What are they?
A German psychiatrist, Alois Alzheimer (1906), described Alzheimer’s disease FIRST TIME. Alzheimer’s disease is a progressive neurodegenerative disorder and is a common cause of dementia. It is usually diagnosed in people 65 years or older. The clinical implications of this disease include –
Atrophy of neurons in cortical and subcortical areas, along with deposition of toxic β amyloid proteins, and formation of neurofibrillary tangles upon tau protein hyperphosphorylation. There is a marked decrease in the neurotransmitter, acetylcholine as well. This progression affects an individual’s cognitive abilities; as a result, the patient loses memory, becomes disoriented, confused, and has difficulty with logical reasoning and language.
Due to the dysregulation of neural connections, the patients exhibit behavioral signs and symptoms – agitation, anxiety, depression, insomnia. The onset is of AD is very slow and gradual, and the severity of the symptoms increases over time.
Figure 1Healthy v/s AD Brain http://www.alz.org/brain/14.asp
The drugs used to treat symptoms of AD are commonly known as anti-Alzheimer drugs.
How do they work
The origin of AD is not yet established. However, environmental and genetic factors are considered to play a role in disease pathology. The amyloid accumulation, tau, and cholinergic hypothesis are the main areas of research.
Therefore, anti-Alzheimer drugs are aimed at treating the symptoms of AD. The drugs ensure an overall slowing of AD, which improves the quality of life of the patients.
The drugs aim to enhance the cognitive functions by multiple mechanisms –
- Increasing global/regional cerebral blood flow (CBF)
- Direct support of neuronal metabolism
- Enhancement of neurotransmission.
- Improvement of discrete cerebral functions (memory)
- Decrease neuroinflammatory response
- Decrease toxic protein formation
Different classes of these drugs
- Anticholinesterases (cholinesterase inhibitors) – Donepezil, Galantamine, Rivastigmine
- NMDA receptor antagonist – Memantine
Drugs for management of behavioral and psychological symptoms of dementia (BPSD)
- Antipsychotics – Aripiprazole, Haloperidol, Risperidone, Quetiapine, Olanzapine
- Antidepressants – Fluoxetine, Citalopram, Paroxetine, Sertraline, Trazadone
- Mood stabilizers – Carbamazepine, Divalproex Sodium, Oxcarbazepine
Miscellaneous Cerebroactive Drugs – Piracetam, Pyritinol (Pyrithioxine), Dihydroergotoxine (Codergocrine), Piribedil, Ginkgo biloba
- Acetyl-L-carnitine – neuroprotective agent
- Cerebrolysin – neurotrophic and neuroprotective
- Xaliproden – neurotrophic agent
- Beta-amyloid fibrillogenesis inhibitor (Alzhemed) – a disease-modifying inhibitor of beta-amyloid fibril formation
- Phenserine – acetylcholinesterase and -amyloid precursor protein inhibitor
- SORLA (sortilin-related, low-density lipoprotein receptor class A repeat-containing protein)
Indications in which they are preferred
The treatment of mild to moderate (anticholinesterase) and moderate to severe Alzheimer’s (NMDA receptor antagonist). All the drugs prescribed aim at improving the overall quality of life in AD patients.
- Cholinesterase inhibitors – Nausea, Vomiting, Diarrhea Weight loss Loss of appetite Muscle weakness Vivid dreams/nightmares (donepezil)
- NMDA receptor antagonist – Dizziness, Headache, Constipation, Confusion
- Antipsychotics – Sedation, Extrapyramidal symptoms (EPS), neuroleptic malignant syndrome, metabolic syndrome, QTc prolongations, Increased risk of cardiovascular events and mortality
- Antidepressants -Anxiety, headaches, sedation, GI symptoms, sexual dysfunction
- Mood stabilizers – Sedation, gait, and balance issues, falls, liver dysfunction, hyperammonemia, thrombocytopenia
- Cholinesterase inhibitors – liver disease, peptic ulcer, hypersensitivity, pregnancy
- NMDA receptor antagonist- hypersensitivity to Memantine and excipients in the formulation.
- Antipsychotics – use of atypical antipsychotics must be minimized patients since it increases the risk of death. (2008 FDA black box warning)
- Antidepressants – SSRI have shown to increase sedation and dementia in the long run
- Mood stabilizers – renal insufficiency, cardiovascular risk, patients suffering from aplastic anemia
What are they
Parkinsonism is a degenerative and progressive neurological disorder that is a consequence of decreased dopamine levels produced in the basal ganglia (substantia nigra) region of the brain. The etiology is unknown, and several factors play a role in disease pathology. Thus, antiparkinsonian drugs are compounds that are used to relieve the patients from symptoms occurring as a cause of dopaminergic imbalance.
Figure 2 Parkinson’s Disease
How do they work
The leading cause of Parkinson’s is yet to be discovered. Hence, drug therapies are used to elicit a beneficial effect on the symptoms. Parkinson’s disease’s primary symptom is extrapyramidal motor function disorder, which is characterized by rigidity, tremor, hypokinesia/bradykinesia, and impairment of postural balance that may cause frequent falling. These symptoms are the result of decreased dopamine levels, with an increase in acetylcholine levels. The standard drug treatment includes anticholinergics and dopamine agonists. However, with advancements in medical research, newer drugs are being tested that modulate the condition via other mechanisms and pathways.
Different classes of these drugs
- Drugs acting on the dopaminergic system:
v Dopamine precursors – the drug under this class most effective agent in PD. It is a prodrug that gets metabolized to form dopamine in neurons. 95% of the dose is metabolized before it enters the brain, and only 1-2% crosses the blood-brain barrier to show a therapeutic effect. It is then stored and released as a neurotransmitter.
Drug – Levodopa (l-dopa)
Peripheral decarboxylase inhibitors – these drugs are widely used to prevent peripheral metabolism of levodopa. However, these drugs do not cross the blood-brain barrier; thus, the conversion of l-dopa to dopamine is not inhibited in the brain. Such peripheral decarboxylase inhibitors are beneficial in increasing the l-dopa bioavailability, half-life, availability in CNS. Due to enhanced availability, the daily dose of levodopa can be reduced to minimize side effects.
Drugs – carbidopa and benserazide
Dopaminergic agonists – – these drugs bind to different dopamine receptors to exert the effect. They are used as first-line treatment for Parkinson’s. They are better tolerated by the body, do not require enzymatic conversion to an active form, do not compete with other substances for transport and can be used to reduce the ‘on-off’ phenomenon, refractory to levodopa
Drugs – Bromocriptine, Ropinirole and Pramipexole
MAO-B inhibitors – the drugs falling under this class, inhibit the monoamine oxidase metabolic system. As a result, there is a decrement in dopamine breakdown. Used as adjunctive therapy to l-dopa, it balances fluctuations in l-dopa response, prolongs, and enhances its effect.
Drugs – Selegiline, Rasagiline
COMT inhibitors – upon inhibition of the dopa-decarboxylase pathway for l-dopa metabolism, the COMT pathway acts as a compensatory mechanism for metabolism. An increase in COMT activity results in an inadequate response of levodopa; hence the inhibitors are targeted to inhibit such an effect.
Drugs – Entacapone, Tolcapone
Dopamine facilitator – The drug used as dopamine facilitator is an antiviral agent that acts by potentiating dopaminergic function by influencing the synthesis, release, reuptake of dopamine in the brain. The effect is short-lived, and its potency is less than levodopa.
Drug – Amantadine
- Drugs acting on the cholinergic system
The drugs are used to provide symptomatic relief by anticholinergic actions of reduction in tremor and rigidity in patients. They, however, show little or no effect on bradykinesia.
v Central anticholinergics – Trihexyphenidyl (Benzhexol), Procyclidine, Biperiden
v Antihistaminics – Orphenadrine, Promethazine
- Newer drugs
v Adenosine A2A receptor antagonists – istradefylline
v Gene therapy –
- Introduction of a gene into putamen coding for aromatic acid decarboxylase. Results in increased metabolism L-Dopa to Dopamine.
- Gene for Glutamic acid decarboxylase into the subthalamic nucleus causing an increase in GABA neuronal inhibition
Indication in which they are preferred
These drugs are indicated for the use of different symptoms of Parkinson’s. The dose of drugs and combination therapy are adjusted as per the severity of the condition.
- Dopamine precursors – Nausea, Vomiting, Postural hypotension, Cardiac arrhythmia, precipitation of angina Prolonged use – abnormal movements, behavioral changes, motor performance fluctuations, dyskinesia, denervation supersensitivity
- Peripheral decarboxylase Inhibitors – dyskinesia
- Dopaminergic agonists – GIT dysregulation, postural hypotension, painless vasospasm, dyskinesia, mental disturbance, somnolence, sleep attacks
- Monoamine oxidase (MAO B) inhibitors – insomnia, hypertensive crisis, atrial fibrillation, confusion and headache
- COMT inhibitors – postural hypotension, fatigue, somnolence, peripheral edema, GIT disturbance, dyskinesia, the orange coloration of urine
- Dopamine facilitator – restlessness, heart failure, irritability, hallucinations, confusion, livedo reticularis (mottled purplish reticulated vascular pattern in lower extremities)
- Anticholinergics – dry mouth, tachycardia, constipation, and central anticholinergic effects
v Dopamine precursors – psychosis, close angle glaucoma, cardiac dysrhythmia, melanoma and skin lesions (undiagnosed)
v Peripheral decarboxylase inhibitors – hepatic insufficiency, GI obstructive diseases
v Dopaminergic agonists – patients with psychotic illness, peptic ulcer, myocardial infarction, peripheral vascular disease
v MAO B inhibitors – tyramine rich diet
v COMT inhibitors – hepatic and renal insufficiency, lactation, hypertensive/hypotensive patients
v Dopamine facilitators – patients with a history of seizures and heart failure
v Anticholinergics – prostatic hyperplasia, obstructive GI disease, close angle glaucoma