Week 2

Catechol

A type of organic compound that contains a catechol ring

Two OH’s on a benzene ring next to each other

Catecholamine

A group of hormones and neurotransmitters in the body

Autoreceptor

Own neuron that released it

Sympathomimetics

Drug that mimics sympathetic nervous system

Sympatholytic

Drug that decreases activity of sympathetic nervous system

Baroreceptor reflex

A natural bodily mechanism that helps regulate blood pressure

Monoamine oxidase (MAO)

An enzyme in the body that breaks down certain important neurotransmitters called mono amines, including serotonin, dopamine, and norepinephrine

• Bound to outer membrane of mitochondria

• Two iOS forms: MAO-A and MAO-B

• Oxidizes amine to carbonyl

Catechol-O-methyl transferase (COMT)

An enzyme in the body that plays a role in the breakdown and inactivation of certain neurotransmitters and catecholamines, such as dopamine, epinephrine, and norepinephrine

• Predominantly cytotoxic

• Significant expression in hepatic tissue

• Methylates the meta hydroxy group

Cheese reaction

A potential interaction when eating cheese and medications with monoamine oxidase

Norepinephrine transporter (NET)

Takes norepinephrine from the synaps back to the neuron

Renin

Substance produced by kidney (blood pressure)

Adrenergic Neurotransmitters

• Adregengic neurons utilize the amino acid tyrosine to synthesize catecholamine neurotransmitters

  • Norepinephrine

  • Epinephrine

  • Dopamine

Catecholamine Metabolism

• Catecholamine neurotransmitter may be recycled or metabolized

  • About 90% of NE taken back up by NET

Focus on the green boxes

Minimum requirements for binding ARs

1. Aromatic ring

2. Basic nitrogen

3. Carbon bridge (two C’s between 1 and 2)

OH

Decreases lipophilicity

Enhances binding alpha and beta receptors

R stereochemistry

Enhances binding alpha and beta receptors

Methlation

Increases stability (MAO) and lipophilicity

Increases potency

1 to 3 carbons (on nitrogen)

Beta selective

4 or more carbons (on nitrogen)

Beta 2 selective

For non essential

Removal of the OH’s will increased stability and increases lipophilicity

Alkyl substituents to on nitrogen increases…

Beta selectivity

(Picture) Para-hydroxyl (4‘) more important for…

Beta activity

Also affects beta 1 & beta 2 selectivity

Norepinephrine

Epinephrine

Isoproterenol

Albuterol

Phenylephrine

Contraction of arterial strips (alpha 1 receptor)

Relaxation of bronchial smooth muscle (beta 2 receptor)

Augmented contraction of heart (beta 1 receptor)

Ruler of the circulatory system

Mean arterial pressure

Know this

Adrenergic receptors activity maintains homeostasis; key cardiovascular effects of agonists include:

alpha 1

Alpha 2

Beta 1

Beta 2

Vasoconstriction, venous tone

Decreases central sympathetic outflow

Increases heart rate and contractility, contractile force

Airway and vascular dilation

Catecholamine (dopamine, NE, Epi)

• Synthesized from amino acids (tyrosine)

• Reuptake: important mode of signal termination

• Degraded MAO and COMT

Structure-activity relationships: key considerations for affinity and selectivity at Adrenergic receptors

• stereochemistry

• Groups on nitrogen

• Groups on aromatic ring

D. Beta 2

Pressor

Anything that increases blood pressure

Endotracheal administration

Delivering medication to the windpipe (trachea) through the mouth or nose

Intracavernous administration

Injection of medication or substances directly into a specific cavity or chamber

Imidazoline

a chemical compound that is often found in various medications and substances

Usually beta receptors

Xerostomia

Dry mouth

Hypokalemia / Hyperkalemia

Low/high potassium

AV node

A node located in the middle of your heart

SABA and LABA

Short / long acting beta agonist

Hypertensive crisis

A severe and potentially life-threatening increase in blood pressure

Hemolytic anemia

A medical condition where the red blood cells in the bloodstream break down or are destroyed more rapidly than the body can replace them

Pheochromocytoma

a rare, usually non-cancerous tumor that develops in the adrenal glands, which are located on top of the kidneys

Studying for adregenerics

1. What happens when stimulated or inhibited

2. Focus on MOA

3. Chemistry: a little knowledge about structure will go long way

   1. Use concept maps, charts, mnemonics

Sympathosmimetic

A substance that enhances activity of the sympathetic nervous system

1. Direct acting

   1. A1 and B agonists, a2 antagonists

2. Indirect acting

   1. Releasing agents

   2. Reuptake inhibitors

3. Mixed acting

Endogenous Catecholamines

Considerations:

• Effects are often dose dependent

• Therapeutic uses: will generally be used in emergency / critical care settings

  • Hemodynamic support

  • Inotropic support

• Pharmacokinetics: no oral availability, doesn’t cross BBB; COMP and MAO substrates

• Common ADRs:

  • CV (hemodynamics, palpitations, arrhythmias)

  • CNS (headache, anxiety)

  • Other (N/V, hyperglycemia (epi), polyuria (dopamine))

• Drug interactions and therapeutic considerations:

  • Other Adrenergic / hemodynamic agents

  • Pregnancy category C

  • IV administration

Direct acting: B agonists

• Increase cardiac output

• Increase smooth muscle relaxation

  • Lungs, uterus, smooth muscle

• Therapeutic uses:

  • Inotropic support, bradycardia, arrhythmias, AV noda block

• Class considerations

  • Usually inhalation or IV administration

  • Selectivity

    • 4’ hydroxy and size of R group on amine

  • Hemodynamics (may increased and or lower BP)

  • Increase glucose

• Common ADRs: CNS (headache. Anxiety, insomnia), tremor, hemodynamic instability, hypokalemia, vision disturbances

Direct acting: B2 agonists

• Mediate bronchodilation

• Chemistry considerations

  • B2 selectivity enhanced by modification of catechol group and large R group on amine

    • Resorcinol or hydroxymethyl group

    • These chagnes also increase stability by decreasing susceptibility to COMT and MAO

  • Long acting B2 agonists (LABAs) utilize very large, lipophilic R groups

• Used for respiratory conditions

  • Typically administered by inhalation

What is the direct effect?

What is the reflex response?

Albuterol (Ventolin)

Extended Duration B2 agonists

Mixed Acting: Ephedrine (Akovaz) and Pseudoephedrine (Sudafed)

Sympatholytics

A substance that inhibits activity of the sympathetic nervous system

1. Indirect acting: principal activity at presynaptic adrenergic receptors (ARs) or do not bind AR

   1. A2 agonists (centrally acting)

2. Direct (peripherally) acting: bind the ARs

   1. A selective antagonists

   2. B selective antagonists (1st generation)

      1. b1 selective antagonist (2nd generation)

   3. non-selective a and b antagonists (3rd generation)

Direct acting: a antagonists

Selectivity:

• Non selective a1 and a2

• Selective: activity at a1

• Consideration: how would you expect the effects of selective vs non selective agents to differ

Significant chemical diversity

Therapeutic uses: non selective

• Pheochromocytoma

• Hypertension

• Benign prostatic hyperplasia (BPH)

Direct acing: a1 antagonists

• Pharmacology: mechanism considerations

  • Inhibits a1 receptors (reduces vasoconstriction)

  • Relatively more NE to bind a2 receptors

• Pharmacological distinctions: two groups

  • Low a1 subtype selectivity: (a1a, A1b, a1d)

  • A1 subtype selective: a1a

• Chemistry distinctions: two groups

  • Piperazynl quinoa olives

  • Benzenesulfonamides/ analogs

• Therapeutic uses

  • Hypertensin

  • Benign prostatic hyperplasia BPH

Prazosin

Tamsulosin

Direct acting: b antagonists

Selectivity

• Non selective (1st gen): activity at b1 and b2

• Selective (2nd gen): activity at b1

• Mixed (3rd gen): activity at a and b

Therapeutic uses

• Arrhythmias

• Ischemia heart disease

• Cardiovascular Disorders

• Additional conditions

B antagonists: Common ADRs

• Cardiovascular

• CNS

• Endocrine

• Other

• Boxed warning

Additional considerations: b antagonists

Hydrophilic vs. Lipophilic

B antagonists: Chemisty considerations

• Required: aryloxypropanolamine

• For b1 selectivity:

  • Para- (4’) group with H-bond acceptor (heteroatom with lone pair of electrons)

• For mixed a and b activity:

  • Larger, aromatic-containing group attached to amine

    • Review structures of a1 antagonists

ISA

Partial agonist

Non-selective b antagonists

• Non selective b1 and b2 antagonists

  • Decrease CO (HR and conractility)

  • Effect dependent on sympathetic tone

  • Reduce renin release (b1); decreased BP over time

• Caution in patients with respiratory or metabolic diseases

D

Goals of Metabolism

• Contribute to elimination

• Reduce toxicity

• Convert to active moieties

Understanding xenobiotic metabolism

Drug → liver → cytochrome p450 → metabolism

Most xenobiotics are hydrophobic chemicals that are normally accumulated

Metabolism convert hydrophobic chemicals into more hydrophilic derivatives that are easily eliminated through the urine or bile

Accomplished via cytochrome p450 enzymes

Give me ⭐️⭐️⭐️⭐️⭐️

Which of the following is accomplished with xenobiotic metabolizing enzymes?

A. Increased hydrophilicity of the xenobiotic

B. Decreased hydrophilicity of the xenobiotic

C. Increased lipophilicity of the xenobiotic

D. Decreased lipophilicity of the xenobiotic

A & D

Why is Metabolism necessary?

• Termination or alteration of a drug

  • The alternate method of termination is renal excretion

• Metabolic products can be:

  • Less phacodynamically active than the parent drug and may be inactive

  • Biotransfermation products with enhanced activity or greater toxic properties

  • Inactive prodrugs that are converted to active molecules via drug-metabolizing enzymes

Metabolism and Clearance

• Renal excretion is most effective when xenobiotics possess polar characteristics; FG that are fully ionized at physiological level

• Most active drugs tend to be lipophilic and remain unionized or partially ionized-

• Hence: metabolism assists the chemical conversion so that excretion of the drug is more efficient

General Pathway of Drug Metabolism

Main goal of first pass effect

Metabolism

(Metabolism → biotransformation)

Phase I vs. Phase II

Prodrugs

1. Patient takes an inactive form of a drug

2. Inactive form is converted by CYP enzymes to either active or inactive metabolites

3. Active metabolites prolong the bioavailability of the drug

4. Inactive metabolites are not bioavailable

Also know which make drugs hydrophilic and hydrophobic

Which structure will increased clearance, half-life, therapeutic window, bioavailability, distribution

Phase I: Redox and Drugs

Oxidation and reduction refers to the overall oxidation state of the drug

Phase I: Oxidation

• Increase of oxidation state of a substance by:

  • Removal of electrons

• Change in polarity

  • Increased polarity of covalent bond to create increase partial charge

• With regards to drugs:

  • Replace hydrogen or carbon on a drug molecule with oxygen

  • May form active or inactive metabolites

• Requirements:

  • Oxidizing agent

  • Enzyme

Phase I: CYP450 Catalytic Cycle Hydroxylation

• Embedded in the lipid bilateral of the ER and mitochondria in hepatocytes

• P450 oxidizes or reduces drugs using a reactive heme ring

• Iron is the electron acceptor or donor

• NADPH is a co-factor

Phase I: Common hydroxylations

Phase I: Dealkylations

Phase I: Deamination

Phase I: Hydrolysis

Phase II

Conjugation of the phase I metabolite (or drug) with an endogenous substrate (increases polarity)

Phase II: Glucuronidation

• Most common pharmacological phase II pathway

• Typically coupled with many phase I oxidation products

Phase II requires

IRON

OTC

Over-the-counter

Herbal

Plants used for medicinal purposes

Boxed warning

A serious and prominent warning placed on the packaging, label, or informational materials for certain prescription drugs

Polyvalent cations

Ions that have multiple positive charges

Ca2+ Fe2+ Fe3+ ✅

H+ Na+ K + ❌

Enol

OH attached to a double bond

Insoluble complex

Type of chemical that doesn’t dissolve or mix well in water or other solvents

Enols create insoluble complex

Booster

Prodrug

A medication that is inactive or less active when you take it but becomes active when processed in your body.

Improve absorption, stability, and reduce side effects

Inhibitor

Interferes with or limits the function of enzymes, reactions, or other process

Inducer

Triggers or encourages a specific process or activity

Substrate

A substance that undergoes a chemical reaction or is acted upon by an enzyme