Examples of calculations of doses of vasoconstrictors

Ratio concentrations represent grams per millilitre

1:100,000 = 0.01 mg/mL or 10 µg/mL

1:200,000 = 0.005 mg/mL or 5 µg/mL

1:50,000 = 0.02 mg/mL or 20 µg/mL

1 cartridge of epinephrine 1:200,000 = 9 µg

1 cartridge of epinephrine 1:100,000 = 18 µg

1 cartridge of epinephrine 1:50,000 = 36 µg

1 cartridge of levonordefrin 1:20,000 = 90 µg

Benzodiazepines (BZ): 

newer; depress CNS, selective anxiolytic effect (no sedative effect); are not general anesthetics (but does produce sedation, stupor) or analgesics 

BZ effects: 

1.  Central: BZs bind GABA_A receptors in limbic system (amygdala, septum, hippocampus; involved in emotions) and enhance inhibition of neurons in limbic system (this may produce anxiolytic effects of BZs)

a. GABA receptor: pentameric (α, β, δ, γ subunits)
i.  Binding sites: GABA (↑ conductance (G) of Cl-, hyperpolarization, inhibition), barbiturate (↑ GABA effect), benzodiazepine (↑ GABA effect), picrotoxin (block Cl channel)

b. GABA agonists: GABA (binds GABA → Cl influx; have ↑ frequency of Cl channel opening; BZs alone- without GABA don’t affect Cl channel function)

c.  Antagonists: bicuculline (competitively blocks GABA binding; ↓ inhibition,→ convulsions; no clinical use), picrotoxin (non-competitively blocks GABA actions,  Cl channel → ↓ inhibition → convulsions)

2.  Other agents at BZ receptor: 

a.    Agonists: zolpidem (acts at BZ receptor to produce pharmacological actions)

b.    Inverse agonists: β-carbolines (produce opposite effects at BZ binding site-- ↓ Cl conductance; no therapeutic uses since → anxiety, irritability, agitation, delirium, convulsions)

3. Antagonists: flumazenil (block agonists and inverse agonists, have no biological effects themselves; can precipitate withdrawal in dependent people)

Metabolism: many BZs have very long action (since metabolism is slow); drugs have active metabolites

2 major reactions: demethylation and hydroxylation (both very slow reactions)

Fast reaction: glucuronidation and urinary excretion

Plasma half life: long (for treating anxiety, withdrawal, muscle relaxants), intermediate (insomnia, anxiety), short (insomnia), ultra-short (<2hrs; pre-anesthetic medication)

Acute toxicity: very high therapeutic index and OD usually not life threatening (rarely see coma or death)

Treatment: support respiration, BP, gastric lavage, give antagonist (e.g., glumazenil; quickly reverses BD-induced respiratory depression)

Tolerance: types include pharmacodynamic (down-regulation of CNS response due to presence of drug; this is probably the mechanism by which tolerance develops), cross-tolerance (with other BZ and CNS depressants like EtOH and BARBS), acquisition of tolerance (tolerance develops fastest in anticonvulsant > sedation >> muscle relaxant > antianxiety; means people can take BZs for long time for antianxiety without → tolerance)

Physical dependence: low abuse potential (no buz) but physical/psychological dependence may occur; physical dependence present when withdrawal symptoms occur (mild = anxiety, insomnia, irritability, bad dreams, tremors, anorexia; severe = agitation, depression, panic, paranoia, muscle twitches, convulsions)

Drug interactions: minimally induce liver enzymes so few interactions; see additive CNS depressant effects (can be severe and → coma and death if BZs taken with other CNS depressants like ethanol)

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)

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

Thiopental 

- A barbiturate that is generally used to induce anesthesia.
- The temporal course of effects from induction to recovery depends almost entirely upon progressive redistribution.
- Metabolic degradation or excretion during anesthesia is negligible, except in the case of methohexital.
- The barbiturates produce minimal analgesia.
- Respiratory depression may be pronounced.
- Cardiac output is reduced while total peripheral resistance is increased.
- It does not sensitize the heart to catecholamines.
- It may cause bronchiospasm, especially in asthmatics.
- It is contraindicated in acute intermittent porphyria.

Clarithromycin Used to treat  pharyngitis, tonsillitis, acute maxillary

sinusitis, acute bacterial exacerbation of chronic  bronchitis,  pneumonia (especially atypical pneumonias associated with Chlamydia pneumoniae or TWAR), skin and skin structure infections, and, in HIV and AIDS patients to prevent, and to treat, disseminated Mycobacterium avium complex or MAC.

Unlike erythromycin, clarithromycin is acid-stable and can therefore be taken orally without being protected from gastric acids. It is readily absorbed, and diffused into most tissues and phagocytes.

Clarithromycin has a fairly rapid first-pass hepatic metabolism, i.e it is metabolised by the liver. However, this metabolite, 14-hydroxy clarithromycin is almost twice as active as clarithromycin.

Contraindications Clarithromycin should be used with caution if the patient has liver or kidney disease, certain heart problems (e.g., QTc prolongation or bradycardia), or a mineral imbalance (e.g., low potassium or magnesium levels).