Pharmacology-Stage (4) Lecture Notes PDF

Pharmacology-Stage (4) Lecture -2- Drugs for Neurodegenerative Diseases Part-2- Dr. Tahssein Ali Mohammed PhD. Clinical Pharmacology& Therapeutics 2 /10 /2024 1  Drugs Used in Alzheimer's Disease  Alzheimer's disease (...

Pharmacology-Stage (4) Lecture -2- Drugs for Neurodegenerative Diseases Part-2- Dr. Tahssein Ali Mohammed PhD. Clinical Pharmacology& Therapeutics 2 /10 /2024 1  Drugs Used in Alzheimer's Disease  Alzheimer's disease (AD): is a type of progressive dementia for which no cause is known, and no cure has been found.  It is a common age related dementia distinct from vascular dementia associated with brain infarction or stroke, brain trauma or alcohol.  Alzheimer's disease is associated with brain shrinkage and localized loss of neurons, mainly in the hippocampus and basal forebrain.  Alzheimer disease has a incredible negative effect on patients and their families because of its devastating effects on the cognitive, emotional, and physical function of the patient with AD  Dementia of the Alzheimer type has three distinguishing features: 1) Accumulation of senile plaques (β-amyloid accumulations), 2) Formation of numerous neurofibrillary tangles or masses , and 3) Loss of cortical neurons, particularly cholinergic neurons.  In patients with AD, there is a deficit in cholinergic neurotransmission due to destruction of neurons producing acetylcholine.  Pharmacologic intervention for Alzheimer's disease is only palliative & provides modest short-term benefit & current therapies are aimed to:  Either improving cholinergic transmission within the CNS or  Preventing excito-toxic actions resulting from over stimulation of N- methyl-D-aspartic acid (NMDA)-glutamate receptors in selected brain areas. 1) Acetyl cholinesterase inhibitors: Donepezil, Galantamine, Rivastigmine &Tacrine  Numerous studies have linked the progressive loss of cholinergic neurons and, presumably, cholinergic transmission within the cortex to the memory loss that is a hallmark symptom of Alzheimer's disease.  Treatment with central anticholinesterase inhibitors is given in an effort to improve cholinergic neurotransmission in the affected areas of the brain.  Although these centrally acting cholinesterase inhibitors may slow the deterioration of cognitive function, they do not affect the underlying neurodegenerative process, so the disease is eventually fatal.  The mechanisms of action for these drugs and other agents are shown in (Figure. 24.3). 1) Tacrine (Cognex®)  It was the first centrally acting cholinesterase inhibitor approved for the treatment of AD.  It has a lower bioavailability and a shorter half-life than donepezil, and it must be administered several times a day.  Tacrine, an acridine compound, is associated with a significant incidence of hepatotoxicity and with peripheral cholinergic side effects such as diarrhea, nausea, and urinary incontinence.  Because of these adverse effects tacrine has been withdrawn from the market ; but few patients can tolerate the higher doses required to demonstrate cognitive improvement in AD. 2) Donepezil (Aricept®)  Studies in patients with AD have demonstrated that those treated with donepezil for 24 weeks had significantly better cognitive function than those treated with a placebo.  Donepezil is a reversible cholinesterase inhibitor that selectively inhibits cholinesterase in the CNS and increases Ach levels in the cerebral cortex.  The drug is well absorbed after oral administration and crosses BBB. Because it has a long half-life of about 70 hours, it is administered once a day.  Common adverse effects include nausea, diarrhea, vomiting, anorexia, tremors, bradycardia, and muscle cramps.  Unlike tacrine , donepezil is not associated with hepatotoxicity. 3) Rivastigmine (Exelon®) :  It is a newer, centrally acting, reversible cholinesterase inhibitor.  Rivastigmine is the only agent approved for the management of dementia associated with Parkinson disease and also the only AChE inhibitor available as a transdermal formulation.  Taken in divided doses, it significantly delays the global cognitive impairment associated with AD for at least 6 months in clinical trials.  Recently, a transdermal formulation of rivastigmine (Exelon Patch) was introduced; it is applied every 24 hours, increasing patient compliance and simplifying caregiver administration.  Rivastigmine is hydrolyzed by AChE to a carbamylate metabolite and has no interactions with drugs that alter the activity of P450- dependent enzymes while the other agents are substrates for P450 and have a potential for such interactions. 4) Galantamine (Razadyen®)  It is also a newer, centrally acting, competitive reversible cholinesterase inhibitor (AChE- inhibitor) &  Also may be acting as an allosteric modulator of the nicotinic receptor in the CNS and, therefore, secondarily increase cholinergic neurotransmission through a separate mechanism.  It was discovered from the extracts from the bulbs of the daffodil, Narcissus pseudo-narcissus.  Like rivastigmine, it has been shown to slow the progression of AD.  Common adverse effects include nausea, diarrhea, vomiting, anorexia, tremors, bradycardia, and muscle cramps. Additional Drugs for Alzheimer Disease: 1) Memantine (Namenda®):  Memantine is (N-methyl-D-aspartic acid (NMDA) - glutamate receptor antagonist) which is recently approved agent with a new mechanism of action for the treatment of the dementia of AD.  Normal stimulation of glutamate receptors in the CNS appears to be critical for the formation of certain memories; however, binding of glutamate to the NMDA receptor assists in the opening of an associated ion channel that allows Na+ and, particularly, Ca2+ to enter the neuron.  Overstimulation of glutamate receptors, particularly of the NMDA type, has been shown to result in excito-toxic effects on neurons. Unfortunately, excess intracellular Ca2+ can activate a number of processes that ultimately damage neurons and lead to apoptosis (programmed cell death). ….So that  NMDA-glutamate receptor Antagonists are often neuroprotective, preventing the loss of neurons following ischemic and other injuries.  Memantine is a low potency, noncompetitive antagonist at the N-methyl-d- aspartate (NMDA) receptor. It is hypothesized to work by attenuating the excitotoxic effects of glutamate that may underlie the pathologic process of neuronal loss in AD.  It is excreted largely unchanged as the parent molecule.  (Namzaric®): is t he combination of memantine extended-release with donepezil is also available to improve efficacy and compliance. 2) Caprylidene (Axona®):  A new approach to treat AD, was developed as medical food that is metabolized into ketone bodies, which the brain can use for energy when the processing of glucose is impaired.  Magnetic resonance imaging (MRI) scans of the elderly and those with AD reveal a significantly decreased ability for glucose uptake, the brain’s preferred source of energy.  Caprylidene replaces depleted glucose levels to treat patients with age- associated memory impairment and AD.  Drugs Used in Multiple Sclerosis (M.S.)  MS is an autoimmune inflammatory demyelinating disease of the CNS. The course of MS is variable. Demyelination leads to disruption of nerve transmission and is accompanied by an inflammatory response and the formation of plaques in the brain and spinal cord.  For some, MS may consist of one or two acute neurologic episodes. In others, it is a chronic, relapsing, or progressive disease that may span 10 to 20 years.  The neurologic symptoms of MS, which depend on the area of the brain that is affected, can include pain, spasticity, weakness, ataxia, fatigue, and problems with speech, vision, gait, and bladder function.  Many patients experience relapses and remissions, but some have a more severe and unremitting progression of disease.  Acute exacerbations M.S. are treated withprednisone shortens the duration of exacerbations and ameliorate symptoms, possibly by decreasing edema. They are administered orally in milder cases and are given parenterally in high doses in more severe cases.   Disease-Modifying Therapies  Drugs currently approved for MS are indicated to decrease relapse rates or, in some cases, to prevent accumulation of disability.  The major target of these medications is to modify the immune response through inhibition of white blood cell-mediated inflammatory processes that eventually lead to myelin sheath damage and decreased or inappropriate axonal communication between cells. 1) Interferon β-1b & Interferon β-1a (Betaseron®):  Interferon β-1b was the first drug to demonstrate an ability to halt and even reverse the progression of MS in some cases.  The immuno-modulatory effects of interferon help to diminish the inflammatory responses that lead to demyelination of the axon sheaths.  In clinical studies, the drug was found to reduce the frequency of relapses and the number of new lesions detected by MRI in patients who were ambulatory, had a relapsing-remitting type of MS, and had experienced at least two exacerbations during the last 2 years. 1) Interferon β-1b is a synthetic analog of a recombinant interferon-β produced in E. coli. Although the drug’s exact mechanism of action is unknown, its effects in patients with MS may be caused by its immuno- modulating properties.  Mechanism of action:  Interferon β-1b increases the cytotoxicity of natural killer cells and increases the phagocytic activity of macrophages.  It reduces the amount of interferon-γ secreted by activated lymphocytes. Because interferon-γ has been shown to exacerbate the symptoms of MS, a reduction in its secretion may halt the disease. 2) Interferon β-1a : was approved to treat the relapsing forms of MS. Like its predecessor, it works as an immunomodulator and is synthesized by recombinant protein pathways. 3) Peginterferon β-1a: is a PEGylated (polyethylene glycol) derivative of interferon β-1a, which provides a longer duration of action.  Adverse effects: may include depression, local injection site reactions, increases in hepatic enzymes, and flu-like symptoms 2) Glatiramer (Copaxone®) :  Glatiramer is a synthetic polypeptide mimics the structure of myelin basic protein, a component of the myelin covering nerve fibers and may act as a decoy or trap to T-cell attack.  In placebo-controlled clinical trials with relapsing-remitting MS, those taking the glatiramer acetate drug had significantly reduced episodes of relapse compared with control subjects.  Some patients experience a post injection reaction that includes flushing, chest pain, anxiety, and itching. It is usually self-limiting. 3) Fingolimod (Gilenya®):  Fingolimod is an oral drug that alters lymphocyte migration, resulting in fewer lymphocytes in the CNS which indicated for patients with the relapsing form of MS.  The exact mechanism by which fingolimod works is unknown but it is a sphingosine-1-phosphate receptor modulator and also  Blocks the egress or outlets of lymphocytes from lymph nodes, reducing the number of lymphocytes in peripheral blood (reduction of lymphocyte migration into the CNS) and decreased immune reactions that destroy nerve myelination).  Fingolimod may cause first-dose bradycardia and is associated with an increased risk of infection and macular edema.  After the success of fingolimod, two other agents of this class were marketed: Siponimod &Ozanimod. 4) Teriflunomide (Aubagio®):  Teriflunomide is another new agent used to treat relapsing forms of multiple MS.  Teriflunomide is an oral pyrimidine synthesis inhibitor that leads to a reduce in the proliferation of overactive immune cells (including T- and B-cells) that attack and damage the nerves in the CNS (lower concentration of active lymphocytes in the CNS).  Teriflunomide may cause elevated liver enzymes which cause hepatic toxicity.  It should be avoided in pregnancy. 5) Dimethyl fumarate (Tecfidera®):  Dimethyl fumarate is another new agent for the treatment of relapsing forms of MS.  Dimethyl fumarate is an oral agent that may alter the cellular response to oxidative stress to reduce disease progression.  Its mechanism of action is unknown, but its main metabolite is mono- methyl fumarate (MMF). MMF activates the Nuclear factor (erythroid derived 2)-like 2 (Nrf2) pathway. The Nrf2 pathway regulates the cellular response to oxidative stress..  Flushing and abdominal pain are the most common adverse events 6) Dalfampridine (Ampyra®):  New drug was recently approved for treatment of MS. Which improve walking in patients with MS. This was demonstrated by an increase in walking speed.  It works by blocking potassium channels and thereby enhances conduction in damaged nerves. 7) Mitoxantrone (Novantrone®)  It belongs to the class of anti-neoplastic agents and was recently approved for the treatment of MS.  It acts by suppressing the activity of T cells, B cells, and macrophages that are thought to lead the attack on the myelin sheath 8) Monoclonal antibodies: These agents may be reserved for patients who have failed other therapies (Alemtuzumab , Daclizumab , Natalizumab , Ocrelizumab 1) Ocrelizumab:  It is the first agent to be approved for primary progressive forms of the disease. 2) Natalizumab (Tysabr®) :  A monoclonal antibody preparation works by blocking the molecular pathway involving cell adhesion that draws lymphocytes into the CNS.  The presence of lymphocytes around neuronal fibers is implicated in the immune processes that contribute to the pathology of MS.  Natalizumab cause significant toxicity as progressive multifocal leuko-encephalopathy  Daclizumab  The monoclonal preparation,, is made up of antibodies to the interleukin-2 (IL-2) receptor.  The exact mechanism of action for daclizumab is unknown, but antibody formation with the IL-2 receptor blocks interleukin mediated activation of lymphocytes.  Daclizumab cause serious infections  Alemtuzumab:  It is a CD52-directed cytolytic monoclonal antibody approved for the treatment of patients with relapsing forms of MS.  Because of its potentially life-threatening adverse effects of autoimmune, infusion reactions, and increased malignancies, alemtuzumab should only be used in patients who have not responded to two or more other treatments for MS.  alemtuzumab cause serious infections and autoimmune disorders.  Drugs Used in Amyotrophic Lateral Sclerosis  ALS also called Lou Gehrig disease is a progressive degeneration disease of the motor neurons resulting in the inability to initiate or control muscle movement.  It is characterized by muscle wasting, weakness, and respiratory failure, leading to death in 2 to 5 years.  The cause of ALS is unknown, but evidence suggests a defect in superoxide dismutase, an enzyme that scavenges superoxide radicals.  The current treatment for ALS is largely symptomatic.  Riluzole & Edaravone :are indicated for the management of ALS.  Baclofen : a GABAB receptor agonist partly controlled spasticity  Gabapentin (Neurontin®) : used to slow the decline in muscle strength  Riluzole (Rilutek®):  The first drug specifically approved for use in the treatment of ALS ;  Its exact mechanism of action is unclear, but it is an oral NMDA receptor antagonist, is believed to act by inhibiting glutamate release and blocking sodium channels in which it may inhibit voltage-gated sodium channels that mediate the release of glutamate from neurons in which it protect motor neurons from the neurotoxic effects of excitatory amino acids (e.g., glutamate) and to prevent the anoxia-related death of cortical neurons.  Riluzole may improve survival time in patients suffering from ALS. This drug has been shown to prolong the time before patients require a tracheotomy and also to prolong life by approximately 3 months. 2) Edaravone (Radicava®)  Edaravone is touted as a nootropic (“smart drug”) and neuroprotective agent used for neurological recovery.  Edaravone is an intravenous free radical scavenger and antioxidant (reduces neuronal damage due to oxidative stress) that may slow the progression of ALS.  Edaravone was effective in clinical trials with ALS patients and is officially FDA-approved for the treatment of amyotrophic lateral sclerosis.  Anti-spastic Agents for M.S. & A.L.S.  Anti-spastic agents are used to treat skeletal muscle spasms that may occur from injury or a neurologic disease.  Spasticity is frequently treated with physical therapy, but anti-spastic drugs may be useful in severe cases. 1) Baclofen (Lioresal®):  Baclofen is a GABAB receptor agonist, and these G protein-coupled receptors (GPCRs), when activated, reduce motor neuron excitability.  It is useful for reducing spasticity resulting from MS, particularly for the relief of flexor spasms & the concurrent pain, clonus & muscular rigidity.  Baclofen is available in oral, injectable, and intrathecal infusion formulations. 2) Methocarbamol :  It is a carbamate derivative of guaifenesin, is a CNS depressant with sedative and musculoskeletal relaxant properties.  Its exact mechanism of action is not known, except to say general CNS depression. It does not directly affect muscle contraction or neurotransmitter action at the muscle end-plate junction. 3) Carisoprodol (Soma®):  It is also indicated for the short-term treatment of muscle spasms caused by musculoskeletal conditions.  The major metabolite of carisoprodol is meprobamate, which is an old barbiturate-like “minor tranquilizer” still available as an anxiolytic, but its use has largely been replaced by the safer benzodiazepines.  It is unclear whether carisoprodol has any effects itself or is simply a prodrug for meprobamate. 4) Tizanidine (Zanaflex®):  A centrally acting alpha2-adrenoceptor agonist, is also indicated for the management of spasticity of MS.  It is thought to reduce spasticity by blocking nerve impulses through presynaptic inhibition of motor neurons, resulting in decreased spasticity without a reduction in muscle strength. 5) Dantrolene (Dantrium®):  It acts by blocking the release of calcium ions from the sarcoplasmic reticulum in muscle fibers. This decouples the excitation-contraction at the muscle endplate and directly relaxes skeletal muscle.  It is a life-saving drug in cases of malignant hyperthermia triggered by halogenated anesthetics & it is used in neuroleptic malignant syndrome seen with high-potency antipsychotics and is also indicated for the management of spasticity from a number of disorders (e.g., after strokes, in paraplegia, in cerebral palsy, or in patients with MS). 6) Botulinum toxin A (Botox®):  Its widely known by its trade name, has recently been approved for a number of medical indications besides the more famous (or infamous) use as a cosmetic agent for removing wrinkles  OnabotulinumtoxinA paralyzes muscles by blocking the release of acetylcholine on the presynaptic side of the muscle end-plate junction  OnabotulinumtoxinA is used to treat upper-limb spasticity in stroke patients, for cervical dystonia and other symptoms of PD, for strabismus (“crosseyed”), and for blepharospasm (spasms of the eyelids).  It was also recently approved to treat urinary incontinence resulting from detrusor over activity in patients with spinal cord injury and MS.  Newer agents include: 1) Abo-botulinum toxin A, 2) Inco-botulinum toxin A, 3) Pra-botulinum toxinA, 4) Ima-botulinum toxinB.