Classification

I) Esters

 1. Formed from an aromatic acid and an amino alcohol.

 2. Examples of ester type local anesthetics:

 Procaine

Chloroprocaine

Tetracaine

Cocaine

Benzocaine- topical applications only

2) Amides

 1. Formed from an aromatic amine and an amino acid.

 2. Examples of amide type local anesthetics:

Articaine

Mepivacaine

Bupivacaine

Prilocaine

Etidocaine

Ropivacaine

Lidocaine

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)

Sulfonylureas

1st generation
tolbutamide
chlorpropamide

2nd generation

glyburide
glimepiride
glipizide

Mechanism

glucose normally triggers insulin release from pancreatic β cells by increasing intracellular ATP
→ closes K+ channels → depolarization → ↑ Ca2+ influx → insulin release

sulfonylureas mimic action of glucose by closing K+ channels in pancreatic β cells 
→ depolarization → ↑ Ca2+ influx → insulin release

its use results in

↓ glucagon release
↑ insulin sensitivity in muscle and liver

Clinical use

type II DM

stimulates release of endogenous insulin 
cannot be used in type I DM due to complete lack of islet function

Toxicity

first generation

disulfiram-like effects
especially chlorpropamide

second generation

hypoglycemia
weight gain

Heparin:

• Inhibits blood coagulation by forming complexes with an α2-globulin (Antithrombin III) and each of the activated proteases of the coagulation cascade (Kallikrein, XIIa, XIa, IXa, Xa, and Thrombin). After formation of the heparin-ATIII-coagulation factor, heparin is released and becomes available again to bind to free ATIII.
• Blocks conversion of Prothrombin to Thrombin and thus inhibits the synthesis of Fibrin from Fibrinogen.
• Inhibits platelet function and increases vascular permeability. May induce moderate to severe thrombocytopenia.
• Is prescribed on a “unit” basis.
• Heparin is not effective after oral administration and is generally administered by intravenous or subcutaneous injection. Intramuscular injections should be avoided.
• Heparin does not cross the placenta and does not pass into the maternal milk.
• is contraindicated in any situation where active bleeding must be avoided.

Ulcerative lesions, intracranial hemorrhage, etc.

Overdosage:

• Simple withdrawal.

• Protamine sulfate: Highly basic peptide that binds heparin and thus neutralizes its effects.

Uses of NSAIDs

NSAIDs are usually indicated for the treatment of acute or chronic conditions where pain and inflammation are present. Research continues into their potential for prevention of colorectal cancer, and treatment of other conditions, such as cancer and cardiovascular disease.

NSAIDs are generally indicated for the symptomatic relief of the following conditions.

rheumatoid arthritis, osteoarthritis, inflammatory arthropathies (e.g. ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome), acute gout, dysmenorrhoea, metastatic bone pain ,headache and migraine, postoperative pain, mild-to-moderate pain due to inflammation and tissue injury, pyrexia, renal colic

Aspirin, the only NSAID able to irreversibly inhibit COX-1, is also indicated for inhibition of platelet aggregation; an indication useful in the management of arterial thrombosis and prevention of adverse cardiovascular events.

DIAGNOSIS

Affective disorders:
I. unipolar depression – depression alone
bipolar affective disorder – alternating II. bipolar affective disorder – alternating depression and mania

Diagnosis is based on 

At least five of the following for 2 weeks
I. Depressed mood most of the day
II. Markedly diminished interest or pleasureII. Markedly diminished interest or pleasure
III. Significant weight loss or weight
IV. Insomnia or hypersomnia
V. Psychomotor agitation or retardation
VI. Fatigue or loss of energy
VII. Feelings of worthlessness or excessive guilt
VIII. Diminished ability to think or concentrate, 
IX. Recurrent thoughts of death

Underlying biological basis for depression is a deficiency of the monoamine neurotransmitters  norepinephrine and/or serotonin in the brain.