A subclass of cholinergic receptors (those that respond to Ach and its analogs)

Muscarinic receptors respond to the alkaloid muscarine as well as to Ach.

5 subtypes M1-M5 are all GPCRs.

Effects of their activation resemble those of postganglionic parasympathetic nerve stimulation.

Located on autonomic effector cells (heart, vascular endothelium, smooth muscle, exocrine glands, and presynaptic nerve terminals).

Prejunctional Muscarinic receptors inhibit the release of Ach.

Muscarinic Cholinergic receptor subclass.

Located on nerve endings

Gq-coupled, ↑ IP₃, DAG cascade.

Muscarinic Cholinergic receptor subclass.

Located in the heart and on some nerve endings.

Gi-coupled, ↓ cAMP, activates K+ channels

Muscarinic Cholinergic receptor subclass.

Located in effector cells in smooth muscle, endothelium and glands.

Gq-coupled, ↑ IP₃, DAG cascade

A subclass of Cholinergic receptors that are parts of ion channels and respond to nicotine as well as to Ach and Ach mimics but not to muscarine.

There are 2 major subtypes (N and M) which are located in ganglia and in skeletal muscle endplates and are the primary transmission receptors there.

Presynaptic nicotinic receptors facilitate the release of Ach.

Subclass of cholinergic, nicotinic receptors.

Located in the ganglia of the ANS.

Ion channel that depolarizes to evoke an action potential.

A subclass of cholinergic, nicotinic receptors.

Located at the NMJ (neuromuscular end plate)

Ion channel that depolarizes to evoke an action potential.

aka Adrenergic Receptors

Those that respond to Norepinephrine.

All postganglionic fibers of the SNS (except those inn. sweat glands) are adrenergic*

Alpha adrenergic receptors are located on vascular smooth muscle, presynaptic nerve terminals, blood platelets, fat cells, and neurons of the brain and are subdivided into alpha 1 and alpha 2 based on the differeng G coupling proteins used.

Beta adrenergic receptors are located on most types of smooth muscle, cardiac muscle, some presynaptic nerve terminals, and fat cells as well as in the brain. It's beta 1, 2 and 3 subtypes are very similar and use the same G protein.

Are a subclass of adrenergic receptors with a different distribution and function.

Dopamine receptors are key in renal and splanchnic receptors as well as in the brain.

There are 5 subtypes but the D₁ is the most important.

Located in smooth muscle, G_S G protien, second messenger: ↑ cAMP, function: relax renal vascular smooth muscle.

Subclass of adrenergic receptor.

Located in teh effector tissues (Smooth Muscles and Glands)

G Protein: G_q

Second Messenger: ↑ IP₃, DAG

Functions: ↑ Ca2+, causes contraction/secretion

Prejunctional Responses: NONE

Postjunctional Responses: vasoconstriction of vessels, ↓ GI motility/tone (sphincter contraction in bladder and GI), ↑ hepatic glycogenolysis, contraction of radial m. in eye→pupillary dilation.

Key Agonists: Epi/NE, Phenylphedrine

Key Antagonists: Phenoxybenzamine, Phentolamine and drugs ending in -azosin.

Subclass of adrenergic receptors.

Located in nerve endings and some smooth muscle.

G Protein: G_i

Second messenger: ↓ cAMP

Function: ↓ neurotransmitter release

Prejunctional Actions: On adrenergic n. inhibits release of NE, on Parasympa n. inhibits Ach release, on Serotoninergic n. inhbits release of serotonin.

Postjunctional Actions: Vasoconstriction (Hypotension in RVLM*), ↓ GI motility, inhibition of pancreatic insulin secretion, ↓ lipolysis in fat cells, ↑ platelet aggregation.

Key Agonists: Epi/NE, Clonidine, alpha-Methyldopa

Key Antagonists: Phenoxybenzamine, Phentolamine.

Subclass of adrenergic receptor.

Located in cardiac muscle and in the juxtaglomerular apparatus

G Protein: G_s

Second Messenger: ↑ cAMP

Prejunctional Actions: NONE

Postjunctional Actions: ↑ heart rate, ↑ force of contraction, ↓ GI motility/tone, ↑ lipolysis/FA mobilization, ↑ renal renin release

Key Agonists: Epi/NE, Isoproterenol, Dobutamine (β₁-specific)

Key Antagonists: end in -olol

Subclass of adrenergic receptors

Located in smooth msucle, liver and heart

G Protein: G_s

Second Messenger: ↑ cAMP

Prejunctional Actions: On adrenergic n (only location of action) ↑ NE release.

Postjunctional Actions: Vasodilation, ↓ GI motility/tone (spec. relaxes bladder's detrussor m.), relaxes bronchial smooth m, ↑ hepatic glycogenolysis and gluconeogenesis, ↑ Insulin and glucagon secretion, relaxes (prevents contraction of) the pregnant uterus.

Key Agonists: Epi, Isoproterenol, Albuterol/Salmeterol, Terbutaline (tx preterm labor).

Key Antagonists end in -olol

A subclass of adrenergic receptors

Located in adipose cells

G Protein: G_s

Second Messenger: ↑ cAMP

Function: ↑ lipolysis

Acts at adrenergic nerve terminals to inhibit uptake of NT and therefore ↑ transmitter effects on post-synaptic receptors.

This is the same effect that tricyclic antidepressants have (via the same mechanism).

Acts on recepotrs at adrenergic junctions.

Binds alpha receptors (preferentially, some beta 1 receptors) and causes activation.

Physiology: attention, arousal, BP, REM sleep, suppression of pain, eating, mood

Related Pathology: ADD, manic depression, narcolepsy, neurogenic pain, obesity.

Is a metabolite of epinephrine breakdown.

24 h excretion of metaneprine is considered a reliable measure of the total body production of catecholamines and is useful in diagnosing conditions such as pheochromocytoma.

Inhibition of MAO (monoamine oxidase, an enzyme which breaks down norepinephrine) ↑ stores of catecholamines and has both thereputic and toxic potential.

Parasympathetic

General Features

Long preganglinoic axon releases Ach which binds Nicotinic receptors on the postsynaptic neurons (which are relatively short) and also release Ach onto their targets (usually Muscarinic receptors with the key exception of nicotinic receptors at the NMJ.

Synthesis of Ach is by Choline aminotransferase (ChAT) which is limited only by choline availibility.

1° Regulation is via metabolism of Ach by acetylcholinesterase.

Actions of Ach-ase are blocked by Saringas, most insectisides and drugs ending in -phorium.

Actions of Achase are ↑ by durgs ending in -stigme and a drug called 2-PAM used to in tx of organophosphate poisoning.

Sympathetic

General Features

Shortpresynaptic neuron releases Ach which binds a Nicotinic receptor on the postganglionic cell which has a long axon. Postgang releases NE (primarily though sometimes Epi) which binds to adrenergic receptors on targets.

Synthesis of catecholamines (NE) is by several step rxn: Tyrosine Hydroxylase is the rate limiting step*

Primary regulation of this system is reuptake of NTs into the presynaptic vessicles by VMAT.

Reuptake is blocked by Cocaine and Reserpine.

Reuptake is enhanced by amphetamines and Tyramine (both of which require uptake themselves to exert their actions from within the neurons.

Blocks actions of Tyrosine hydroxylase in converting Tyr > DOPA.

Rx: HTN, Pheochromocytoma

Blocks action of DA hydroxylase in converting DA > NE and the actions of acetylaldehyde dehydrogenase in the breakdown of alcohol.

↓ free catecholamines but more importantly causes a build up of acetylaldehyde by inhbiting Alcohol Dehydrogenase→vasodilation and hypotension +very sick feeling.

Rx: Alcoholism

Pheochromocytoma

Caused by catecholamine-secreting tumors typically of adrenal medullary origin.

Urine Assay: ↑ Creatine and metanephrine

24h Urine: ↑ metanephrine and ↑ free catecholamines

CT/MRI: may show tumor

Precusor to DA (NE/Epi) used in tx Parkinsonism to ↑ Dopamine in compensation for lost dopamanergic activity.

DA does not cross the BBB so L-DOPA (does cross) must be given and can cross and be converted to DA in the brain and exert its actions there.

Side Effects (SE): nausea and vomiting at high doses.

Given with Carbidopa and/or Entacapone (which ↓ metabolism of L-DOPA).

Blocks DOPA decarboxylase in the periphery which ↓ L-DOPA metabolism in the periphery and GI allowing more to get to the brain and lower doses of L-DOPA to be given.

Used with L-DOPA to tx Parkinsonism

Blocks COMT in the liver and kidney which ↓ peripheral metabolism of L-DOPA allowing more to get to the brain.

Used with L-Dopa in tx Parkinsonism.

Allows lower doses of L-DOPA to be given.

Inhibits VMAT (the transporter that brings NE into the vessicles which damages vessicles leading to 'depletion' of NE from n. terminals blocking sympathetic fxn and thereby ↑ paraysma fxn.

Rx: HTN, agitation, psychosis

SE: Sedation, diarrhea (due to ↑ GI motility/secretions)

Contraindications: Pt with Peptic Ulcers (bc it ↑ gastric acid secretions).

L-DOPS is a prodrug/synthetic precursor to NE (L-DOPS > NE by DOPA decarboxylase)

Rx: Familial Dysautonomia (ANS dysfunction)

A false NT/α₂ adrenergic agonist*

α-Methyldopa→(DOPA decarboxylase)→α-Methyldopamine → (Dopamine hydroxylase)→ α-Methylnorepinephrine.

Rx: Preeclapsia, HTN

Rostral Ventrolateral Medulla (from wiki)

Control of bp is crucially dependent on the integrity of the RVLM which contains cells that control the heart, blood vessels, swallowing, breathing and many other unconscious/'autonomic' activities.

(RVLM) is also known as the pressor area of the medulla (medulla pressor). It receives inhibitory GABAergic input and is the primary regulator of the sympathetic nervous system, sending excitatory fibers (catecholaminergic) to the sympathetic preganglionic neurons in the spinal cord.

The RVLM is notably involved in the baroreflex.

Physostigmine, a choline-esterase inhibitor, elevates endogenous levels of acetylcholine by stimulation of the RVLM

From frog venom.

Activates Na+ channels causing depolarization-induced release and depletion of NT.

From black widow and brown spider venom.

Initally ↑ NT release then blocks transmission and depletes vesicles of NT.

A bacterial toxin.

A protease that inhibits NT release by cleaving synaptobrevin, syntaxin and SNAP-25 components of the NT exocytosis machinery.

From snake venom.

Blocks the Na+ channels on Nicotinic receptors in skeletal muscles.

Inhibits NE release.

Produces an initial transient ↑ followied by inhbiition of NE release → ↑ ventricular fibrillation threshold and AP duration/effective refractory period.

Does not affect hr.

Given IV or IM as a last-resort drug in cases of life-threatening ventricular arrhythmias

SE: hypotension, bradycardia, dizziness, vertigo, diarrhea, abdominal pain.

Tricyclic Antidepressant (TCA)

Blocks the amine transporter that is responsible for the reuptake of NE from the synaptic cleft.

TCA

Blocks reuptake of NE by the amine transporter in the presynaptic neuron.

Monoamine Oxygenase

A key enzyme in the breakdown of catecholamines.

MAO-A: GI and Liver

MAO-B: Brain and Platelets

Non-specific (A and B) MAO inhibitor.

↑ NE levels by blocking NE metabolism.

Rx: Depression, panic disorders.

Non-specific MAO (A and B) inhbitor.

↑ NE levels

Rx: Depression, panic disorders.

(Just like Tranylcypromine)

MAO-B specific inhbitor

[Bud Selig is the commissioner of Baseball]

Rx: +/- L-DOPA in tx Parkensonism.

Non-specific (α_1/2) alpha adrenergic antagonist

Blocks the effects of NE and Epi on α_1/2 adrenergic receptors.

Rx: now obsolete for tx HTN but used to treat Pheochromocytoma.

α₁-specific receptor agonist

Causes vasoconstriction and ↑ bp (and reflex ↓ hr).

Used to increase the blood pressure in unstable patients with hypotension and is useful in counteracting the hypotensive effect of anesthetics. It is not inotropic or chronotropic, and so it strictly ↑ bp without ↑ the hr or contractility (reflex bradycardia may result from the ↑ in bp). This is useful if the heart is already tachycardic and/or has a cardiomyopathy.

Rx: proxymal atrial tachycardia (if pt not hypertensive as tx ↑ parasympa activity)

Can act as a nasal decongestant by causing vasoconstriction of the highly vascularized nasal mucosa.

Also dialates the pupils.

*If given with Atropine then Phenylephrine will cause ↑ bp w/o Δ hr*

Because it acts directly its effects are not altered by cocaine, TCAs or reserpine.

α₁-selective receptor antagonist

Opposes directly Phenylephrine

α₂-specific receptor Agonist

Causes an initial ↑ in bp by acting on vessels as it crossess the BBB then acts on RLVM to ↓ bp by ↓ flow of impulses in this region of the brain that signal release of NE.

Rx: preanesthetic drug (sedative, antianxiety, pain) and in heroin/nicotine withdrawl (pt in withdrawl have ↑ sympa activity)

Effects = those of Guanabenz and both are > NE

α₂-specific receptor Agonist

Causes an initial ↑ in bp by acting on vessels as it crossess the BBB then acts on RLVM to ↓ bp by ↓ flow of impulses in this region of the brain that signal release of NE.

Rx: preanesthetic drug (sedative, antianxiety, pain) and in heroin/nicotine withdrawl (pt in withdrawl have ↑ sympa activity)

Effects = those of Clonidine and both are > NE

Non-specific β receptor Agonist

↓ TPR, ↑ systolic P, ↓ diastolic P (=↓ MAP), direct reflexes cause a large ↑ in hr.

Rx: AV heart block.

*↑ in hr caused by isoproterenol can be blocked by coadminstration of Probanolol (a β receptor antagonist).

A non-specific β receptor antagonist

Tx: migrane headaches, nervousness

Has high lipid-solublility

β₁-specific Agonist

(@ high doses acts on β₂ and α₁ receptors also)

↑ hr

Rx: Cardiac decompensation after surgery, CHF

β₁-specific Antagonist

A cardioselective blocker

Is ok for use in asthmatics (who should under most circumstances avoid taking beta blockers)

Short-acting β₂-selective Agonist

Tx: asthma

Along with Bitolterol, Metaproterenol, Terbutaline, and Pirbuterol

β₂ -specific Antagonist

Contraindicated for use in asthmatics.

Non-selective (D_1/2) receptor Agonist

Rx: Parkinson's

(acts on DA receptors in the hypothalamus)

D₁ selective Agonist

Promotes diuresis and natriuresis

Rx: to Pt in renal failure and shock (↓ bp)

D₂-specific Agonist

Rx: Parkinson's, Impotency

α₁-specific Agonist

Causes ↑ bp and a reflex ↓ in hr

Rx: as a decongestant (like all

α₁-specific agonists due to the vascular nature of the nasal mucosa).

α₂-specific agonist

Rx: Open Angle Glaucoma

↓ synthesis of aqueous humor in the eye and ↑ the amount of humor outflow lessening the pressure.

β₂-specific agonist

Causes dilation of arteries and veins, relaxation of bronchial smooth muscle and other actions.

Rx: asthma (Short-acting)

β₂-specific agonist

Rx: Asthma (Short-acting)

and to prevent premature labor.

β₂-specific agonist

Rx: Asthma (Long-acting)

β₂-specific agonist

Rx: Asthma (Long-acting)

Epi (α_1/2,β_1/2), Ephedrine (indirect α_1/2,β_1/2)

β₂ Agonists: Albuterol, Bitolterol, Salmeterol, Formoterol, and Terbutaline.

Epi (α_1/2,β_1/2 agonist)

Isoproterenol (β_1/2 agonist)

Epi (α_1/2,β_1/2agonist)

Used with local anasthetics to prolong their action and with cases of hypotension.

Phenylephrine (α₁)

Digitalis (cardiac glycoside) or Quinidine (channel blocker) *not this assessment but were on the table.

Dobutamine (β₁ agonist but in high doses also acts at α₁/β₂)

Used followign surgery or in CHF

Meteramol (direct and indierct actions at α₁)

Used in cases of drug-induced hypotension (OD), pheochromocytoma excision and in orthostatic hypotension.

Clonidine (α₂agonist, acts through RVLP)

α-Methyldopa (false precursor)

Clonidine (α₂)

Effect is sedative, antianxiety and relief of pain.

↓ NE (levels are high in heroin/nicotine addicts)

Epi/Propine (α_1/2,β_1/2agonist),

Brimonidine (α₂agonist, ↓ production of aqueous humor and ↑ humor outflow through the uveovisceral outflow by acting on the a-2 receptors and ↓ cAMP),

and Timolol (β_1/2antagonist, reduces aqueous humor production by blocking the beta receptors on the ciliary epithelium).

An alkaloid, ↑ outflow of aqueous humor, constricts the pupils.

Acts only on Muscarinic receptors (more on this next assessment).

Rx: Acute/Closed-angle glaucoma

Terbutaline (β₂agonist)

(remember β₂receptor mediates relaxation of uterine smooth muscle)

*Note that this is only administered in emergency situations as there are several known risks.

Ephedrine, Amphetamine, Dextroamphetamine (indirect actions via α_1/2,β_1/2)

Modafinil (α₁agonist)

Amphetamine and dextroamphetamines (via indirect actions on α_1/2,β_1/2)

Haloperido (nonselective D antagonist)

α₁-selective antagonist (-osins)

Rx: incomplete urinary voiding, autonomic hyperreflexia, BPH

α₁-selective antagonist (-osins)

Rx: incomplete urinary voiding, autonomic hyperreflexia, BPH

α₁-selective antagonist (-osins)

(aka Flomax)

Rx: incomplete urinary voiding, autonomic hyperreflexia, BPH

Non-selective α adrenergic antagonist (the -amines)

Used in tx Pheochromocytoma

Non-selective α adrenergic antagonist (the -amines)

Rx: Used in diagnosis of Pheochromocytoma,

Used to tx ED

Used to reverse anestesia of soft tissues in dentistry

Postural hypotension

Tachycardia

Palpations

Arrhythmias

Dizziness

Drowsiness

Headaches

Salt/Water Retention

Abdominal pain, diarrhea, nasuea and vomiting

Retrograde ejaculation

Hypertensive states (because they ↑ Paraysmpa activity by depressing Sympathetic)

Heart Disease

Pt with Peptic ulcers (they ↑ gastric secretions)

Non-specific β-antagonist/partial agonist

with low lipid solubility and membrane stabilizing ability.

Non-specific β-antagonist

Non-specific β-antagonist

Rx: Open angle Glaucoma

β₁-specific antagonist

β₁-specific antagonist

(NO release)

What are some of the conditions treated by

β antagonists?

Cardiac arrythmias

Angina pectoris

Cardiomyopaties

MI

Dissecting aortic aneurysm

Marfan's syndrome

Tetrology of fallot

Stress/fear-induced tachycardia/tremor

Glacuoma

Pheochromocytoma

Hyperthyroidism (causes tachycardia)

HTN

Migrane

AV block (or otherise ↓ cardiac conduction)

Bradycardia/Hypotension

PVD

Bronchiospasms

Hypoglycemia

limping

nightmares, depression, fatigue

Non-specific (D_1/2) receptor agonist

Causes renal and mesenteric vasodilation

Does not cross BBB (must be given as L-DOPA if effects in the brain are desired).

Involved in perception, cognition, motor movements, suppression of prolactin secretion (D2), elation, eupohria.

Related Pathophysiology: Schizophrenia, Parkinson's Tic, addiction.

Non-selective dopaminergic (D1/2) Antagonist

Rx: psychogenic disorders

OTC sedative used off-label as a mornign sickness drug.

Teratogenic

Resulted in limb malformations and Phocomelia (congenital disorder invoving the limbs and a wide range of other deformities).

Changed the way drugs are evaluated with regards to teratogenicity.

Drugs are now all assuemed to be teratogenic and confirmation of teratogenicity requires a charactaristic set of malformations that exert their effects during a particular stage of fetal development in a dose-dependant manner.

FDA now employs Pregnancy Categories to define the level of teratogenicity of drugs.

A (Adequate studies in PG women have not demonstrated risk in the 1st trimester with no indications of risk later).

B (Animal studies have demonstrated no risk but there are not adequate studies in PG women OR animal studies show risk but studies in PG women do not)

C (Anomal studies have shown adverse effects but no adequate human studies or animal reproductive studies).

D (Evidence of risk to human fetus but potential benefits may make this risk acceptable, esp in some emergency situations).

X (Human and animal studies demonstrate fetal risk which clearly outweighs benefits of use).

aka Accutane

Rx: Nodular acne

Well-documented teratogenicity (CNS malformationsm hydrocephalus, skull and head abnormalities, low IQ, thymic deficiency and more)

Pt are req to sign an informed consent, show 2 negative PG tests + monthly tests, abstain from sex or use 2 forms of birth control, and refrain from donating blood.

Fetal/Infant dose = Adult Dose x (fetal wt in kg/70kg)

* Note that even more accurate dosing can be acheived by using the SA and a dosing conversion chart).

GFR = (114 (0.8 x age) / serum creatinine

[*Use 0.85 for women]

Remember that serum creatinine is often within normal range and is not an indication of decline in renal fxn.

1) Osmotic Diuretics (Urea, Mannitol)

2) Chelators (Ca2+ EDTA for lead toxicity)

3) Volitile Anesthetics (Isoflourine)

Pharmacokinetic Equations

DR = ?

Effect = ?

[DR] = [R_t][D] / Kd + D

Effect = Effect_max [D] /  Kd + [D]

Where [DR]: concentration of Drug:Receptor Compex

R_t: Total receptors

Kd=K₂/K₁ (or affinity of D for R, the [D] that binds 50% of the receptors in a system)

[D]: concentration of drug

E_max: the max effect that can be acheived with a drug regardless of dose.

Tyrosine is imported into the neruon where it is converted →DOPA→Dopamine→Norepinephrine.

NE is concentrated in vesicles which are exocytosed in response to Ca2+ influx where they can either bind an Adrenoceptor (α or β), diffuse away, or be reuptaken into the neuron through a reuptake transporter.

This system is highly regulated:

NE itself negatively feeds back on α₂ release-modulating (presynaptic autoreceptor) receptors on the neuron which inhibits NE vesicle budding.

 ACh and ATII also act on presynaptic release-modulating receptors (ACh on M₂ receptors to inhibit NE release and ATII on its own receptors to promote NE release)

Full agonists have asigmoidal curve when their dosage is plotted against percent maximal effect and the upper limit reaches 100% of maximal effect.

Partial agonists have a depressed curve that shows that partial agonsits, though they act on the same receptor system as a full agonist, have a lower maximal effacacy regardless of the dose.

*In the presence of full agonists, partial agonists act as inhbitors*

Neutral Agonists bind the active and inactive recepor confirmations equally well inhbiting agonist binding and any deviation from constituitive levels of activity.

Inverse Agonists bind with higher affinity to the inactive form of the receptor thereby reducing constiuitive activity of the receptor.

Note that Potency is an independant factor (a partial agonist may be less, more or equally as potent as a full agonist)

(Pharmacological Antagonists)

Competitive Antagonists shift the dose-response curve to the right thereby decreasing potency and increasing EC₅₀

Remember that @ equillibirum binding of a competitive antagonist causes a right shift of the curve but that Non-equillibrium binding of a competitive antagonist causes curve depression and looks like the changes caused by a non-competitive antagonist (psudo-irreversible fashion)*

Noncompetitive Antagonists depress the dose-response curve, decreasing effacacy.

[image]

All adrenergics

(Alpha 1 and 2, Beta 1 and 2)

A quantitative comparison of drug effect to that of a standard drug on the same receptor.

How much of the drug do you need to acheive a given effect?

Is primarily determined by the affinity of the drug for the receptor and the number of availible receptors.

Potent drugs have a low Kd/EC50

Very high affinity binding drugs have Kd in the nanamolar and even subnanamolar range)

Potency is reduced (Kd/EC50 ↑) by competitive but not by non-competitive antagonists*

The maximal drug effect reflected as the plateau in the bindig curve.

Effacacy can be reduced by non-competitive but not by competitive antagonists.

Drugs that bind the receptor without activating it or prevents activation of a receptor by its agonist.

Can be competitive or non-competitive.

Thereputic Index

and

Thereputic Window

TI : TD₅₀/ED₅₀

Thereputic Window= Min Toxic [Drug] - Min Effective [Drug]

The larger the thereputic window the safer and easier to control the drug is.

aka Hypo-sensitivity

Noraml effects seen only at unusually high drug dosages.

Hypoactivity implies prior exposure to drug(?)

Inhbitory Concentration 50%

The concentration of an antagonist or partial agonist that reduces the activity of a known and labeled ligand by 50%.

The lower the IC₅₀ value the higher the affinity of the new antagonist/partial agonist has for the receptor (lower its Kd value).

Valium

Is an example of modulation of binding affinity.

Benzos promotoe the binding of GABA to its receptor by binding with an associated membrane component (a strong allosteric action that brings about Cl- channel opening).

Barbituates also have this effect.

Motor Control

Related Pathophysiology: Siezures, neurodegenerative diseases.

Perceptions, mood, sleep, pain suppression, arousal, central vascular tone (actions are similar to NE)

Related Pathophysiology: Hallucinations, depression, anxiety, OCD, eating disorders, neurogenic pain and vascular headaches.

An inhibitory NT involved in arousal, consciousness, motor control, muscle tone.

Related Pathophysiology: Anxiety, mania, seizures, spasticity.

A neurotransmitter that plays a role in food intake, lipid storage, locomotion, embryonic implantation and anxiety.

Related Pathophysiology: Septic shock, cirrhosis, cognition impairments.

The NT that binds cholinergic receptors (N and M types) in PNS (pre and post ganglionic), the NMJ (N), preganglionic fibers to the adrenal gland, somatic nerves, and in SNS when the target is a sweat gland*

Has been indicated to play a role in memory and motor movement.

Related Pathophysiology: Alzheimer's and Parkinson's

Those that release Nitric Oxide (NO)

Postganglionic fibers innervating the corpra cavernosa and blood vessels in sex organs.

NO → ↑cAMP and PK activation leading to inhibition of Ca2+ release and decreased sensitivity of myosin = Relaxation of Smooth Muscle*

Actions are ↓ or eliminated by sympathectomy, or tx with cocaine or reserpine (they require uptake to work)

COMT and MAO do not effect the duration of their actions.

Effects have longer duration than direct-acting sympathomimetics.

Have oral activity (unlike direct)

Receptor blockade still decreases their action (like it does with direct-acting)

Indirect Sympathomimetic

Taken up by the amine pump at teh nerve terminal and then pushes the NTs in the terminal out → ↑ [NT] in the synaptic cleft.

↑ [NE] (primary effect): ↑ alertness

Then, ↑ DA: Eupohria

↑ Serotonin: euporia then hallucination

Crosses BBB* however, amphetamine and ephedrine are the only sympathomimetics that have notable CNS actions.

Rx: Psychogenic disorders

Narcolepsy (bc NE is low in the brains of these pt)

Indirect Sympathomimetic

Taken up by the amine pump at the nerve terminal and triggers the release of NE.

Is found in many foods (wine, chees) and is normally metabolized by MAO-A*

When MAO-A is blocked (by Tranylcylcypromine or Phenelzine), Tyramine is absorved in the intestines and taken up into nerves, acts on the amine pump and causes ↑ NE that can cause a hypertensive crisis.

Mixed-Action Sympathomimetic

Acts directly on α₁ and β₂ receptors and indirectly by ↑ the release of NE (indirect actions on α₁, α2 and β₁)

Given with Reserpine you will see decreased function because reserpine dpeletes NE in nerve terminals.

Crosses BBB and (along with amphetamine) is one of the few sympathomimetics that has CNS fxn.

Rx: Narcolepsy (these pt have low NE levels in their brains).

Mixed-Action Sympathomimetic

Acts directly on α₁ receptors and indirectly by ↑ NE (via indirect actions on α₁,α₂, β₁)

Is a false NT: Is taken up, stored in vessicles, and released with NE.

Rx: when you want to temporarily increase BP (eg in cases of drug-induced hypotension, pheochromocytoma excision or othostatic hypotension)

*Note that any α₁ agonist can be used to do this*