Drug Receptors and Response

Receptors

• Sensitivity is when a low concentration causes a drug response.
• Selectivity is when structurally similar chemicals cause a drug response.
• Specificity is the cells determine the response so the response from a set of receptors is always the same.

Drug Response Equation

• D stands for drug.
• R stands for receptor.
• DRC stands for drug receptor complex.
• TR stands for tissue response.
• Tissue Response can vary between individual patients.
• The magnitude of response depends on the number of receptors occupied.

Compartment Model

• There are 2 compartments: central and peripheral
• Central is 10% of body mass, 75% of CO.
• Peripheral is 90% of body mass, 25% of CO.
• Drugs enter the central compartment and leave by distribution to tissues, and metabolism and excretion.
• As blood flows through tissues, drug is deposited in those peripheral tissues, but not at a high rate like VRG's.
• If serum concentration drops and is lower than tissue concentration, the drug re-enters the central compartment.

Plasma Concentration Curve

• Drugs have a distribution and elimination phase.

Metabolism

• Metabolism changes lipid soluble to water soluble for elimination.
• Metabolism can occur in many places, but the liver is most common.
• Phase I includes oxidation, reduction, and hydrolysis.
• Phase I increases polarity of the molecule making it water soluble instead of lipid soluble.
• Phase II is conjugation.
• Conjugation synthesizes a new compound, a conjugate.
• In the conjugation phase there is a more polar compound that is easily extracted by kidneys.
• Rarely is there any biological activity in Phase II of metabolism.

Elimination

• Half life is the time it takes a drug to drop to half of its concentration in the plasma.
• The amount of drug left is related to how many half lives have passed.
• Half Life 0, Drug eliminates 0%, Drug Remaining 100%
• Half Life 1, Drug eliminates 50%, Drug Remaining 50%
• Half Life 2, Drug eliminates 75%, Drug Remaining 25%
• Half Life 3, Drug eliminates 87.5%, Drug Remaining 12.5%
• Half Life 4, Drug eliminates 93.75%, Drug Remaining 6.25%
• Half Life 5, Drug eliminates 96.875%, Drug Remaining 3.125%
• Context Sensitive Half-Time is the time to halving of the blood concentration after termination of drug administration by an infusion designed to maintain a constant concentration.
• Context Sensitive Half-Time only describes time to 50% decrease in central compartment level.
• This may not be enough decrease for full recovery.

Central Nervous System

• The sympathetic preganglionic fiber uses Cholinergic ACh (nicotinic).
• Postganglionic fiber uses Adrenergic NE receptor
• The parasympathetic preganglionic fiber uses Cholinergic ACh (nicotinic)
• The parasympathetic postganglionic fiber uses Cholinergic ACh receptor (muscarinic)

Sedatives, Hypnotics, etc.

• Sedatives, Hypnotics, etc are facilitated via GABA receptors.
• This process can be altered using benzodiazepine, propofol, volatile anesthetics, ethanol, and neurosteroids.

NMDA

• NMDA uses a NMDA receptor.
• NMDA receptor contains a Zn2+ modulatory site, polyamine modulatory site, NMDA recognition site, and Mg2+ binding site.
• The post-synaptic membrane in NMDA contains NMDAR1, NMDA-R2A / -R2B / -R2C / -R2D.
• Dissociative anesthetics and dizocilpine binding site work in this system.

Neuromuscular Junction

• The Axon of a motor neuron connects to muscle fibers.
• Important features include: Axon terminal, Terminal button, Vesicle of acetylcholine, Voltage-gated Na+ channel, Voltage-gated calcium channel, Plasma membrane of muscle fiber, Acetylcholine receptor site, Acetylcholinesterase, Neurotransmitter-gated channel, Motor end plate.

Andrenoceptors

• Alpha 1 receptors cause vasoconstriction, increased peripheral resistance, increased blood pressure, mydriasis and increased closure of the internal sphincter of the bladder.
• Alpha 2 receptors cause inhibition of norepinephrine release, inhibition of acetylcholine release and inhibition of insulin release.
• Beta 1 receptors cause tachycardia, increased lipolysis, increased myocardial contractility and increased release of renin.
• Beta 2 receptors cause vasodilation, slightly decreased peripheral resistance, bronchodilation, increased muscle and liver glycogenolysis, increased release of glucagon and relaxed uterine smooth muscle.

Alpha and Beta Receptors

• Alpha receptors uses the synaptic negative feedback to adrenergic synapse.
• Clonidine and Dexmedetomidine act as alpha receptors.
• Beta receptors uses cardiac myocyte to perform cardiac contractions.
• Alpha-Receptors vessel constricts
• Beta-Receptors vessel dilates.

Nitroglycerin

• Nitroglycerin is converted to nitric oxide.
• Nitroglycerin is a potent vasodilator.

Hydralazine

• Hydralazine causes direct relaxation of arterial smooth muscle.
• It combines with receptors in endothelium of arterioles, which causes Nitric oxide release and Relaxation of vascular smooth muscle.

Chemoreceptor Trigger Zone

• Important entities include: 5-HT, RAS Promethazine Atropine Droperidol NK-1 RA, Histamine, Muscarinic Dopamine (D₂), Substance P, Area Postrema.
• The Chemoreceptor Trigger Zone (CTZ) is triggered by nitrogen mustard, Cisplatin, Digoxin glycoside, and Opioid analgesics.
• It activates the vestibular portion of 8th nerve, Mediastinum, Parvicellular Reticular Formation and Gl tract distension.
• The emetic center is affect by higher centers (vision, taste) and pharynx.