Sympatholytics And Alpha Adrenergic Blockers 

Types 
1.    Alpha 1-receptor blockers: prazocin,doxazocin. 
2.    Centrally acting alpha 2- agonists: methyldopa, clonidine. 
3.    Peripherally acting adrenergic antagonists: reserpine. 
4.    Imidazoline receptor agonists: rilmenidine, moxonidine. 
 
Advantages 

- Alpha1- receptor blockers and imidazoline receptor agonists improve lipid profile and insulin sensitivity. 
- Methyldopa: increases renal blood flow. Drug of choice during pregnancy. 
- Reserpine: neutral metabolic effects and cheap. 

Indications: 

- Diabetes mellitus: alpha1- receptor blockers, imidazoline receptor agonists. 
- Dyslipidemia: alpha 1- receptor blockers, imidazoline receptor agonists. 
- Prostatic hypertrophy: alpha 1- receptor blockers. 
- When there is a need for rapid reduction in blood pressure: clonidine. 

Side Effects 

- Prazocin: postural hypotension, diarrhea, occasional tachycardia, and tolerance (due to fluid retention). 
- Methyldopa: sedation, hepatotoxicity, hemolytic anemia, and tolerance. 
- Reserpine: depression, lethargy, weight loss, peptic ulcer, diarrhea, and impotence
- Clonidine: dry mouth, sedation, bradycardia, impotence, and rebound hypertension if stopped suddenly. 

Considerations 
- Prazocin, methyldopa, and reserpine should be combined with a diuretic because of fluid retention. 

Direct Arterial Vasodilators 

Types: hydralazine, diazoxide, nitroprusside, and minoxidil

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)

Distal (Potassium Sparing) Diuretics

Agents:

spironolactone
triamterene

Mechanism of action

Inhibition of Na/K exchange at aldosterone dependent distal tubular site

Spironolactone - competes with aldosterone for regulatory site

Triamterene - decreases activity of pump directly
•    Either mechanism decreases potassium wasting
•    Either mechanism produces poor diuresis (when used alone)
o    relatively unimportant Na recovery site

Diurectic activity increased if:

•    sodium load (body) is high 
•    aldosterone concentrations are high 
•    sodium load (tubule) is high - secondary to diuresis

Other electrolytes unaffected

Toxicity

•    spironolactone may produce adrenal and sex hormone effects with LONG-TERM use
•    Both drugs may produce electrolyte imbalance
 

Example calculations of maximum local anesthetic doses for a 15-kg child

Articaine

5 mg/kg maximum dose × 15 kg = 75 mg

4% articaine = 40 mg/mL

75 mg/(40 mg/mL) = 1.88 mL

1 cartridge = 1.8 mL

Therefore, 1 cartridge is the maximum

Lidocaine

7 mg/kg × 15 kg = 105 mg

2% lidocaine = 20 mg/mL

105 mg/(20 mg/mL) = 5.25 mL

1 cartridge = 1.8 mL

Therefore, 2.9 cartridges is the maximum

Mepivacaine

6.6 mg/kg × 15 kg = 99 mg

3% mepivacaine = 30 mg/mL

99 mg/(30 mg/mL) = 3.3 mL

1 cartridge = 1.8 mL

Therefore, 1.8 cartridges is the maximum.

Prilocaine

8 mg/kg × 15 kg = 120 mg

4% prilocaine = 40 mg/mL

120 mg/(40 mg/mL) = 3 mL

1 cartridge = 1.8 mL

Therefore, 1.67 cartridges is the maximum

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.

Dissociation constants