Lecture 3 Pharma PDF

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- Cl...

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. cells Neurodegenerative diseases: neuronal damage in certain brain areas. Causes of neuronal damage: the neurons function exceeds their limits which causes degeneration 1. Excessive excitotoxicity (excess glutamate → acts on N methyl aspartate receptors NMDA). 2. Stroke, head trauma. when someone hits his head by accident pollution and f 3. Oxidative stress →  reactive oxygen species (ROS) →  free radical as OH..ree radicals 4. Apoptosis (programmed cell death). the body is programmed to kill cells 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. managment not treatment the case 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: formation of dopamine in substantia nigra and releasased from it and then goes to stratium ❖ 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). Ach ❖ Mesolimbic-mesocortical tracts: Cell bodies in midbrain project to cerebrocortical and limbic structures and release dopamine. Regulates cognitive functions, sensory perception, psychomotor functions. reactions + feelings ❖ Tuberoinfundubular: Cell bodies in hypothalamus project to anterior pituitary and release dopamine →  prolactin. decs prolactin ❖ Chemoreceptor trigger zone: in medulla activation of DA receptors →  emesis vomiting 1  Pharmacology-2, BUE, 2024-2025, Prof. Dr. Marwa Safar PARKINSON'S DISEASE "Paralysis Agitans" Management Overview of Parkinson’s disease due to impaired part of basal ganglia 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). nigrostriatal releases 2 types of hormones dopamine is inhibitory and Ach is excitatory. when there is a problem such as neurodegenertaion. when neurodegeneration occurs in this part the dopamine release decreases and Ach release increases tremors as the Ach is excitatory (there should be balance between Ach and dopamine in the stratium when the dopamine is released from substantia nigra to stratium) 2  Pharmacology-2, BUE, 2024-2025, Prof. Dr. Marwa Safar Classification: no reason mainly genetics 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: vessels el fel mo5 7asal galatat 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. et5abat fe raso 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. the drug has dopamine I. Dopaminergic drugs main treatment 1. Levodopa (l-dopa): Mechanism of action: blood brain barrier 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? organs and the rest of the body 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  tolcapone: causes hepato toxciticy (liver problem) Pharmacology-2, BUE, 2024-2025, Prof. Dr. Marwa Safar COMT is increased as a backup for dopa decarboxylase in case dopa decarboxylase is inhibited COMT inhibitors: Entacapone & Tolcapone: it(notalsoonlybreaks down Ldopa giving 3-O-methyldopa Dopa decarboxylase the one that breaks down Ldopa) Catechol-O-methyltransferase 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. yewa2af symptoms w fag2a ye5tefy w beyraga3 el a3rad (on off phenomena) 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. solution small divided doses 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 abnormal rapid heart rate 2.  β1→ tachycardia and arrhythmia. a problem with the rate or rhythm of your heartbeat 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.oxidation of dopamine 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. closes dopamine receptors so the dopamine decreases 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. a sudden drop in blood pressure 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) IT HAS ANTIOXIDANT EFFECT - 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?? - 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. Postural hypotension. 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