NEET MDS Lessons
Pharmacology
Antipsychotic Drugs
A. Neuroleptics: antipsychotics; refers to ability of drugs to suppress motor activity and emotional expression (e.g., chlorpromazine shuffle)
Uses: primarily to treat symptoms of schizophrenia (thought disorder); also for psychoses (include drug-induced from amphetamine and cocaine), agitated states
Psychosis: variety of mental disorders (e.g., impaired perceptions, cognition, inappropriate or ↓ affect or mood)
Examples: dementias (Alzheimer’s), bipolar affective disorder (manic-depressive)
B. Schizophrenia: 1% world-wide incidence (independent of time, culture, geography, politics); early onset (adolescence/young adulthood), life-long and progressive; treatment effective in ~ 50% (relieve symptoms but don’t cure)
Symptoms: antipsychotics control positive symptoms better than negative
a. Positive: exaggerated/distorted normal function; commonly have hallucinations (auditory) and delusions (grandeur; paranoid delusions particularly prevalent; the most prevalent delusion is that thoughts are broadcast to world or thoughts/feelings are imposed by an external force)
b. Negative: loss of normal function; see social withdrawal, blunted affect (emotions), ↓ speech and thought, loss of energy, inability to experience pleasure
Etiology: pathogenesis unkown but see biochemical (↑ dopamine receptors), structural (enlarged cerebral ventricles, cortical atrophy, ↓ volume of basal ganglia), functional (↓ cerebral blood flow, ↓ glucose utilization in prefrontal cortex), and genetic abnormalities (genetic predisposition, may involve multiple genes; important)
Dopamine hypothesis: schizo symptoms due to abnormal ↑ in dopamine receptor activity; evidenced by
i. Correlation between potency and dopamine receptor antagonist binding: high correlation between therapeutic potency and their affinity for binding to D2 receptor, low correlation between potency and binding to D1 receptor)
ii. Drugs that ↑ dopamine transmission can enhance schizophrenia or produce schizophrenic symptoms:
A) L-DOPA: ↑ dopamine synthesis
B) Chronic amphetamine use: releases dopamine
C) Apomorphine: dopamine agonist
iii. Dopamine receptors ↑ in brains of schizophrenics: postmortem brains, positron emission tomography
Dopamine pathways: don’t need to know details below; know that overactivity of dopamine neurons in mesolimbic and mesolimbocortical pathways → schizo symptoms
i. Dorsal mesostriatal (nigrostriatal): substantia nigra to striatum; controls motor function
ii. Ventral mesostriatal (mesolimbic): ventral tegmentum to nucleus accumbens; controls behavior/emotion; abnormally active in schizophrenia
iii. Mesolimbocortical: ventral tegmentum to cortex and limbic structures; controls behavior and emotion; activity may be ↑ in schizophrenia
iv. Tuberohypophyseal: hypothalamus to pituitary; inhibits prolactin secretion; important pathway to understand side effects
Antipsychotic drugs: non-compliance is major reason for therapeutic failure
1. Goals: prevent symptoms, improve quality of life, minimize side effects
2. Prototypical drugs: chlorpromazine (phenothiazine derivative) and haloperidol (butyrophenone derivative)
a. Provide symptomatic relief in 70%; delayed onset of action (4-8 weeks) and don’t know why (maybe from ↓ firing of dopamine neurons that project to meso-limbic and cortical regions)
3. Older drugs: equally efficacious in treating schizophrenia; no abuse potential, little physical dependence; dysphoria in normal individuals; high therapeutic indexes (20-1000)
Classification:
i. Phenothiazines: 1st effective antipsychotics; chlorpromazine and thioridazine
ii. Thioxanthines: less potent; thithixene
iii. Butyrophenones: most widely used; haloperidol
Side effects: many (so known as dirty drugs); block several NT receptors (adrenergic, cholindergic, histamine, dopamine, serotonin) and D2 receptors in other pathways
i. Autonomic: block muscarinic receptor (dry mouth, urinary retention, memory impairment), α-adrenoceptor (postural hypotension, reflex tachycardia)
Neuroleptic malignant syndrome: collapse of ANS; fever, diaphoresis, CV instability; incidence 1-2% of patients (fatal in 10%); need immediate treatment (bromocriptine- dopamine agonist)
ii. Central: block DA receptor (striatum; have parkinsonian effects like bradykinesia/tremor/muscle rigidity, dystonias like neck/facial spasms, and akathisia—subject to motor restlessness), dopamine receptor (pituitary; have ↑ prolactin release, breast enlargement, galactorrhea, amenorrhea), histamine receptor (sedation)
DA receptor upregulation (supersensitivity): occurs after several months/years; see tardive dyskinesias (involuntary orofacial movements)
Drug interactions: induces hepatic metabolizing enzymes (↑ drug metabolism), potentiate CNS depressant effects (analgesics, general anesthetics, CNS depressants), D2 antagonists block therapeutic effects of L-DOPA used to treat Parkinson’s
Toxicity: high therapeutic indexes; acute toxicity seen only at very high doses (hypotension, hyper/hypothermia, seizures, coma, ventricular tachycardia)
Mechanism of action: D2 receptor antagonists, efficacy ↑ with ↑ potency at D2 receptor
Newer drugs: include clozapine (dibenzodiazepine; has preferential affinity for D4 receptors, low affinity for D2 receptors), risperidone (benzisoxazole), olanzapine (thienobenzodiazepine)
Advantages over older drugs: low incidence of agranulocytosis (leucopenia; exception is clozapine), very low incidence of motor disturbances (extrapyramidal signs; may be due to low affinity for D2 receptors), no prolactin elevation
Side effects: DA receptor upregulation (supersensitivity) occurs after several months/years; may → tardive diskinesias
Kinins
Peptide that are mediated in the inflammation.
Action of kinin:
On CVS: vasodilatation in the kidneys, heart, intestine, skin, and liver. It is 10 times active than histamine as vasodilator.
On exocrine and endocrine glands: kinin modulate the tone of pancreas and salivery glands and help regulate GIT motility, also affect the transport of water and electrolytes, glucose and amino acids through epithelial cell transport.
OXYMETAZOLINE
It is a directly acting sympathomimetic amine used in symptomatic relief in nasal congestion which increases mucosal secretion.
It is used:
- As a nasal decongestant in allergic rhinitis, with or without the addition of antazoline or sodium chromoglycate.
- As an ocular decongestant in allergic conjunctivitis.
Compounds like naphazoline and xylometazoline are relatively selective α2 agonists, which on topical application produce local vasoconstriction.
Different Systems of the CNS & their functions
These systems are pathways formed of specific parts of the brain and the neurons connecting them.
They include:
1.The pyramidal system
2.The extrapyramidal system
3.The limbic system
4.The reticular formation
5.The tuberohypophyseal system
The pyramidal system:
It originates from the motor area of the cerebral cortex and passes through the spinal cord, therefore it is also known as the “corticospinaltract”.
It is responsible for the regulation of the fine voluntary movements.
The extrapyramidal system:
It also controls the motor functionbut involves areas other than the corticospinal tract.
It is involved in the regulation of gross voluntary movements, thus it complements the function of the pyramidal system.
The “basal ganglia” constitute an essential part of this system.
Degenerative changes in the pathway running from the “substantianigra”to the “corpus striatum”(or nigrostriatal pathway) may cause tremors and muscle rigidity characteristic of “Parkinson’s disease”.
The limbic system:
The major parts of this system are: the hypothalamus, the basal ganglia, the hippocampus(responsible for short term memory), and some cortical areas.
The limbic system is involved in the control of “behavior”& “emotions”.
The reticular formation:
It is composed of interlacing fibers and nerve cells that run in all directions beginning from the upper part of the spinal cord and extending upwards.
It is important in the control of “consciousness” and “wakefulness”.
The tuberohypophyseal system:
It is a group of short neurons running from the hypothalamusto the hypophysis(pituitary gland) regulating its secretions.
Phenobarbital (Luminal): for generalized tonic-clonic and partial seizures (not used for absence seizures)
Mechanism: enhances GABA inhibition (↑ open time of Cl channels in presence of GABA)
Side effects: sedation, ataxia, cognitive impairment, induction of hepatic microsomal enzymes
Mucosal protective agents.
These are locally active agents that help heal gastric and duodenal ulcers by forming a protective barrier between the ulcers and gastric acid, pepsin, and bile salts. They do not alter the secretion of gastric acid. These drugs include sucralfate and colloid bismuth compounds. (e.g. tripotassium, dicitratobismuthate). Colloidal bismuth compounds additionally exert bactericidal action against H.pylori. Also, Prostaglandins have both antisecretory and mucosal protective effects.
Example: Misoprostol- used for prevention of NSAID – induced ulcer.
- Drugs that exert antimicrobial action against H.pylori such as amoxicillin, metronidazole, clarithromycin and tetracycline are included in the anti-ulcer treatment regimens.
VITAMIN -K
- Group of lipophilic, hydrophobic vitamins.
- Needed for the post-translational modification of coagulation proteins.
- Phylloquinone (vitamin K1) is the major dietary form of vitamin K.
- Vitamin K2 (menaquinone, menatetrenone) is produced by bacteria in the intestines.