NEET MDS Lessons
Pharmacology
Morphine
Morphine is effective orally, but is much less effective than when given parenterally due to first-pass metabolism in the liver. Metabolism involves glucuronide formation, the product of which is excreted in the urine.
1. Central Nervous System Effects
• Morphine has mixed depressant and stimulatory actions on the CNS.
• Analgesia:
• Dysphoria – Euphoria
- morphine directly stimulates the chemoreceptor trigger zone, but later depresses the vomiting center in the brain stem. This center is outside the blood/brain barrier.
- opiates appear to relieve anxiety
• Morphine causes the release of histamine and abolishes hunger.
- causes the body to feel warm and the face and nose to itch.
• Pupils are constricted.- due to stimulation of the nuclei of the third cranial nerves.
- tolerance does not develop to this effect.
• Cough reflex is inhibited. - this is not a stereospecific effect.
- dextromethorphan will suppress cough but will not produce analgesia.
• Respiration is depressed
- due to a direct effect on the brain stem respiratory center.
- death from narcotic overdose is nearly always due to respiratory arrest.
- the mechanism of respiratory depression involves:
• a reduction in the responsiveness of the brain stem respiratory centers to an increase in pCO2.
• depression of brain stem centers that regulate respiratory rhythm.
- hypoxic stimulation of respiration is less affected and O2 administration can produce apnea.
2. Cardiovascular Effects
• Postural orthostatic hypotension.- due primarily to peripheral vasodilation, which may be due in part to histamine release.
• Cerebral circulation is also indirectly influenced by increased pCO2, which leads to cerebral vasodilation and increased cerebrospinal fluid pressure.
• In congestive heart failure, morphine decreases the left ventricular workload and myocardial oxygen demand.
3. Endocrine Effects
• Increases prolactin secretion
• Increases vasopressin (ADH) secretion
• Decreases pituitary gonadotropin (LH & FSH) secretion.
• Decreases stress induced ACTH secretion.
4. Gastrointestinal Tract Effects
• Constipation (tolerance does not develop to this effect).
• Several of these agents can be used in the treatment of diarrhea.
There is an increase in smooth muscle tone and a decrease in propulsive contractions.
Adverse Reactions
Generally direct extensions of their pharmacological actions.
1. respiratory depression, apnea
2. nausea and vomiting
3. dizziness, orthostatic hypotension, edema
4. mental clouding, drowsiness
5. constipation, ileus
6. biliary spasm (colic)
7. dry mouth
8. urine retention, urinary hesitancy
9. hypersensitivity reactions (contact dermatitis, urticaria)
Precautions
1. respiratory depression, particularly in the newborn
3. orthostatic hypotension
4. histamine release (asthma, shock)
5. drug interactions (other CNS depressants)
6. tolerance:
- analgesia, euphoria, nausea and vomiting, respiratory depression
7. physical dependence (psychological & physiological)
Carbenicillin
Antibiotic that is chemically similar to ampicillin. Active against gram-negative germs. It is well soluble in water and acid-labile.
Insulin
Insulin is only given parenterally (subcutaneous or IV) Various preparations have different durations of action
|
Preparation |
Onset (hrs) |
Peak (hrs) |
Duration (hrs) |
| Lispro (rapid-acting) | 15 min | 0.5-1.5 | 3-4 |
| Regular (short-acting) | 0.5-1 | 2-4 | 5-7 |
| NPH (intermediate) | 1-2 | 6-12 | 18-24 |
| Glargine (long-acting) | 1 | None | >24 |
Mechanism
bind transmembrane insulin receptor
activate tyrosine kinase
phosphorylate specific substrates in each tissue type
liver
↑ glycogenesis
store glucose as glycogen
muscle
↑ glycogen and protein synthesis
↑ K+ uptake
fat
increase triglyceride storage
Clinical use
type I DM
type II DM
life-threatening hyperkalemia
increases intracellular K+
stress-induced hyperglycemia
Toxicity
hypoglycemia
hypersensitivity reaction (very rare)
Insulin Synthesis
first generated as preproinsulin with an A chain and B chain connected by a C peptide.
c-peptide is cleaved from proinsulin after packaging into vesicles leaving behind the A and B chains
SGLT-2 Inhibitors
canagliflozin
empagliflozin
Mechanism
glucose is reabsorbed in the proximal tubule of the nephron by the sodium-glucose cotransporter 2 (SGLT2)
SGLT2-inhibitors lower serum glucose by increasing urinary glucose excretion
the mechanism of action is independent of insulin secretion or action
Clinical use
type II DM
Benzodiazepines (BZ):
newer; depress CNS, selective anxiolytic effect (no sedative effect); are not general anesthetics (but does produce sedation, stupor) or analgesics
BZ effects:
1. Central: BZs bind GABAA receptors in limbic system (amygdala, septum, hippocampus; involved in emotions) and enhance inhibition of neurons in limbic system (this may produce anxiolytic effects of BZs)
a. GABA receptor: pentameric (α, β, δ, γ subunits)
i. Binding sites: GABA (↑ conductance (G) of Cl-, hyperpolarization, inhibition), barbiturate (↑ GABA effect), benzodiazepine (↑ GABA effect), picrotoxin (block Cl channel)
b. GABA agonists: GABA (binds GABA → Cl influx; have ↑ frequency of Cl channel opening; BZs alone- without GABA don’t affect Cl channel function)
c. Antagonists: bicuculline (competitively blocks GABA binding; ↓ inhibition,→ convulsions; no clinical use), picrotoxin (non-competitively blocks GABA actions, Cl channel → ↓ inhibition → convulsions)
2. Other agents at BZ receptor:
a. Agonists: zolpidem (acts at BZ receptor to produce pharmacological actions)
b. Inverse agonists: β-carbolines (produce opposite effects at BZ binding site-- ↓ Cl conductance; no therapeutic uses since → anxiety, irritability, agitation, delirium, convulsions)
3. Antagonists: flumazenil (block agonists and inverse agonists, have no biological effects themselves; can precipitate withdrawal in dependent people)
Metabolism: many BZs have very long action (since metabolism is slow); drugs have active metabolites
2 major reactions: demethylation and hydroxylation (both very slow reactions)
Fast reaction: glucuronidation and urinary excretion
Plasma half life: long (for treating anxiety, withdrawal, muscle relaxants), intermediate (insomnia, anxiety), short (insomnia), ultra-short (<2hrs; pre-anesthetic medication)
Acute toxicity: very high therapeutic index and OD usually not life threatening (rarely see coma or death)
Treatment: support respiration, BP, gastric lavage, give antagonist (e.g., glumazenil; quickly reverses BD-induced respiratory depression)
Tolerance: types include pharmacodynamic (down-regulation of CNS response due to presence of drug; this is probably the mechanism by which tolerance develops), cross-tolerance (with other BZ and CNS depressants like EtOH and BARBS), acquisition of tolerance (tolerance develops fastest in anticonvulsant > sedation >> muscle relaxant > antianxiety; means people can take BZs for long time for antianxiety without → tolerance)
Physical dependence: low abuse potential (no buz) but physical/psychological dependence may occur; physical dependence present when withdrawal symptoms occur (mild = anxiety, insomnia, irritability, bad dreams, tremors, anorexia; severe = agitation, depression, panic, paranoia, muscle twitches, convulsions)
Drug interactions: minimally induce liver enzymes so few interactions; see additive CNS depressant effects (can be severe and → coma and death if BZs taken with other CNS depressants like ethanol)
Chloral hydrate
1. Short-acting sleep inducer—less risk of “hangover” effect the next day.
2. Little change on REM sleep.
3. Metabolized to trichloroethanol, an active metabolite; further metabolism inactivates the drug.
4. Used for conscious sedation in dentistry.
5. Can result in serious toxicity if the dose is not controlled.
Midazolam -Intravenous Anesthetics
Midazolam is a benzodiazepine used for preoperative sedation, induction of anesthesia, or maintenance of anesthesia in short procedures.