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.
Non-barbiturate sedatives
1- Chloral hydrate is trichlorinated derivative of acetaldehyde that is converted to trichlorethanol in the body. It induces sleep in about 30 minutes and last up to 6 hr. it is irritant to GIT and produce unpleasant taste sensation.
2- Ramelteon melatonin receptors are thought to be involved in maintaining circadian rhythms underlying the sleep-wake cycle. Ramelteon is an agonist at MT1 and MT2 melatonin receptors , useful in patients with chronic insomnia with no rebound insomnia and
withdrawal symptoms
3- Ethanol (alcohol) it has antianxiety sedative effects but its toxic potential out ways its benefits.
Ethanol is a CNS depressant producing sedation and hypnosis with increasing dose.
Absorption of alcohol taken orally is rapid, it is highly lipid soluble, presence of food delayed its absorption, maximal blood concentration depend on total dose, sex, strength of the solution, the time over which it is taken, the presence of food and speed of metabolism.
Alcohol in the systemic circulation is oxidized in the liver principally 90% by alcohol dehydrogenase to acetaldehyde and then by acetaldehyde dehydrogenase to products that enter the citric cycle.
Alcohol metabolism by alcohol dehydrogenase follows first order kinetics in the smallest doses. Once the blood concentration exceeds about 10 mg/100 ml, the enzymatic processes are saturated and elimination rate no longer increases with increasing
concentration but become steady at 10-15 ml/ 1 hr. in occasional drinkers.
Thus alcohol is subject to dose dependant kinetics i.e. saturation or zero order kinetics.
Actions
- Ethanol acts on CNS in a manner similar to volatile anesthetic.
- It also enhances GABA so stimulating flux of chloride ions through ion channels.
- Other possible mode of action involve inhibition of Ca-channels and inhibition of excitatory NMDA receptors.
- Ethanol has non selective CNS depressant activity.
- It causes cutaneous vasodilatation, tachycardia and myocardial depression
Doxycycline
Commonly prescribed for infections and to treat acne. treat urinary tract infections, gum disease, and other bacterial infections such as gonorrhea and chlamydia., as a prophylactic treatment for infection by Bacillus anthracis (anthrax). It is also effective against Yersinia pestis and malaria.
Sympatholytics (Antiadrenergic Agents)
PHENOXYBENZAMINE
It is a potent alpha-adrenergic blocking agent
It effectively prevents the responses mediated by alpha receptors and diastolic blood pressure tends to decrease.
It interferes with the reflex adjustment of blood pressure and produces postural hypotension.
It increases the cardiac output and decreases the total peripheral resistance.
It is used in the management of pheochromocytoma and also to treat peripheral vasospastic conditions e.g. Raynaud’s disease and shock syndrome.
Phentolamine, another alpha blocker is exclusively used for the diagnosis of pheochromocytoma and for the prevention of abrupt rise in blood pressure during surgical removal of adrenal medulla tumors.
ERGOT ALKALOIDS
Ergotamine is an important alkaloid that possesses both vasoconstrictor and alpha-receptor blocking activity. Both ergotamine and dihydroergotamine are used in the treatment of migraine.
METHYSERGIDE
It is a 5-hydroxytryptamine antagonist ). It is effective in preventing an attack of migraine.
SUMATRIPTAN
It is a potent selective 5-HT 1D receptor agonist used in the treatment of migraine.
PRAZOSIN
It is an piperazinyl quinazoline effective in the management of hypertension. It is highly selective for α1 receptors. It also reduces the venous return and cardiac output. It is used in essential hypertension, benign prostatic hypertrophy and in Raynaud’s syndrome.
Prazosin lowers blood pressure in human beings by relaxing both veins and resistance vessels but it dilates arterioles more than veins.
TERAZOSIN
It is similar to prazosin but has higher bioavailability and longer plasma t½
DOXAZOSIN
It is another potent and selective α1 adrenoceptor antagonist and quinazoline derivative.
It’s antihypertensive effect is produced by a reduction in smooth muscle tone of peripheral vascular beds.
TAMSULOSIN
It is uroselective α1A blocker and has been found effective in improving BPH symptoms.
Other drugs used for erectile dysfunction
Sildenafil: It is orally active selective inhibitor of phosphodiesterase type 5 useful in treatment of erectile dysfunction.
Propoxyphene
- A methadone analog.Used orally to relieve mild to moderate pain.
- A typical opiate, it does not possess anti-inflammatory or antipyretic actions, but has little or no antitussive activity.
- Cannot be used parenterally because of irritant properties.
- Has a low addiction potential primarily due to its lack of potency as an opiate.
- The most common adverse side effects are:• dizziness, drowsiness, and nausea and vomiting. • these effects are more prominent in ambulatory patients.
- Withdrawal symptoms have occurred in both adults and in neonates following use of the drug by the mother during pregnancy.
- CNS depression is additive with other CNS depressants.
Dental implications of these drugs:
1. Adverse effects: gingival hyperplasia (phenytoin), osteomalacia (phenytoin, Phenobarbital), blood dyscrasias (all but rare)
2. Drug interactions: additive CNS depression (anesthetics, anxiolytics, opioid analgesics), induction of hepatic microsomal enzymes (phenytoin, Phenobarbital, carbamazepine), plasma protein binding (phenytoin and valproic acid)
3. Seizure susceptibility: stress can → seizures
Loop (High Ceiling) Diuretics
Loop diuretics are diuretics that act at the ascending limb of the loop of Henle in the kidney. They are primarily used in medicine to treat hypertension and edema often due to congestive heart failure or renal insufficiency. While thiazide diuretics are more effective in patients with normal kidney function, loop diuretics are more effective in patients with impaired kidney function.
Agent: Furosemide
Mechanism(s) of Action
1. Diuretic effect is produced by inhibit of active 1 Na+, 1 K+, 2 Cl- co-transport (ascending limb - Loop of Henle).
o This produces potent diuresis as this is a relatively important Na re-absorption site.
2. Potassium wasting effect
a. Blood volume reduction leads to increased production of aldosterone
b. Increased distal Na load secondary to diuretic effect
c. a + b = increase Na (to blood) for K (to urine) exchange which produces indirect K wasting (same as thiazides but more likely)
3. Increased calcium clearance/decreased plasma calcium
o secondary to passive decreases in loop Ca++ reabsorption.
o This is linked to inhibition of Cl- reabsorption.
o This is an important clinical effect in patients with ABNORMAL High Ca++