Westminster Peer Barb Pp's

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Ach receptor types

Back 1

Muscarinic: G-coupled proteins
Nicotinic: ligand-gated, multi-unit proteins

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The nicotinic receptor

Back 2

ligand-gated channel composed of five subunits. It is primarily the responsible for the peripheral effects of acetylcholine at the autonomic ganglia and the neuromuscular junction.
Acetlycholine receptors are multi-subunit membrane spanning proteins consisting of five distinct subunits; (a,b,d,g).
Acetylcholine binds to the a subunits, of which there are two on each of the acetylcholine receptor ion channels.
Once bound, acetylcholine causes ligand-gated ion channels in the post synaptic membrane to open.
These channels are relatively non-selective so the passage of different ions, such as Na+, K+ and Li+ occurs.

Front 3

Nicotinic locations

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sympathetic-adrenal medulla
sympathetic first synapse
parasym first synapse
striated muscle

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Agonists and indirect agonists

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ACh-like drugs (methacholine, carbacholine, nicotine)
Bind and activate nicontinic ACh receptors
Not destroyed by AChE so the effects are prolonged

Anti-AChE (neostigmine, physostigmine, disopropyl fluorophosphate or “nerve gas”, and insecticides)
Block the degradation of ACh, thereby prolonging it’s effects

Front 5

inhibitors-curariform

Back 5

block nicotinic aCh channels by competing for aCh binding site

reduces amplitude of end plate potential thereforre, no AP

Front 6

inhibitors-botulism toxin

Back 6

decreases the release of Ach from nerver terminal

isufficient stimulus to initiaate the AP

Front 7

Antimuscarinics

Back 7

Atropine
Scopolamine

Two of the oldest known molecules

Front 8

Ganglionic Blockers

Back 8

Ganglionic Blockers

cigarettes

Front 9

Neuromuscular blockers

Back 9

Pancuronium
Rocuronium (Roc)
Succinylcholine (Sux)
Vecuronium (Vec)

Pancuronium
Rocuronium (Roc)
Succinylcholine (Sux)
Vecuronium (Vec)

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GABA Receptors

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They are the main inhibitory receptors, mostly found in the CNS.
They are involved with many neuroactive drugs.
There are 3 subtypes of GABA receptors

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GABA A and GABA C- Ligand or voltage-gated Chloride ion channels, an “ionotropic receptor”,

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which are opened in response to the GABA neurotransmitter or other drugs like volatile anesthetics, alcohol, steroids, Benzodiazepines, Barbiturates and Anticonvulsants. GABA A’s are the most common type.

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GABA B- is a G Coupled Protein

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a “metabotropic receptor”, that regulates biochemical pathways and/or ion channels. Baclofen (used for muscle spasticity) is an agonist and Saclofen is an antagonist.

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GABA A Receptors

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When GABA A receptors are activated, chloride ions rush inside the cell. This activity hyperpolarizes the cell, so the cell cannot depolarize. This action is inhibitory. The various protein subunits of the receptor are each specific for a certain type of substance as shown.

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GABA B Receptors

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GABA B receptors belong the G Protein Couple Family (GPCF) of receptors. When the receptor is activated, it stimulates a G Protein, attached to it inside the cell, to release a subunit which activates (think phosphorylation, cAMP, cGMP, etc.) either a biochemical pathway (an enzyme system) or an ion channel.

Front 15

Barb history

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Drugs that act on CNS as depressants
Derived from Barbituric Acid
Acts on GABA-A receptor
Wide spectrum of effects-mild sedation to anesthesia

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more barb history

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Discovered in 1864 by Adolf von Baeyer
1903- 1st medicinal barbiturate
1912- Phenobarbital introduced as sedative hypnotic
1950’s- Reports about dependance related to barbiturates
1970- Barbiturates become controlled substances

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Uses of Barbiturates

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Induction of anesthesia

Treatment of increased ICP

Treatment of seizures

Treatment of Hyperbilirubinemia

Treatment of kernicterus

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Barb-Induction of Anesthesia

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Gold standard from 1934-1989
Given IV, has CNS effects within 30 secs
Virtually no side effects on skeletal, cardiac, and smooth muscle
Propofol is used in place of most barbiturates

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Increased ICP treatment

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Decreases cerebral blood volume by causing vasoconstriction and decreased blood flow

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Seizures treatment

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Enhance GABA activity

General depressant of nerve and muscle tissue

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Hyperbilirubinemia and Kernicterus treatment

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Increases hepatic glucuronyl transferase activity

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Non-Therapeutical barb Uses

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Physician assisted suicide

Euthanasia

Lethal injection

Front 23

Barb SAR

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Inactivated structures don’t have carbon chains at the 5th position. The sulfur on the thiobarbiturate causes an increase in lipophilicity thus a more rapid onset and shorter duration with quicker recovery.

Front 24

Barb SAR

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Hypnotic Activity: Side chains at position 5 (especially if one of them is branched).
Potency and duration of action: Length of side chain at position 5 (so secobarbital and thiamylal are slightly more potent than pentobarbital and thiamylal are slightly more potent than pentobarbital and thiopental, respectively.
More rapid onset and shorter duration of action: Sulfur instead of oxygen atom at position 2 (so thiamylal and thiopental have more rapid onset and shorter duration of action than secobarbital and pentobarbital, respectively.)
Increased incidence of excitatory side effects: Methylation at position 1 (methohexital).
Stereoisomerism: Though their levo-isomers are nearly twice as potent as their dextro-isomers, barbiturates are marketed as racemic mixtures. Methohexital has two asymmetric carbon atoms, so exists as 4 stereoisomers (alpha, beta, dextro, levo, methohexital).

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Primary Barbiturates Used in Anesthesia

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Sodium Thiopental (Sodium Pentathal)
Introduced in 1936
Methohexital (Brevital)
Introduced 1952

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Barb SAR

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Side Chains at Number 5 Allow for Increased Hypnotic Activity and Increased Potency (For Both)
Sulfur on Number 2 of Thiopental Allows for More Rapid Onset and Shorter Duration of Action (“Ultra Short-Acting”)
Methylation on number 1 of methohexital causes increased incidence of excitatory effects.
Convulsions were common when methohexital was introduced but isolation and elimination of the beta isomer has decreased the incidence of seizure activity to only increasing the chances of seizures in those individuals who already have a pre-existing seizure disorder. Methohexital is marketed as racemic alpha –d,l-methohexital.

Front 27

CNS barbiturate S/A's?

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Confusion
Depression
Unusual excitement
Hallucinations
Unusual tiredness or weakness
Decrease or loss of reflexes
Irritability
Poor judgment, slurred speech
Insomnia, nightmares
Unusual movements of the eyes
Dizzy or lightheadedness
Anxiety or nervousness
Headache
Visual changes

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Cardiovascular barbiturate S/A's?

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Chest pain
Unusual bleeding or bruising
Bradycardia
Tachycardia

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Repiratory barbiturate S/A's?

Back 29

Wheezing or tightness in chest
SOB, slow or troubled breathing

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GI/GU barbiturate S/A's?

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Loss of appetite
Constipation
Diarrhea
Nausea or vomiting
Difficulty urinating
Dry mouth

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Musculoskeletal barbiturate S/A's?

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Muscle or joint pain
Bone pain, tenderness, or aching
Muscle weakness
Staggering, clumsy, or unsteadiness

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other barbiturate S/A's

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Bleeding sores on lips
Fever
Red, thickened or scaly skin
Yellow eyes or skin
Rash or hives
Sores, ulcers, or white spots in mouth (painful)
Sore throat
Swelling of eyelids, face or lips
Weight loss (unusual)
Low body temp
Decreased libido
Addictive
An overdose can cause Resp/cardiac depression & DEATH