-Modifies sodium channel function by blocking the

 Na channel

-Enhancing membrane excitability

-No interaction with pain receptors

Lipophilic portion (aromatic) lined to an ester or amide intermediate chain linked to a hydrophilic portion (except in benzocaine)

Usually weak bases pKa 7-9

Electron donating=increase potency

Electron withdrawing=decrease potency

Branching=hinders metabolism=may increase toxicity

-LAs are amphoteric

-They block the action potential generated by blocking the sodium channels

-LAs work by being charged (ionized) but have to cross the membrance unionized to have an effect.

1. Small myelinated axons

2. Non-myelinated axons

3. Large myelinated axons

Thus, nociceptive and sympathetic transmission is blocked first.

CNS side effects: agitation,confusion, tremors, convulsions, respiratory depression (death)

Cardiovascular side effects: myocardial depression, vasodilation (decreased bp)

1. Epidural anethesia: injected into epidural space/ spinal anesthesia and childbirth/ lidocaine and sometimes bupivacaine

2. Spinal anesthesia: injected into subarachnoid space/ surgery to abdomen, pelvis, leg; used when gen. anesthesia can not be used/ mainly lidocaine

3. Nerve block anesthesia:injected close to nerve trunks to produce loss of sensation PERIPHERALLY/ dentistry/ most drugs come in this form

4. Surface anesthesia: used in nose, mouth, bronchial tree, cornea, and urinary tract/ lidocaine, tetracaine, amethocaine, benzocaine

5. Infiltration anesthesia: direct into tissues and nerve branches/ minor surgery/ most drugs

6. IV regional anesthesia: injected IV distal to a pressure cuff/ limb surgery/ lidocaine and prilocaine

Monoethylglyinexylidide

(has CNS toxicities)

This metablote is created from N-dealkylation

1. Reversible blockade of sensory nerve fibers with MINIMAl effect on motor fibers.
2. Rapid Onset
3. Sufficient duration of action for procedure
4. Minimal irritation when topical or injection
5. No systemic toxicity.

-Act from OUTSIDE the membrane.

-Independent of wheteher channel is open or closed.

From puffer fish: causes severe weakness to complete paralysis or death.

Not used clinically bc too expensice and poor tissue penetration bc low lipid solubility.

-Act from OUTSIDE the membrane.

-Independent of wheteher channel is open or closed.

From marine microorganism: gives "red tide" phenomenon. Typically with shellfish.

Not used clinically bc too expensice and poor tissue penetration bc low lipid solubility.

1. Benzodiazepines (most preferred)
2. Barbituates (largely obsolete)
3. Non-Benzodiazepine GABAA agonists

-Most preferred

-Used for: reduction of anxiety and aggression, sedation (induction of sleep), reduction of muscle tone and coordination, and anti-convulsant therapy (epilepsy)

-They are well-absorbed orally.

-Fewer side effects

-Very lipophilic=rapid absorption

-No active metabolites

-Can be administered without regard to meals

1. Reduce caffine intake
2. Avoid alcohol
3. Get adequate exercist
4. Have regular sleep and waking times

-Lasts less than 3 days

-Caused by brief stressor

-May respond to sleep hygiene

-Drugs: Lowest dose for 2-3 nights

-3 days to 3 weeks

-Caused by personal stressor

-Sleep hygiene education is 1st step

Drugs: adjunctively for 7-10 nights

-Lasts more than 3 weeks

-No stressor indicated

-Medical evaluation reqd.

Drugs: Hypnotics prescribed

1. Rapid onset when taken at bedtime
2. Sufficiently sustained action for sleep throughout entire night
3. No residual action the following morning
4. No potential for decresed respiration
5. No dependence with chronic use.

-Act selectively on GABAA receptors.

-They enhance the response to GABA by facilitatitng opening of GABA activated chloride channels.

-When they bind they bind specifically to a site on the receptor, distinct from the GABA site, and act allosterically to increase affinity of GABA for receptor.

-GABA-enhancing effect of Benzos reach a max at low concentrations which is why drug really only exerts effects for a couple of weeks.

Benzodiazepine ANTAGONIST

-Mainly used to reverse the sedative action of benzos during anesthesia and also in acute benzo overdose.

-Acts quickly and effectively when giver by injection.

-Convulsions may rarely occur.

N-desmethyldiazepam

(Nordiazepam)

-Has a half-life of 60 hours.

What is the most common route of administration of benzos?

-Well absorbed orally

-High lipid solubility

1. Long acting (Medazepam, Chlordiazepoxide, Chlorazepate,Diazepam : All go through nordiazepam)

2. Short acting (Lorazepam)

3. Mid acting (Triazolam, alprazolam, midazolam, clonazepam, and temazepam and oxzepam)

Drowsiness, confusion, amnesia...more pronounced with CNS depressants.

Considered relatively safe overall.

Tolerance and dependence are the main drawbacks.

Short acting benzos have MORE abrupt withdrawal effects.

Long acting benzos have slower and less intense onset of withdrawal.

"Z" drugs

Zolpidem (Ambien) and Zaleplon (Sonata)

Have affinity for GABAa receptor complex.

More efficacious with fewer side effects.

Very lipophilic and have rapid absorption.

No active metabolites.

Approved for 7-10 days at a time.

Ranging from sedation and reduction of anxiety to unconciousness and even death from respiratory/cardiac failure.

Drug interactions bc induce hepatic drug-metabolizing enzymes (CYPs)

1) Alcohol dehydorgenase pathway (ADH)

-Primary pathway NAD+ to NADH

2) Microsomal EtOH Oxidizing system (MEOS)

-NADPH to NASP

-Only induced with chronic alcohol consumption.

Both give same metabolite: acetalaldehyde

-Drug used to treat alcoholism

-Long-acting opiod antaganist blocks effects of alcohol at opiod receptors.

-Reduces craving for alcohol, reduced relapse rate

-Patient must be opiod free before treatment

Drug used to treat alcoholism

-Actions on GABA, glutamte, serotonin, noradrenergic, and dopaminergic receptors.

-No drug-drug interactions

-ADRs: GI related

Drug used to treat alcoholism

-Inhibitor of ALDH pathway-accumulation of acetaldehyde.

-Causes extreme discomfort in patients that drink.

-Drug inhibits metabolism of many other drugs.

-Very low adherence with this medication.

Most common affective disorder

-Can be very mild to severe

-Emotional symptoms include misery,apathy,pessimism,low self-esteem,loss of motivation

-Biological symptoms include: retarddation of thought, loss of libido, decrease in energy, sleep issues, loss of appetite.

Excessive exuberance,enthusiasm, and self-confidence with very impulsive actions.

Combined with irritability, impatience, aggression, and sometimes delusions.

Two types:

1) Endogenous depression: 25%; show familial pattern; unrelated to external stressors.

2)Reactive depression: 75%; Non-familial; caused by triggers. May also have symptoms of anxiety and agitation.

-Depression alternates with mania.

-Usually appears in early adult life.

-Less common than other forms of depression but has a STRONG hereditary tendency.

Most widely accepted depression theory.

Proposed by Schildkraut in 1965.

States: Depression is caused by a functional deficit in monoamine transmitters at certain sites in the brain. ex)serotonin, dopamine, etc.

Mania is caused by excess.

Controversy with this theory bc many anomilies amongst the evidence.

Tricyclic Antidepressants

Block NE and 5-HT reuptake

Increase mood

Increase stores of NE and 5-HT

Increase mood

Inhibits NE and 5HT storage

Decreases mood

Inhibits NE synthesis

Decreased mood (calming of manic patients)

Inhibits NE synthesis

Decreases mood

Increases CNS responses to NE and 5HT

Increases mood

Increases 5HT synthesis

Elevated mood in some studies

Mice determine there is no escape and eventually stop struggling.

Anti-depressants INCREASE struggling (not giving up) and sedatives DECREASE

"Persolt test of swimming despair"

Animal confined to inescapable test chamber

Anti-depressants increase time of animal not giving up.

Selective inhibitors of serotonin reuptake

fluoxetine

paroxetine

sertraline

fluvxamine

citalopram

phenelzine

tranyclpromine

isocarboxazid

Act like TCAs but have a different structure: maprotiline

Compounds with different pharmacological actions. These drugs do not affect amine reuptake: venlaflaxine, trazodone, buproprion

Atypical vs. TCA    Atypicals have fewer side effects and produce action with less delay.

Tricyclic ring (3 rings fused together)

Center ring is always 7 membered

Tertiary amine: rapidly N-dealkylated to 2nd amine

Secondary amines are active compounds themselves and are administered as drugs.

Same pharmacophore just differnt R1s and R2s

Amitriptyline

nortriptyline

imipramide

desipramide

clomipramide

Inhibits 5HT reuptake.

Less likely than TCAs to cause side effects.

Less dangerous in overdose than TCAs.

Less effective than TCAs in severe depression.

Can cause serotonin syndrom=tremor,hyperthermia, and cardio collapse which can result in death. This is from too much serotonin in the synapse.

-Among 1st used as antidepressant NOW third choice as one.

-Side effects: hypotension, weight gain, severe hepatotoxicity (rare)

-"Cheese reaction": Tyramine is normally metabolized by MAO, when given an MAOI the tyramine builds up and enhances its sympathomimetic effects. Results in hypertension, a severe headache, and can create an intracranial hemorrhage.

anxiolytics used by 10% population

-expressed complaint: feeling of anxiety as a symptom

-somatic effetcs: restlessness, agitation, tachycardia, sweating, weeping, GI disorders, and sleep disturbance.

-treatment for severe depression

-at least as effective as antidepressant drugs

-response rates range from 60-80%

-most effective treatment for suicidal depression

-main disadvantage: causes confusion and memory loss that lasts for days to weeks

-Controls the manic phase of bipolar and is effective in treating unipolar as well.

-Given in an acute attack it is only effective in reducing mania.

-MOA: not understood but we know it interferes with the formation of IP3 and cAMP.

-Side effects are common.

-Alternative mood stabilizing drugs: carbamazepine and valproate.

Phobic: triggered by specific circumstances (spiders)

Panic: attacks of overwhelming fear in association with marked somatic symptoms.

-Animal models for testing anxiety drugs

-Rat placed in  unfamiliar environment-normally stays immobile but alert (anxiety)

-Immobility is reduced with administration of anxiolytics...also animal is more liekly to be in open spaces and is not afraid of falling off the maze.

-animal model for testing anxiolytic drugs

-conflict element is introduced.

-rat will cease to press the bar.

-when drugs are admin. rat continues to press the bar in spite of punishment

***Benzodiazepines

2nd most is 5-HT1A: no sedation)

Barbituates: now largely obsolete

Beta-adrenoceptor  antagonists: used mainly to reduce physical symptoms of anxietyzx