Non-barbiturate sedatives

1- Chloral hydrate is trichlorinated derivative of acetaldehyde that is converted to trichlorethanol in the body. It induces sleep in about 30 minutes and last up to 6 hr. it is irritant to GIT and produce unpleasant taste sensation.

2- Ramelteon melatonin receptors are thought to be involved in maintaining circadian rhythms underlying the sleep-wake cycle. Ramelteon is an agonist at MT1 and MT2 melatonin receptors , useful in patients with chronic insomnia with no rebound insomnia and
withdrawal symptoms

3- Ethanol (alcohol) it has antianxiety sedative effects but its toxic potential out ways its benefits.
Ethanol is a CNS depressant producing sedation and hypnosis with increasing dose.

Absorption of alcohol taken orally is rapid, it is highly lipid soluble, presence of food delayed its absorption, maximal blood concentration depend on total dose, sex, strength of the solution, the time over which it is taken, the presence of food and speed of metabolism.

Alcohol in the systemic circulation is oxidized in the liver principally 90% by alcohol dehydrogenase to acetaldehyde and then by acetaldehyde dehydrogenase to products that enter the citric cycle. 

Alcohol metabolism by alcohol dehydrogenase follows first order kinetics in the smallest doses. Once the blood concentration exceeds about 10 mg/100 ml, the enzymatic processes are saturated and elimination rate no longer increases with increasing
concentration but become steady at 10-15 ml/ 1 hr. in occasional drinkers. 

Thus alcohol is subject to dose dependant kinetics i.e. saturation or zero order kinetics.

Actions

- Ethanol acts on CNS in a manner similar to volatile anesthetic.
- It also enhances GABA so stimulating flux of chloride ions through ion channels.
- Other possible mode of action involve inhibition of Ca-channels and inhibition of excitatory NMDA receptors.
- Ethanol has non selective CNS depressant activity.
- It causes cutaneous vasodilatation, tachycardia and myocardial depression

CNS acting drugs are of major therapeutic and clinical importance. 

They can produce diverse physiologicaland psychologicaleffects such as:

•Induction of Anesthesia 
•Relief of Pain 
•Prevention of Epileptic seizures 
•Reduction of Anxiety 
•Treatment of Parkinsonism 
•Treatment of Alzheimer's disease 
•Treatment of Depression 
•Centrally acting drugs also include drugs that are administered without medical intervention like tea, coffee, nicotine, and opiates.
 

Types of Neurons (Function)

•There are 3 general types of neurons (nerve cells): 

1-Sensory (Afferent ) neuron:A neuron that detects changes in the external or internal environment and sends information about these changes to the CNS. (e.g: rods and cones, touch receptors). They usually have long dendrites and relatively short axons. 

2-Motor (Efferent) neuron:A neuron located within the CNS that controls the contraction of    a muscle or the secretion of a gland. They usually have short dendrites and long axons. 

2-Interneuron or association neurons: A neuron located entirely within the CNS in which they form the connecting link between the afferent and efferent neurons. They have short dendrites and may have either a short or long axon.

CHOLINERGIC DRUGS

Produce actions similar to Acetylcholine (Ach)

Cholinergic Agonists
1 Acetylcholine  2 Methacholine  3. Carbachol 4 Bethnechol

Alkaloids
1.Muscarine 2 Pilocarpine 3. Arecoline

MECHANISM OF ACTION
I Heart- hyperpolarizes the SA node and decreases the rate of diastolic depolarisation. thus the frequcncy of impulse generation is decreased. bradycardia.
2 Blood vessels- vasodilatation
3. Smooth muscles - increased contraction. increased tone. increased peristalsis.
4. Glands- increased sweating. increased lacrimation.
5 Eye- contraction of the circular muscle of iris (miosis).

Nicotinic action
Autonomic ganglia - stimu1ation of sympathetic and parasympathetic system.
Skeletalmuscles - contraction of fibres.
CNS..No effect as it does not penetrate the blood-brain barrier.

Toxic effects
Flushing. sweating.salivation. cramps. belching. involuntary mictuirition. defaccation.

Contraindication
1.. Anginapectoris- decreases the coronary flow.
2 Pepticulcer - increases the gastric secretion
3 Asthma- bronchoconstriction
4 Hyperthyroidisim

Cholinomimetic Alkaloids
Pilocarpine
Prominent muscarinic actions. causes marked sweating. salivation. Increase of secretions. small doses cause fall in BP but higher doses increase in BP. Applied to the eye cause miosis. fall in intraocular tension

Uses
I. .Open angle glaucoma
2. To counteract mydriasis

Anticholinesterase
They inhibit the enzyme cholinestrase and prolong the action of Ach

Reversible 
Physostigamine, Ncostigamine, Pyridostigamine, Ambenonium, Edrophonium, Demecarium

Irreverible
Dyflos. Echothiphate.

Pharmacological Actions
I Ganglia - persistent depolarisation of ganglionic nicotinic receptors.
2 CVS - unprcdictable as Muscarinic-I receptor causes bradycardia but ganglionic stimulation
tachycardia.
3. Skeletal muscles - as Ach is not destroyed and rebinds to the same receptor or it diffuses on to the neighbouring receptors to cause repetitive firing. twitching and fasciculations.

Uses 
I As miotic
a) Glaucoma :  Acute congestive (narrow angle) glaucoma,  Chronic simple (wide angle)  glaucoma
b) Counter act  atropine mydriasis.
2) Post operative paralytic ileus
3) Myasthenia gravis
4) Postoperativedecurarization
5) Cobra bite
6) Belladona poisoning
7) Other drug overdoses

BETA-LACTAM ANTIBIOTICS
β-lactam antibiotics are a broad class of antibiotics including penicillin derivatives, cephalosporins, monobactams, carbapenems and β-lactamase inhibitors; basically any antibiotic agent which contains a β-lactam nucleus in its molecular structure. They are the most widely used group of antibiotics available.

Mode of action All β-lactam antibiotics are bactericidal, and act by inhibiting the synthesis of the peptidoglycan layer of bacterial cell walls.β-lactam antibiotics were mainly active only against Gram-positive bacteria, the development of broad-spectrum β-lactam antibiotics active against various Gram-negative organisms has increased the usefulness of the β-lactam antibiotics.

Common β-lactam antibiotics

Penicillins

Narrow spectrum penicillins:  

benzathine penicillin
benzylpenicillin (penicillin G)
phenoxymethylpenicillin (penicillin V)
procaine penicillin

Narrow spectrum penicillinase-resistant penicillins

methicillin
dicloxacillin
flucloxacillin

Moderate spectrum penicillins : 

amoxicillin, ampicillin

Broad spectrum penicillins :      

co-amoxiclav (amoxycillin+clavulanic acid)

Extended Spectrum Penicillins:    

piperacillin
ticarcillin
azlocillin
carbenicillin
 

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)