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⁺⁺
 

Anti-Parkinson Drugs
The disease involves degeneration of dopaminergic neurons in the nigral-striatal pathway in the basal ganglia. The cause is usually unknown. Sometimes it is associated with hypoxia, toxic chemicals, or cerebral infections.

Strategy
1. Increase dopamine in basal ganglia.
2. Block muscarinic receptors in the basal ganglia, since cholinergic function opposes the action of dopamine in the basal ganglia.
3. Newer therapies, such as the use of β-adrenergic receptor blockers.

Drugs
a. L-dopa plus carbidopa (Sinemet).
b. Bromocriptine, pergolide, pramipexole, ropinirole.
c. Benztropine, trihexyphenidyl, biperiden, procyclidine.
d. Diphenhydramine.
e. Amantadine.
f. Tolcapone and entacapone.
g. Selegiline.

Mechanisms of action of three drugs affecting DOPA

1. L-dopa plus carbidopa:
L-dopa is able to penetrate the blood–brain barrier and is then converted into dopamine. Carbidopa inhibits dopa decarboxylase, which catalyzes the formation of dopamine.
Carbidopa does not penetrate the blood–brain barrier; it therefore prevents the conversion of L-dopa to dopamine outside the CNS but allows
the conversion of L-dopa to dopamine inside the CNS.

2. Bromocriptine, pergolide, pramipexole, and ropinirole are direct dopamine receptor agonists.
3. Benztropine, trihexyphenidyl, biperiden, and procyclidine are antimuscarinic drugs.
4. Diphenhydramine is an antihistamine that has antimuscarinic action.
5. Amantadine releases dopamine and inhibits neuronal uptake of dopamine.
6. Selegiline is an irreversible inhibitor of monoamine oxidase B (MAO-B), which metabolizes dopamine. Selegiline therefore increases the level of dopamine.
7. Tolcapone is an inhibitor of catechol-O-methyl transferase (COMT), another enzyme that metabolizes dopamine.
8. Entacapone is another COMT inhibitor.

Dopamine and acetylcholine.
 Loss of dopaminergic neurons in Parkinsonism leads to unopposed action by cholinergic neurons. Inhibiting muscarinic receptors can help alleviate symptoms of Parkinsonism

Adverse effects

1. L-dopa 
-  The therapeutic effects of the drug decrease with time.
- Oscillating levels of clinical efficacy of the drug (“on-off” effect).
- Mental changes—psychosis.
- Tachycardia and orthostatic hypotension.
- Nausea.
- Abnormal muscle movements (dyskinesias).

2. Tolcapone, entacapone (similar to L-dopa).

3. Direct dopamine receptor agonists (similar to L-dopa).

4. Antimuscarinic drugs
-  Typical antimuscarinic adverse effects such as dry mouth.

b. Sedation.

5. Diphenhydramine (see antimuscarinic drugs).

6. Amantadine
-  Nausea.
- Dizziness.
- Edema.
- Sweating.

7. Selegiline
- Nausea.
- Dry mouth.
- Dizziness.
- Insomnia.
- Although selegiline is selective for MAO-B, it still can cause excessive toxicity in the presence of tricyclic antidepressants, SSRIs, and meperidine.

Indications

Parkinson’s disease is the obvious major use of the above drugs. Parkinson-like symptoms can occur with many antipsychotic drugs. These symptoms are often treated with antimuscarinic drugs or diphenhydramine.

Dental implications of anti-Parkinson drugs
1. Dyskinesia caused by drugs can present a challenge for dental treatment.
2. Orthostatic hypotension poses a risk when changing from a reclining to a standing position.
3. The dentist should schedule appointments at a time of day at which the best control of the disease occurs.
4. Dry mouth occurs with several of the drugs.
 

ANTICHOLINERGIC DRUGS
Blocks the action of Ach on autonomic effectors.

Classification
Natural Alkaloids - Atropine. Hyoscine

Semi-synthetic deriuvatives:- Homatropine, Homatropine methylbromide, Atropine methonitrate.

Synthetic compounds 

(a) Mydriatics - Cyclopentolate. Tropicamide.
(b) Antisecretory - Antispasmodics - Propantha1ine. Oxy-phenonium, Pirenzipine.
c) Antiparkinsonism- Benzotopine, Ethopropazine, Trihexyphenidyl, Procyclidine, Biperiden 
Other drugs with anticholinergic properties • Tricyclic Antidepressants • Phenothiazines • Antihistaminics • Disopyramide

MUSCARINIC RECEPTORS SUBTYPES & ANTAGONISTS 
• M 1 Antagonists – Pirenzepine, Telenzepine, dicyclomine, trihexyphenidyl 
• M 2 Antagonists – Gallamine, methoctramine 
• M 3 Antagonists – Darifenacin, solifenacin, oxybutynin, tolterodine

Pharmacological Actions
CNS - stimulation of medullary centres like vagal. respiratory. vasomotor and inhibition of vestibular excitation and has anti-motion sickness properties.
CVS - tachycardia.
Eye - mydriasis
Smooth muscles - relaxation of the muscles receiving parnsympathetic motor innervation.
Glands - decreased secretion of sweat and salivary glands
Body Temperature - is increased as there is stimulation of  temperature regulating centre.
Respiratory System- Bronchodilatation & decrease in secretions. For COPD or Asthma - antimuscarinic drugs are effective
GIT - Pirenzepine & Telenzepine - decrease gastric secretion with lesser side effects.

Fentanyl (Sublimaze)

• Related chemically to meperidine.
• Approximately 80 times more potent than morphine.
• Duration of action very short (t1/2 20 min).
• Used mainly following general anesthesia.
• Neurolept analgesia: Fentanyl & Droperidol (Innovar)
• fentanyl in analgesic (2-10 µg/kg), or anaesthetic (30-100 µg/kg) doses seldom causes significant decreases in blood pressure when given alone, even in patients with poor LV function
• hypotension following fentanyl is mostly due to bradycardia and can be prevented by the use of anticholinergics, sympathomimetics or agents such as pancuronium this is more likely to occur in patients with high pre-existing sympathetic tone
• hypertension is the commonest disturbance with high dose fentanyl anaesthesia, usually accompanying intubation, sternotomy, or aortic root dissection

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)

Second Generation Cephalosporins

Prototype drug is CEFUROXIME (IV) and CEFUROXIME AXETIL (oral). CEFOXITIN has good activity vs. anaerobes.

1. Expanded activity against gram negative bacilli. Still have excellent activity against gram positive (Staph. and Strep.) bacteria.

Activity for Gram negative bacteria

Neisseria sp. (some gonococci resistant)
H. influenzae (including some ampicillin-resistant strains)
Moraxella catarrhalis (some resistance esp. to cefaclor)
E. coli
Proteus mirabilis
Indole + Proteus (some strains resistant)
Morganella morganii (some strains resistant)
Klebsiella pneumoniae
Serratia sp. (many strains resistant)

2. Anaerobic infections - CEFOXITIN & CEFOTETAN only

Moderate activity against Bacteroides fragilis group.

Good activity for other Bacteroides sp., Peptostreptococcus, Fusobacterium, Clostridium sp

Uses
1. Community-acquired pneumonia - Cefuroxime is widely used for empiric therapy. Has activity vs. many ampicillin-resistant H. influenzae strains.
2. Skin and soft tissue infection
3. Urinary tract infections
4. Upper respiratory tract infections (otitis media, sinusitis). Some resistance to H.influenzae to cefaclor (20-30%).
5. Mixed aerobic & anaerobic infections - Cefoxitin & Cefotetan. Resistance to B.fragilis is increasing.
6. Surgical prophylaxis - Cefoxitin or cefotetan are widely used in cases where mixed aerobic & anaerobic infections may occur, esp. intra-abdominal, colorectal, and gynecologic operations. For cardiovascular and orthopedic procedures, cefuroxime and others may be used, but cefazolin is cheaper and appears to work well.