Phenylephrine

Alpha 1 Agonist

Causes vasoconstriction and increased BP --> reflex decrease in HR

Clinical Uses

Sinus and nasal congestion

mydriasis (pupil dilation)

Hypotension

Alpha 2 Agonist

causes hypotension, bradycardia, sedation

Clinical Uses

hypertension

opiate agonist withdrawal

sever pain in cancer patients

ADHD

Beta 1 Agonist

stimulates heart (increases HR and contractility)

Clinical Uses

congestive heart failure

cardiogenic shock

septic shock

Beta 2 Agonist

bronchdilators

little effect on beta 1 receptors

Clinical Uses

asthma

treatment of hyperkalemia (albuterol)

inhibition of uterine contraction in premature labor (terbutaline)

Indirect Adrenergic Receptor Agonist

• present in cheese, fermented sausage and wines
• enters synaptic vesicle and causes displacement and release of NE
• tyramine is normally degraded by MAO
• treatment w/ MAOI's in conjunction w/ foods containing tyramine causes:
• rapid release of NE
• severe hypertension

Indirect Adrenergic Receptor Agonist

• stimulates release of NE
• directly acts on beta and alpha receptors
• ephedrine is not a substrate for MAO or COMT
• lipid soluble, crosses BBB

Clinical Uses

astham, orthostatic hypotension, nasal congestion, depression

Indirect Alpha and Beta Agonist

stimulates release of NE

presumed to cross placenta and BBB (pseudo)

Clinical Uses

nasal congestion, urinary incontinence due to urethral sphincter weakness (pseudo)

Indirect Adrenergic Receptor Agonist

• facilitates release and blocks reuptake of NE
• has minimal peripheral sympathomimetic effects
• CNS stimulant due to release and blockage of reuptake of dopamine in limbic regions of brain
• No activation of beta 2 receptors

Clinical Uses

ADHD, narcolepsy, obesity

Indirect Adrenergic Receptor Agonist

• facilitates release and blocks reuptake of NE
• causes tachycardia and hypertension
• CNS stimulant due to release and blockage of reuptake of dopamine in limbic regions of the brain

Clinical Uses

local anesthesia, ophthalmic anesthesia

CNS, peripheral neurons, gastric parietal cells

Coupled with Gq protein

• Heart, presynaptic terminals of peripheral and central neurons
• Coupled with Gi protein
• In the postganglionic terminal, M2 receptors located on the presynpatic autoregulate cholinergic transmission by inhibiting ACh release

glandular secretion (bronchial, salivary, sweat), contraction of visceral smooth muscle 

Coupled with Gq proteins

Localized in CNS

Coupled with Gi protein

Localized in CNS

Coupled with Gq proteins

Non-Depolarizing Blocking Agent

Found in various dart poisons in South America

Blocks postsynaptic ACh receptors

Non-Depolarizing Blocking Agent

 Found in venom of the elapid

Blocks ACh repectors

Muscarinic Agonist

bladder emptying, stimulate GI motility

Muscarinic Agonist

glaucoma

Muscarinic Agonist

-Used for Glaucoma

-Causes miosis (pupil constriction)

Muscarinic Antagonist

 mydriasis (pupil dilation), adjunct for anesthesia, anticholinesterase poisoning, bradycardia, GI hypermotility

Muscarinic Antagonist

bronchodilator

Muscarinic Antagonist

motion sickness

Muscarinic Antagonist

mydriasis (pupil dilation)

Muscarinic Antagonist

Mydriasis (pupil dilation)

Non-Depolarizing Blocking Drug

muscle relaxant in anesthesia

Non-Depolarizing Blocking Drug

muscle relaxant in anesthesia

Non-Depolarizing Blocking Drug

muscle relaxant in anesthesia

Non-Depolarizing Blocking Drug

rarely used; muscle relaxant

• competitive reversible antagonists
• Blockade of ACh access to its receptor
• blocks endplate potential which blocks the initiation of an action potential in the skeletal muscle
• anticholinesterase can reverse the effects because it results in an increase in ACh at the synaptic cleft

1. Fall in aterial pressure due to ganglion block
2. Release of histamine from mast cells
3. Tachycardia (increased HR) due to blockade of mAChR's in the heart

Depolarizing Blocking Drug

• excess depolarizing agonist
• maintains endplate membrane depolarization
• prevents transmission of another action potential 

Phase I Block

Caused by Depolarizing Blocking Drugs

1. binding of succinylcholine to nicotinic receptors
2. unorganized opening of ion channels and Na+ influx
3. depolarization of muscle cell end-plate membrane
4. generalized disorganized contraction of muscles
5. Membranes remain depolarized and unresponsive
6. results in flaccid paralysis (reduced muscle tone)

Caused by Depolarizing Blocking Drugs

1. repeated dosing and increased concentration of  succinylcholine
2. decreased endplate depolarization due to inactivated nAChR's
3. repolarization of membrane
4. membrane becomes desensitized and depolarization by ACh cannot occur

Ganglion Stimulant

Used clinically for smoking cessation

Ganglion Stimulant

No Clinical Uses

Ganglion Stimulant

No Clinical Uses

Ganglion Stimulant

No Clinical Uses

Ganglion Blocking Drug

Side Effects:

-no venoconstricition so when you stand up, this results in a sudden fall in CO and arterial pressure (postural hypotension)

-decrease in secretions (saliva, tears, sweat)

-poor circulation --> causes chills

-constipation and urine retention

Ganglion Blocking Drug

Controlled hypotension during surgery

Acetylcholinesterase

• bound to basement membrane in the synpatic cleft at cholinergic synapses
• specificity for ACh and closely related esters

AKA Pseudocholinesterase, Plasma Cholinesterase

• Wide distribution; liver, skin, brain, GI smooth muscle, plasma
• Not associated with cholinergic synapses
• Broader substrate specificity (procaine, succinylcholine, propanidid)

Edrophonium

Short Acting Anticholinesterase

• Reversible
• Used in diagnosis of myasthenia gravis

Medium Duration Anticholinesterase

• Myasthenia gravis
• Transfers carbamyl group to cholinesterase which inactivates the enzyme
• Carbamyl group is difficult to hydrolyze and reactivation of the enzyme takes awhile

Medium Duration Anticholinesterase

• Myasthenia gravis
• Transfers carbamyl group to cholinesterase which inactivates the enzyme
• Carbamyl group is difficult to hydrolyze and reactivation of the enzyme takes awhile

Medium Duration Anticholinesterase

• Glaucoma
• Transfers carbamyl group to cholinesterase which inactivates the enzyme
• Carbamyl group is difficult to hydrolyze and reactivation of the enzyme takes awhile

Irreversible Anticholinesterase

• Used as an insecticide
• Dyflos phosphorylates cholinesterase
• No appreciable hydrolysis occurs and new enzyme must be made

Irreversible Anticholinesterase

• Used as a an insecticide
• Parathion phosphorylates cholinesterase
• No appreciable hydrolysis occurs and new enzyme must be made

Irreversible Anticholinesterase

• Glaucoma
• Ecothiopate phosphorylates cholinesterase
• Slow hydrolysis occurs over days

Autonomic Synapses: enhances ACh activity

Neuromuscular Junction: reverses effects of tubocurarine or myasthenia gravis (tubo. blocks ACh access to nAChR so enhancing ACh activity by blocking acetylcholinesterase activity reverses tubo.'s effects)

CNS: convulsion, depression, unconsciousness, respiratory failure, used to treat dementia

Neurotoxicity of Organophosphates: peripheral nerve demyelination leading to slowly developing weakness and sensory loss

• Chronic autoimmune neuromuscular disease
• Caused by a defect in the transmission of nerve impulses to muscles
• Autoantibodies block, alter, or destroy nAChR's at the neuromuscular junction

Symptoms:

1. facial muscle weakness, drooping eyelids
2. double vision
3. difficulty in breathing, talking, chewing, or swallowing
4. muscle weakness in arms or legs
5. fatigue brought on by repetitive motions

Sympathomimetic = mimics actions of NE and epinephrine, increase sympathetic activity

Sympatholyitc      = decrease sympathetic activity

Chronotrophic Effects vs Inotrophic Effects

Chronotrophic = increases HR

Inotrophic      = increases contractility

Non-Selective Alpha Blocker

• Irreversible alpha 1 and alpha 2 receptor blockade
• Blocks catecholamine-induced vasoconstriction
• Causes postural hypotenstion, tachycardia

 Clinical Uses

• Pheochromocytoma
• Used to correct sever hypertension

Phentolamine

Non-Selective Alpha Blocker

• Potent competitive reversible alpha 1 and alpha 2 blocker
• Causes postural hypotension and tachycardia

Clinical Uses

• Pheochromocytoma
• Used to treat episodes that occur during surgical removal of the tumor

Selective Alpha 1 Blocker

• Reversible Antagonist
• Causes dilation of arterial and venous smooth muscle
• Effective in the management of chronic hypertension
• Causes less tachycardia compared to non-selective blockers because alpha 2 receptors are not blocked

Selective Alpha 2 Blockers

• Used in treatment of male impotence
• Proposed to block central alpha 2 receptors thereby producing an increase in sympathetic output

1. Postural Hypotension
2. Reflex Tachycardia
3. Inhibition of ejaculation
4. Nasal Stuffiness

• Have equal affinity for beta 1 and beta 2 receptors
• Decrease Heart Rate
• Reduce the force of cardiac contraction
• Peripheral resistance increases initially as a result of blocking beta 2 receptors in blood vessels (when NE and E bind to beta 2 receptors, they normally cause relaxation of blood vessles)
• long-term use of beta blockers decrease peripheral resistance

Non-Selective Beta Blocker

Potent reversible beta 1 and beta 2 receptor antagonist

Blocks positive Chronotrophic (HR) and Inotrophic (contractility) effects on the heart

Effects are more dramatic during exercise

Clinical Uses

1. Various cardiovascular diseases
2. hypertension
3. angina
4. dysrhythmia
5. postmyocardial infarction

Patients with diabetes

• Blocks metabolic effects of beta receptor stimulation (inhibits lipolysis and glycogenolysis)
• Can increase insulin-induced hypoglycemia

Patients with asthma

• beta 2 receptor blockade can increase airway resistance
• selective beta 1 blockers should be used

Patients with heart disease

• contraindicated in patients with sinus bradycardia, partial heart block, and congestive heart failure
• cardiac output is decreased with beta blockers
• Withdrawal symptoms (angina, tachycardia, dysrhythmias) may develop after withdrawal from long term patients

Non-Selective Beta Blocker

Used orally for hypertension and angina, and topically for treatment of glaucoma

• Hypertension
• Angina
• Heart Failure
• Migraine Prophylaxis (Metoprolol, Atenolol)
• Tremor (Metoprolol)

Inhibits Synthesis of NE

• by inhibiting tyrosine hydroxlyase --> decreased dopamine, NE, Epinephrine
• Used in patients with Pheochromocytoma

Inhibits synthesis of NE

• Blocks peripheral DOPA decarboxylase activity ---> decreased formation of dopamine (no effect on NE)
• Does not cross BBB; used to treat patients with Parkinson's disease along with L-DOPA and Entacapone

Prevents Storage of NE

decreases storage of NE which leaks from vesicles and is deaminated by MAO

decreased peripheral resistance, Cardiac Output, and Blood Pressure

Used in low doses with diuretics to treat mild hypertension

Long duration of action

Inhibits release of NE

• transported to presynaptic nerve terminal by uptake 1
• decreases release of NE in response to action potentials or indirect acting sympathomimetics
• doesn't cross BBB
• decreases response of alpha and beta

Side Effects

1. decreased BP, HR, and CO
2. postural hypotension
3. increased gut motility and diarrhea

Inhibits release of NE

• initially release NE from adrenergic nerve terminals
• blocks NE reuptake
• accumulates in noradrenergic sympathetic neurons ---> decreased release of NE
• used for IV treatment of ventricular dysrhythmias

Reduction in CNS sympathetic outflow

• activate alpha 2 receptors in hypothalamus and medulla
• results in decreased sympathetic outflow which results in decreased total peripheral resistance, HR, CO, and BP

Antidote to Organophosphate Poisoning

-if taken within 5 hrs of exposure to irreversible anticholinesterase drugs, it can still reactivate the enzyme

-antidote for sarin, tabun, soman

• Inhibition of synthesis of NE
• Blocks dopamine to NE (DBH)

Selective Alpha 1 Agonist

treats nasal decongestion

Presynaptic Activity

• Inhibits ACh synthesis
• Taken up through the same transporter and reacts w/ choline and is then stored in the vesicle  --> when released, cannot cause effects because ACh cannot bind to nAChR
• Precursor to cholinergic false transmitter

Indirect Acting Adrenergic Agonist

stimulate NE release

directly acts on alpha and to a lesser degree on beta receptors

Uses:

Nasal congestion

Muscarinic Receptor Antagonist

No CNS effect --> Do not penetrate BBB

Uses:

 GI hypermotility

• Inhibits COMT --> increased NE because it cannot be degraded by COMT
• Treatment for Parkinson's Disease

Muscarinic Receptor Antagonist

• Selective for M1
• Inhibits gastric secretion

• Antidote for malignant hyperthermia (intense muscle spasm caused by genetic mutation in Ryanodine Receptor)
• Malignant hyperthermia is a side effect of depolarizing blocking agents (succinylcholine)

Presynaptic Activity

-Inhibit ACh release

-Aminoglycoside antibiotics

-blocks Ca2+ entry into nerve terminal --> cannot stimulate exocytosis

Irreversible Anticholinesterase Organophosphates

-War gases

-Results in SLUDGE

Presynaptic Activity

-inhibit ACh synthesis

-blocks reuptake of choline by choline transporter at presynaptic membrane