toxicity involves I.V. administration of the antagonist naloxone Therapeutic uses: 1. Analgesia for severe pain (e.g. trauma, cancer) 2. Antidiarrheal (loperamide, diphenoxylate are better) 3. Antitussive (codeine is better) Pinpoint pupil associated with morphine use 4 Pharmacology- 2, 2024-2025, Prof. Dr. Marwa Safar Functional classification of opioids: Agonist or Mixed agonist/ antagonist or Antagonist 1. Agonists: Exert maximal analgesic effects I. Strong agonists: - Diacetyl morphine derivative (Diamorphine) semisynthethic - Highly Lipophilic enters CNS Heroin - Highly addictive. (Diamorphine) - It has no direct activity on -receptor. It is rapidly converted within minutes into morphine and 6-monoacetylmorphine which act mainly on -receptor. - Binds primarily to -receptor with some  agonist activity. - Does not cause pinpoint pupil like other opiates (less miotic), but rather causes mydriasis in overdose due to its anticholinergic activity. Pethidine - Used in labor (Short term management of pain). (Meperidine) - Meperidine has an active metabolite called Normeperidine - Normeperidine has neurotoxic actions (delirium, hyperreflexia, myoclonus seizures) specially in patients with renal ins

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