NEET MDS Lessons
Pharmacology
Pharmacodynamic Effects of NSAIDs
A. Positive
analgesic - refers to the relief of pain by a mechanism other than the reduction of inflammation (for example, headache);
- produce a mild degree of analgesia which is much less than the analgesia produced by opioid analgesics such as morphine
anti-inflammatory - these drugs are used to treat inflammatory diseases and injuries, and with larger doses - rheumatoid disorders
antipyretic - reduce fever; lower elevated body temperature by their action on the hypothalamus; normal body temperature is not reduced
Anti-platelet - inhibit platelet aggregation, prolong bleeding time; have anticoagulant effects
B. Negative
Gastric irritant
Decreased renal perfusion
Bleeding
(CNS effects)
Adverse effects
The two main adverse drug reactions (ADRs) associated with NSAIDs relate to gastrointestinal (GI) effects and renal effects of the agents.
Gastrointestinal ADRs
The main ADRs associated with use of NSAIDs relate to direct and indirect irritation of the gastrointestinal tract (GIT). NSAIDs cause a dual insult on the GIT - the acidic molecules directly irritate the gastric mucosa; and inhibition of COX-1 reduces the levels of protective prostaglandins.
Common gastrointestinal ADRs include:
Nausea, dyspepsia, ulceration/bleeding, diarrhoea
Risk of ulceration increases with duration of therapy, and with higher doses. In attempting to minimise GI ADRs, it is prudent to use the lowest effective dose for the shortest period of time..
Ketoprofen and piroxicam appear to have the highest prevalence of gastric ADRs, while ibuprofen (lower doses) and diclofenac appear to have lower rates.
Commonly, gastrointestinal adverse effects can be reduced through suppressing acid production, by concomitant use of a proton pump inhibitor, e.g. omeprazole
Renal ADRs
NSAIDs are also associated with a relatively high incidence of renal ADRs. The mechanism of these renal ADRs is probably due to changes in renal haemodynamics (bloodflow), ordinarily mediated by prostaglandins, which are affected by NSAIDs.
Common ADRs associated with altered renal function include:
salt and fluid retention,hypertension
These agents may also cause renal impairment, especially in combination with other nephrotoxic agents. Renal failure is especially a risk if the patient is also concomitantly taking an ACE inhibitor and a diuretic - the so-called "triple whammy" effect.
In rarer instances NSAIDs may also cause more severe renal conditions.
interstitial nephritis, nephrotic syndrome, acute renal failure
Photosensitivity
Photosensitivity is a commonly overlooked adverse effect of many of the NSAIDs. These antiinflammatory agents may themselves produce inflammation in combination with exposure to sunlight. The 2-arylpropionic acids have proven to be the most likely to produce photosensitivity reactions, but other NSAIDs have also been implicated including piroxicam, diclofenac and benzydamine.
ibuprofen having weak absorption, it has been reported to be a weak photosensitising agent.
Other ADRs
Common ADRs, other than listed above, include: raised liver enzymes, headache, dizziness.
Uncommon ADRs include: heart failure, hyperkalaemia, confusion, bronchospasm, rash.
The COX-2 paradigm
It was thought that selective inhibition of COX-2 would result in anti-inflammatory action without disrupting gastroprotective prostaglandins.
The relatively selective COX-2 oxicam, meloxicam, was the first step towards developing a true COX-2 selective inhibitor. Coxibs, the newest class of NSAIDs, can be considered as true COX-2 selective inhibitors and include celecoxib, rofecoxib, valdecoxib, parecoxib and etoricoxib.
Anticonvulsant Drugs
A. Anticonvulsants: drugs to control seizures or convulsions in susceptible people
B. Seizures: abnormal neuronal discharges in the nervous system produced by focal or generalized brain disturbances
Manifestations: depend on location of seizure activity (motor cortex → motor convulsions, sensory cortex → abnormal sensations, temporal cortex → emotional disturbances)
Causes: many brain disorders such as head injury (glial scars, pH changes), anoxia (changes in pH or CSF pressure), infections (tissue damage, high T), drug withdrawal (barbiturates, ethanol, etc.), epilepsy (chronic state with repeated seizures)
C. Epilepsy: most common chronic seizure disorder, characterized by recurrent seizures of a particular pattern, many types (depending on location of dysfunction)
Characteristics: chronic CNS disorders (years to decades), involve sudden and transitory seizures (abnormal motor, autonomic, sensory, emotional, or cognitive function and abnormal EEG activity)
Etiology: hyperexcitable neurons; often originate at a site of damage (epileptogenic focus), often found at scar tissue from tumors, strokes, or trauma; abnormal discharge spreads to normal brain regions = seizure
Idiopathic (70%; may have genetic abnormalities) and symptomatic epilepsy (30%; obvious CNS trauma, neoplasm, infection, developmental abnormalities or drugs)
Neuropathophysiology: anticonvulsants act at each stage but most drugs not effective for all types of epilepsy (need specific drugs for specific types)
Seizure mechanism: enhanced excitation (glutamate) or ↓ inhibition (GABA) of epileptic focus → fire more quickly → ↑ release of K and glutamate → ↑ depolarization of surrounding neurons (=neuronal synchronization) → propagation (normal neurons activated)
Warfarin (Coumadin):
- The most common oral anticoagulant.
- It is only active in vivo.
- Warfarin is almost completely bound to plasma proteins. -96% to 98% bound.
- Warfarin is metabolized by the liver and excreted in the urine.
- Coumarin anticoagulants pass the placental barrier and are secreted into the maternal milk.
- Newborn infants are more sensitive to oral anticoagulants than are adults because of lower vitamin K levels and lower rates of metabolism.
- Bleeding is the most common side effect and occurs most often from the mucous membranes of the gastrointestinal tract and the genitourinary tract.
Oral anticoagulants are contraindicated in:
• Conditions where active bleeding must be avoided, Vitamin K deficiency and severe
hepatic or renal disease, and where intensive salicylate therapy is required.
Miconazole
Miconazole is an imidazole antifungal agent commonly used in topical sprays, creams and ointments applied to the skin to cure fungal infections such as Athlete's foot and Jock itch. It may also be used internally to treat vaginal yeast infection.
When used by a person taking the anticoagulant medication warfarin, Miconazole may cause an adverse reaction which can lead to excessive bleeding or bruising.
Antiemetics
Antiemetic drugs are generally more effective in prophylaxis than treatment. Most antiemetic agents relieve nausea and vomiting by acting on the vomiting centre, dopamine receptors, chemoreceptors trigger zone (CTZ), cerebral cortex, vestibular apparatus, or a combination of these.
Drugs used in the treatment of nausea and vomiting belong to several different groups. These include:
1. Phenothiazines, such as chlorpromazine, act on CTZ and vomiting centre, block dopamine receptors, are effective in preventing or treating nausea and vomiting induced by drugs, radiation therapy, surgery and most other stimuli (e.g. pregnancy).
They are generally ineffective in motion sickness.
Droperidol had been used most often for sedation in endoscopy and surgery, usually in combination with opioids or benzodiazepines
2. Antihistamines such as promethazine and Dimenhyrinate are especially effective in prevention and treatment of motion.
3. Metoclopramide has both central and peripheral antiemetic effects. Centrally, it antagonizes the action of dopamine. Peripherally metoclopramide stimulates the release of acetylcholine, which in turn, increases the rate of gastric. It has similar indications to those of chlorpromazine.
4. Scopolamine, an anticholinergic drug, is very effective in reliving nausea & vomiting associated with motion sickness.
5. Ondansetron, a serotonin antagonist, is effective in controlling chemical-induced vomiting and nausea such those induced by anticancer drugs.
6. Benzodiazepines: The antiemetic potency of lorazepam and alprazolam is low. Their beneficial effects may be due to their sedative, anxiolytic, and amnesic properties
Adverse effects
Nitrates
– Headache, hypotension, dizziness, lightheadedness, tachycardia, palpitations
Beta-adrenergic blocking agents
– hypotension, bradycardia, bronchospasm, congestive heart failure
Calcium channel blockers
– hypotension, dizziness, lightheadedness, weakness, peripheral edema, headache, congestive heart failure, pulmonary edema, nausea, and constipation
Drugs that increase effects of Antianginal drugs
• Antihypertensive
• Diuretics
• Phenothiazine antipsychotic agents
• Cimetidine
• Digoxin
Drugs that decrease effects of Antianginal
• Adrenergic drugs - epinephrine
• Anticholinergic
• Calcium salts
• Phenobarbital, Phenytoin
Adjunctive Antianginal Drugs
In addition to antianginal drugs, several other drugs may be used to control risk factors and prevent progression of myocardial ischemia to myocardial infarction and sudden cardiac death.
These may include:
• Aspirin. This drug has become the standard of care because of its antiplatelet (ie, antithrombotic) effects. Recommended doses vary from 81 mg daily to 325 mg daily or every other day; apparently all doses are beneficial in reducing the possibility of myocardial reinfarction, stroke, and death. Clopidogrel 75 mg/day,
Is an acceptable alternative for individuals with aspirin allergy.
• Antilipemics. These drugs may be needed by clients who are unable to lower serum cholesterol levels sufficiently with a low-fat diet. Lovastatin or a related “statin” is often used. The goal is usually to reduce the serum cholesterol level below 200 mg/dL and lowdensitylipoprotein cholesterol to below
130 mg/dL.
• Antihypertensives. These drugs may be needed for clients with hypertension. Because beta blockers and calcium channel blockers are used to manage hypertension as well as angina, one of these drugs may be effective for both disorders.
Excretion
Routes of drug excretion
The most important route of drug elimination from the body is via the kidney
Renal Drug Excretion
- Glomerular Filtration
- Passive Tubular Reabsorption: drugs that are lipid soluble undergo passive reabsorption from the tubule back into the blood.
- Active Tubular Secretion
Factors that Modify Renal Drug Excretion
- pH Dependent Ionization: manipulating urinary pH to promote the ionization of a drug can decrease passive reabsorption and hasten excretion.
- Competition for Active Tubular Transport
- Age: Infants have a limited capscity to excrete drugs.
Nonrenal Routes of Drug Excretion
Breast Milk
Bile, Lungs, Sweat and Saliva
The kidney is the major organ of excretion. The lungs become very important for volatile substances or volatile metabolites.
Drugs which are eliminated by the kidney are eliminated by:
a) Filtration - no drug is reabsorbed or secreted.
b) Filtration and some of the drug is reabsorbed.
c) Filtration and some secretion.
d) Secretion
By use of the technique of clearance studies, one can determine the process by which the kidney handles the drug.
Renal plasma clearance = U x V ml/min U / Cp = conc. of drug in urine
Cp = conc. of drug in plasma
V = urine flow in ml/min
Renal clearance ratio = renal plasma clearance of drug (ml/min) / GFR (ml/min)
Total Body Clearance = renal + non-renal