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
Gastric acid neutralizers (antacids)
Antacids act primarily in the stomach and are used to prevent and treat peptic ulcer. They are also used in the treatment of Reflux esophagitis and Gastritis.
Mechanism of action:
Antacids are alkaline substances (weak bases) that neutralize gastric acid (hydrochloric acid) they react with hydrochloric acid in the stomach to produce neutral or less acidic or poorly absorbed products and raise the pH of stomach secretion.
Antacids are divided into systemic and non-systemic.
• Systemic antacids (e.g. sodium bicarbonate) are highly absorbed into systemic circulation and enter body fluids. Therefore, they may alter acid–base balance. They can be used in the treatment of metabolic acidosis.
Non-systemic: they do not alter acid–base balance significantly, because they are not well-absorbed into the systemic circulation. They are used as gastric antacids; and include:
• Magnesium compounds such as magnesium hydroxide and magnesium sulphate MgS2O3. They have relatively high neutralizing capacity, rapid onset of action, however, they may cause diarrhoea and hypermagnesemia.
• Aluminium compounds such as aluminium hydroxide. Generally, these have low neutralizing capacity, slow onset of action but long duration of action. They may cause constipation.
• Calcium compounds such as. These are highly effective and have a rapid onset of action but may cause hypersecretion of acid (acid - rebound) and milk-alkali syndrome (hence rarely used in peptic ulcer disease).
Therefore, the most commonly used antacids are mixtures of aluminium hydroxide and magnesium hydroxide .
CLASSICATION OF ANTICOAGULANT DRUGS
1. Direct Acting Anticoagulants
a) Calcium Chelators (sodium citrate, EDTA)
b) Heparin
2. Indirect Acting Anticoagulant Drugs
a) Warfarin
Amphotericin B
Main use is in systemic fungal infections (e.g. in immunocompromised patients), and in visceral leishmaniasis. Aspergillosis, cryptococcus infections (e.g. meningitis) and candidiasis are treated with amphotericin B. It is also used empirically in febrile immunocompromised patients who do not respond to broad-spectrum antibiotics.
MOA:
As with other polyene antifungals, amphotericin B associates with ergosterol, a membrane chemical of fungi, forming a pore that leads to K+ leakage and fungal cell death
Side effects: nephrotoxicity (kidney damage) , headache, vomiting, convulsions and fever
The side-effects are much milder when amphotericin B is delivered in liposomes
Anti-Histamines:
The effect of histamine can be opposed in three ways:
1. Physiological antagonism: by using a drug to oppose the effect (e.g adrenaline). Histamine constricts bronchi,
causes vasodilatation which increases capillary permeability. Adrenaline opposes this effect by a mechanism unrelated to histamine.
2. By preventing histamine from reaching its site of action (receptors), By competition with H1-H2 receptors (Drug antagonisms).
3. By preventing the release of histamine. (adrenal steroids and sodium-cromoglycate can suppress the effect on the tissues)
Types of Anti-histamine drugs
Selected H1 antagonist drugs
First-generation H1 receptor antagonists:
Chlorpheniramine (Histadin) & Dexchlorpheniramine
Diphenhydramine (Allermine)
Promethazine (Phenergan) - strong CNS depressants
Cyproheptadine (Periactin)
ACTION
These drugs bind to both central and peripheral H1 receptors and can cause CNS depression or stimulation.
- They usually cause CNS depression (drowsiness,sedation) with usual therapeutic doses
- Cause CNS stimulation (anxiety, agitation)
with excessive doses, especially in children.
They also have Anticholinergic effects (e.g. dry mouth, urinary retention, constipation, blurred vision).
Second-generation H1 receptor antagonists (non-sedating) agents
Terfenadine
Fexofenadine
Loratadine
Acravistine and Cetirizine
Astemizol
Action
They cause less CNS epression because they are selective for peripheral H1 receptors and do not cross the blood brain barrier.
Indications for use
The drugs can relieve symptoms but don’t relieve hypersensitivity.
1) Allergic rhinitis. Some relief of sneezing, rhinorrhea, nasal airway obstruction and conjunctivitis are with the use of antihistamine.
2) Anaphylaxis. Antihistamine is helpful in treating urticaria and pruritus.
3) Allergic conjunctivitis. This condition, which is characterized by redness, itching and tearing of the eyes.
4) Drug allergies. Antihistamines may be given to prevent or treat reactions to drugs (e.g, before a dignostic test that
uses an iodine preparation).
5) Transfusions of blood and blood products.
6) Dermatologic conditions. Antihistamines are the drug of choice for treatment of allergic contact dermatitis and
acute Urticaria. Urticaria often occurs because the skin has many mast cells to release histamine.
7) Miscellaneous. Some antihistamines are commonly used for non-allergic disorder such as motion sickness, nausea, vomiting, sleep, cough or add to cough mixtures.
Contraindication
hypersensitivity to the drugs, narrow-angle glaucoma, prostatic hypertroph, stenosing peptic ulcer, bladder neck obstruction, during pregnancy and lactating women
Adverse effects:
Drowsiness and sedation
Anticholinergic
Some antihistamines may cause dizziness, fatigue, hypotention, headache, epigastric distress and photosensitivity
Serious adverse reaction including cardiac arrest & death, have been reported in patients receiving high dose astemizole
H2-receptor antagonists
Cimetidine (Tagamate), Ranitidine (Zantac), Fomatidine, Nizatidine.
Mechanism of action
Numerous factors influence acid secretion by the stomach, including food, physiological condition and drugs. H2 receptor blockers reduce basal acid-secretion by about 95% and food stimulated acid-secretion by about 70%. Both conc. and vol. of H ions will decrease.
Pharmacokinetics:
1) They are all well absorbed after oral dose.
2) Antacids decrease their absorption in about 10-20%
Uses
Cimetidine - reduction of gastric secretion is beneficial, these are in main duodenal ulcer, benign gastric ulcer, stomach ulcer and reflux eosophagitis.
Rantidine -used as alternative for duodenal ulcer
Adverse effects:
headache, dizziness, constipation, diarrhoea, tiredness and muscular pain.
Phenytoin (Dilantin): for tonic-clonic and all partial seizures (not effective against absence seizures)
Mechanism: ↓ reactivation of Na channels (↑ refractory period, blocks high frequency cell firing, ↓ spread of seizure activity from focus)
Side effects: ataxia, vertigo, hirsutism (abnormal hair growth), gingival hyperplasia, osteomalacia (altered vitamin D metabolism and ↓ Ca absorption), blood dyscrasias (rare; megaloblastic anemia, etc)
Drug interactions: induces hepatic microsomal enzymes (can ↓ effectiveness of other drugs); binds tightly to plasma proteins and can displace other drugs
Nystatin
Candida spp. are sensitive to nystatin.
Uses: Cutaneous, vaginal, mucosal and esophageal infections.
Candida infections can be treated with nystatin.
Cryptococcus is also sensitive to nystatin.
Nystatin is often used as prophylaxis in patients who are at risk for fungal infections, such as AIDS patients with a low CD4+ count and patients receiving chemotherapy.
MOA
nystatin binds to ergosterol, the main component of the fungal cell membrane. When present in sufficient concentrations, it forms a pore in the membrane that leads to K+ leakage and death of the fungus.