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
ANTIBIOTICS
Chemotherapy: Drugs which inhibit or kill the infecting organism and have no/minimum effect on the recipient.
Antibiotic these are substances produced by microorganisms which suppress the growth of or kill other micro-organisms at very low concentrations.
Anti-microbial Agents: synthetic as well as naturally obtained drugs that attenuate micro-organism.
SYNTHETIC ORGANIC ANTIMICROBIAL DRUGS
Sulfonamides
Trimethoprim-sulfamethoxazole
Quinolones – Ciprofloxacin
ANTIBIOTICS THAT ACT ON THE BACTERIAL CELL WALL
Penicillins
Cephalosporins
Vancomycin
INHIBITORS OF BACTERIAL PROTEIN SYNTHESIS
Aminoglycosides - Gentamicin
Antitubercular Drugs: Isoniazid & Rifampin
Tetracyclines
Chloramphenicol
Macrolides – Erythromycin, Azithromycin
Clindamycin
Mupirocin
Linezolid
ANTIFUNGAL DRUGS
Polyene Antibiotics (Amphotericin B, Nystatin and Candicidin)
Imidazole and Triazole Antifungal Drugs
Flucytosine
Griseofulvin
ANTIPROTOZOAL DRUGS
Antimalarial Drugs – Quinine, Chloroquine, Primaquine
Other Antiprotozoal Drugs – Metronidazole, Diloxanide, Iodoquinol
ANTIHELMINTHIC DRUGS
Praziquantel
Mebendazole
Ivermectin
ANTIVIRAL DRUGS
Acyclovir
Ribavirin
Dideoxynucleosides
Protease inhibitors
TRICYCLIC ANTIDEPRESSANTS
e.g. amitriptyline, imipramine, nortriptyline
Belong to first generation antidepressants
ACTION:
Inhibit 5-HT(5-hydroxytryptamine) and norepinephrine reuptake
slow clearance of norepinephrine & 5-HT from the synapse
enhance norepinephrine & 5-HT neuro-transmission
MODE OF ACTIONMODE OF ACTION
TCAs also block
– muscarinic acetylcholine receptors
– histamine receptors
– 5-HT receptors
– α1 adrenoceptors
Onset of antidepressant activity takes 2-3 weeks
PHARMACOKINETICS
- Readily absorbed from the gastro-intestinal tract
- Bind strongly to plasma albumin
- Has a large volume of distribution(as a result of binding to extravascular tissues)
- Undergo liver CYP metabolism into biologically active metabolites
- These metabolites are inactivated via glucuronidation and excreted in urine
ADVERSE DRUG REACTIONS
Antimuscarinic - dry mouth, blurred vision, constipation and urinary retention
Antihistamine – drowsiness
adrenoceptor blockage(+/- central effect) postural hypotension
Reduce seizure threshold
Testicular enlargement, gynaecomastia, galactorrhoea
AV-conduction blocks and cardiac arrhythmias
TOXICITY
- Fatal in toxicity
- Most important toxic effect is, slowing of depolarisation of the cardiac action potential by blocking fast sodium channels ("quinidine-like" effect)
- delays propagation of depolarisation through both myocardium and conducting tissue
- prolongation of the QRS complex and the PR/QT intervals
- predisposition to cardiac arrhythmias
DRUG INTERACTIONS
Pharmacodynamic:
– ↑ sedation with antihistamines, alcohol
– ↑ antimuscarinic effects with anticholinergics– ↑ antimuscarinic effects with anticholinergics
– Hypertension and arrhythmias with MAOIs- should be given at least 14 days apart
Pharmacokinetic (via altering CYP metabolism)
– ↓ plasma concentration of TCA by- carbamazepine, rifampicin
– ↑ plasma concentration of TCA by- cimetidine, calcium channel blockers,fluoxetine
OTHER CLINICAL USES OF AMITRIPTYLINE
- Treatment of nocturnal enuresis in children
- Treatment of neuropathic pain
- Migraine prophylaxis
Mixed Narcotic Agonists/Antagonists
These drugs all produce analgesia, but have a lower potential for abuse and do not produce as much respiratory depression.
A. Pentazocine
- Has a combination of opiate analgesic and antagonist activity.
- Orally, it has about the same analgesic potency as codeine.
- In contrast to morphine, cardiac workload tends to increase due to an increase in pulmonary arterial and cerebrovascular pressure. Blood pressure and heart rate both also tend to increase.
- Adverse reactions to Pentazocine
• Nausea, vomiting, dizziness.
• Psychotomimetic effects, such as dysphoria, nightmares and visual hallucinations.
• Constipation is less marked than with morphine.
B. Nalbuphine
- Has both analgesic and antagonist properties.
- Resembles pentazocine pharmacologically.
- Analgesic potency approximately the same as morphine.
- Appears to be less hypotensive than morphine.
- Respiratory depression similar to morphine, but appears to peak-out at higher doses and to reach a ceiling.
- Like morphine, nalbuphine reduces myocardial oxygen demand. May be of value following acute myocardial infarction due to both its analgesic properties and reduced myocardial oxygen demand.
- Most frequent side effect is sedation.
C. Butorphanol
- Has both opiate agonist and antagonist properties.Resembles pentazocine , pharmacologically., 3.5 to 7 times more potent than morphine., Produces respiratory depression, but this effect peaks out with higher doses. The respiratory depression that does occur lasts longer than that seen following morphine administration.
- Butorphanol, like pentazocine, increases pulmonary arterial pressure and possibly the workload on the heart.
- Adverse reactions include sedation, nausea and sweating.
D. Buprenorphine
- A derivative of eto`rphine. Has both agonist and antagonist activity. 20 to 30 times more potent than morphine.Duration of action only slightly longer than morphine, but respiratory depression and miosis persist well after analgesia has disappeared.
- Respiratory depression reaches a ceiling at relatively low doses.
- Approximately 96% of the circulating drug is bound to plasma proteins.
- Side effects are similar to other opiates:
- sedation, nausea, vomiting,
- dizziness, sweating and headache.
Ketoconazole
synthetic antifungal drug
used for infections such as athlete's foot, ringworm, candidiasis (yeast infection or thrush), jock itch.
Ketoconazole is used to treat eumycetoma, the fungal form of mycetoma.
MOA: Ketoconazole is imidazole structured, and interferes with the fungal synthesis of ergosterol, the main constituent of cell membranes, as well as certain enzymes. It is specific for fungi, as mammalian cell membranes contain no ergosterol.
Sensitive fungi Ketoconazole inhibits growth of dermatophytes and yeast species (such as Candida albicans).
Glucocorticoids
Cortisol (hydrocortisone) and its synthetic derivatives
|
Drug |
Duration |
| Cortisol | Short |
| Prednisone | Medium |
| Triameinolone | Intermediate |
| Betamethasone | Long |
| Dexamethasone | Long |
Mechanism
↓ the production of leukotrienes and prostaglandins - inhibits phospholipase A2 , inhibits expression of COX-2 , will also stimulate the bone marrow to produce neutrophils resulting in leukocytosis
halts inflammatory cascade
↓ leukocyte migration
↓ capillary permeability
↓ phagocytosis
↓ platelet-activating factor
↓ interleukins (e.g. IL-2)
may trigger apoptosis in dividing and non-dividing cells
used in cancer chemotherapy
Clinical use
anti-inflammatory
immunosuppression
cancer chemotherapy (prednisone most common)
CLL
Hodgkin's lymphomas
part of MOPP regimen
Addison disease
asthma
Toxicity
1) must taper dose to avoid toxicity
2) suppression of ACTH → shock state if abrupt withdrawal - > cortical atrophy, malaise, myalgia, arthralgia, fever
3) iatrogenic Cushing syndrome ->buffalo hump, moon facies, truncal obesity, muscle weakness and atrophy, thin skin, easy bruising, acne
4) osteoporosis - vertebral fractures, aseptic hip necrosis, ↓ skeletal growth in children
5) hyperglycemia (diabetes) -due to ↑ gluconeogenesis , glaucoma, cataracts, and other complications can subsequently result
6) ↑ GI acid release -ulcers
7) Na+ retention -> edema, HTN, hypokalemia alkalosis, hypocalcemia
8)↓ wound healing
9) ↑ infections
10) mental status changes
11) cataracts
Thiopental
- A barbiturate that is generally used to induce anesthesia.
- The temporal course of effects from induction to recovery depends almost entirely upon progressive redistribution.
- Metabolic degradation or excretion during anesthesia is negligible, except in the case of methohexital.
- The barbiturates produce minimal analgesia.
- Respiratory depression may be pronounced.
- Cardiac output is reduced while total peripheral resistance is increased.
- It does not sensitize the heart to catecholamines.
- It may cause bronchiospasm, especially in asthmatics.
- It is contraindicated in acute intermittent porphyria.