NEET MDS Lessons
Pharmacology
Barbiturates (BARBS):
were used for antianxiety, sedation but now replaced by BZs; for IV sedation & oral surgery
Advantages: effective and relatively inexpensive (common in third world countries), extensively studied so have lots of information about side effects/toxicity
Peripheral effects: respiratory depression (with ↑ dose), CV effects (↓ BP and HR at sedative-hypnotic doses), liver effects (bind CYP450 → induction of drug metabolism and other enzymes → ↑ metabolism of steroids, vitamins K/D, cholesterol, and bile salts)
General mechanisms: potently depress neuron activity in the reticular formation (pons, medulla) and cortex
o Bind barbiturate site on GABAA receptor → enhanced inhibitory effect and ↑ Cl influx; → ↓ frequency of Cl channel opening but ↑ open time of Cl channels (in presense of GABA) so more Cl enters channel (at high [ ] they directly ↑ Cl conductance in absence of GABA- act as GABA mimetics)
Metabolism: liver microsomal drug metabolizing enzymes; most are dealkylated, conjugated by glucoronidation; renal excretion
Uses: anticonvulsant, preoperative sedation, anesthesia
Side effects: sedation, confusion, weight gain, N/V, skin rash
Contraindications: pain (can ↑ sensitivity to painful situations → restlessness, excitement, and delirium) and pulmonary insufficiency (since BARBS → respiratory depression)
Drug interactions: have additive depressant affects when taken with other CNS depressants, enhance depressive effects (of antipsychotics, antihistamines, antiHTNs, ethanol, and TCAs), and accelerates metabolism (of β blockers, Ca-channel blockers, corticosteroids, estrogens, phenothiazines, valproic acid, and theophylline; occurs with chronic BARB ingestion)
Acute toxicity: lower therapeutic index; can be fatal if OD; BARB poisoning a major problem (serious toxicity at only 10x hypnotic dose; → respiratory depression, circulatory collapse, renal failure, pulmonary complications which can be life-threatening)
Symptoms: severe respiratory depression, coma, severe hypotension, hypothermia
Treatment: support respiration and BP, gastric lavage (if recent ingestion)
Tolerance: metabolic (induce hepatic metabolic enzymes, occurs within a few days), pharmacodynamic (↓ CNS response with chronic exposure occurs over several weeks; unknown mechanism), and cross tolerance (tolerance to other general CNS depressants)
Physical dependence: develops with continued use; manifest by withdrawal symptoms (mild = anxiety, insomnia, dizziness, nausea; severe = vomiting, hyperthermia, tremors, delirium, convulsions, death)
Other similar agents: meprobamate (Equanil; pharmacological properties like BZs and barbiturates but mechanism unknown) and chloral hydrate (common sedative in pediatric dentistry for diagnostic imaging; few adverse effects but low therapeutic index)
Other drugs for antianxiety: β-adrenoceptor blockers (e.g., propranolol; block autonomic effects- palpitations, sweating, shaking; used for disabling situational anxiety like stage fright), buspirone (partial agonist at serotonin 1A receptor, produces only anxiolytic effects so no CNS depression, dependence, or additive depression with ethanol but onset of action is 1-3 weeks), lodipem (not a BZ but does act at BZ receptors)
Third Generation Cephalosporins
Prototype drugs are CEFOTAXIME (IV) and CEFIXIME (oral). CEFTAZIDIME (for Pseudomonas aeruginosa.).
Further expansion of Gm negative spectrum to include hard to treat organisms such as Enterobacter, Serratia, and Pseudomonas.
In addition to better Gm negative spectrum, this group has improved pharmacokinetic properties (longer half-lives) that allow once daily dosing with some agents. In general, activity toward Gm + bacteria is reduced. These are specialty antibiotics that should be reserved for specific uses.
Enterobacteriaciae that are almost always sensitive (>95% sensitive)
E. coli
Proteus mirabilis (indole –)
Proteus vulgaris (indole +)
Klebsiella pneumoniae
Gram negative bacilli that are generally sensitive (>75% sensitive)
Morganella morganii
Providencia retgerri
Citrobacter freundii
Serratia marcescens
Pseudomonas aeruginosa (Ceftazidime only)
Gram negative bacilli that are sometimes sensitive (<75% sensitive)
Enterobacter
Stenotrophomonas (Xanthomonas) maltophilia (Cefoperazone & Ceftazidime only)
Acinetobacter
--> cefepime & cefpirome are promising for these bacteria
Bacteria that are resistant
Listeria monocytogenes
Pseudomonas cepacia
Enterococcus sp.
Uses
1. Gram negative septicemia & other serious Gm – infections
2. Pseudomonas aeruginosa infections (Ceftazidime - 90% effective)
3. Gram negative meningitis - Cefotaxime, Ceftriaxone, Cefepime. For empiric therapy add vancomycin ± rifampin to cover resistant Strep. pneumoniae
4. Gonorrhea - Single shot of Ceftriaxone is drug of choice. Oral cefixime and ceftibuten are also OK.
5. Complicated urinary tract infections, pyelonephritis
6. Osteomyelitis - Ceftriaxone in home health care situations
7. Lyme disease - ceftriaxone in home health care situations
Mechanism of Action
When a local anesthetic is injected, it is the ionized [cation] form of the local anesthetic that actually binds to anionic channel receptors in the sodium channel, thus blocking the influx of sodium ions which are responsible for lowering the -70mv resting potential towards the firing threshold of -55mv which then results in depolarization of the nerve membrane. However, only the lipid soluble nonionized [base] form of the local anesthetic can penetrate the various barriers [e.g., nerve membrane, fibrous tissue] between the site of injection and the targeted destination which is the sodium channel.
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)
Specific Agents
Hydralazine [orally effective]
MOA: Not completely understood. Seems to be partially dependent on the release of EDRF and perhaps partially due to K+-channel activation
- in clinical doses action is manifest primarily on vascular smooth muscle (non-vascular muscle is not much affected).
- Re: Metabolism & Excretion. In cases of renal failure the plasma half life may be substantially increased (4-5 fold). One mode of metabolism is
via N-Acetylation (problem of slow acetylators)
Side Effects
- those typical of vasodilation = headache, nasal congestion, tachycardia etc.
- chronic treatment with high doses > 200 mg/day may induce a rheumatoid-like state which may resemble lupus erythematosus.
Minoxidil (Loniten) [orally effective]
MOA: K+-channel agonist
- very effective antihypertensive. Used primarily to treat life-threatening hypertension or hypertension resistant to other agents.
Side effects - growth of hair
Diazoxide (Hyperstat) [used only IV]
MOA: K+-channel agonist
- Administered by rapid IV injection; action appearing after 3-5 min; action may last from 4 to 12 hours.
Nitroprusside (Nipride) [used only IV]
MOA: increase in cGMP
- unlike the other vasodilators, venous tone is substantially reduced by nitroprusside.
- rapid onset of action (.30 sec); administered as an IV-infusion.
- particularly useful for hypertension associated with left ventricular failure.
Use of local anesthetics during pregnancy
Local anesthetics (injectable)
Drug FDA category
Articaine C
Bupivacaine C
Lidocaine B
Mepivacaine C
Prilocaine B
Vasoconstrictors
Epinephrine 1:200,000 or 1:100,000 C (higher doses)
Levonordefrin 1:20,000 Not ranked
Local anesthetics (topical)
Benzocaine C
Lidocaine B
Cells of the Nervous System
1-Neurons (Nerve Cells):function units of the nervous system by conducting nerve impulses, highly specialized and amitotic. Each has a cell body (soma), one or more dendrites, and a single axon.
• Cell Body: it has a nucleus with at least one nucleolus and many of the typical cytoplasmic organelles, but lacks centriolesfor cell division.
• Dendrites:Dendrites and axons are cytoplasmic extensions (or processes), that project from the cell body. They are sometimes referred to as fibers. Dendrites (afferent processes) increase their surface area to receive signals from other neurons, and transmit impulses to the neuron cell body.
• Axon: There is only one axon (efferent process) that projects from each cell body.
It carries impulses away from the cell body.
2-Glial cells: do not conduct nerve impulses, but support, nourish, and protect the neurons. They are mitotic, and far more numerous than neurons.
Astrocyte: A glialcell that provides support for neurons of the CNS, provides nutrients regulates the chemical composition of the extracellularfluid.
• Oligodendrocyte: A type of glialcell in the CNS that forms myelin sheaths.
• Microglia:The smallest glialcells; act as phagocytes (cleaning up debris) and protect the brain from invading microorganisms.
• Schwann cell:A cell in the PNS that is wrapped around a myelinatedaxon, providing one segment of its myelin sheath.