NAPLEX Pharmacy Foundations 1: Chapter 2 Basic Science Concepts

Define substrate (or ligand)

A substance that creates a signal or produces an effect by binding to a receptor, enzyme, or transporter

Define endogenous

A substance produced by the body (such as a naturally produced substrate)

Define exogenous

Substances produced outside of the body (e.g. drugs and chemicals)

Define agonist

A substance that combines with a receptor to initiate a reaction

Can be endogenous or exogenous (i.e. mimicking an endogenous substrate)

Define antagonist

A substance that combines with a receptor and blocks or reduces a reaction by preventing the agonist from binding to the receptor

Can be endogenous or exogenous

Define induction

When a substance increases the activity of an enzyme

induction = increase

Define inhibition

When a substance decreases or blocks the activity of an enzyme

What makes up the central nervous system (CNS)?

brain and spinal cord

What does the CNS control? How?

Controls bodily functions by sending signals to the peripheral nervous system (PNS)

What are the two systems of the PNS?

somatic nervous system and autonomic nervous system

What does the somatic nervous system control?

skeletal muscles (i.e. voluntary movements)

What does the autonomic nervous system control?

Digestion, cardiac muscle, BP (i.e. involuntary actions)

How is signal transmission between the CNS and PNS accomplished?

Via Neurotransmitters (NTs)

What are neurotransmitters? Where are they released?

chemical messengers released by presynaptic neurons

What are common neurotransmitters?

Acetylcholine (ACh)

Epinephrine (Epi)

Norepinephrine (NE)

Dopamine (DA)

Serotonin (5-HT)

What is the primary NT involved in the somatic nervous system?

ACh

What receptors in the skeletal muscles do ACh bind to affect muscle movement?

nicotinic receptors (Nn)

What are the two divisions of the autonomic nervous system?

Parasympathetic nervous system (PSNS) and sympathetic nervous system (SNS)

What is the PSNS responsible for?

rest and digest

How does the PSNS work?

Releases ACh, which binds to muscarinic receptors throughout the body (e.g. GI tract, bladder, eyes)

What is the physiologic response to activation of the PSNS?

increased SLUDD

What does SLUDD stand for?

Salivation

Lacrimation

Urination

Defecation (peristalsis)

Digestion (peristalsis)

What is SNS known as?

fight or flight

How does the SNS work?

Releases Epi and NE, which act on adrenergic receptors (alpha-1, beta-1, and beta-2) in the cardiovascular and respiratory systems

What is the physiologic response on SNS activation?

increased BP, HR, and bronchodilation

Describe the process and effects of a substrate binding to a receptor

A substrate (ligand) binds to a receptor. The receptor-substrate complex causes a signal cascade into the cell which causes a biologic effect/response

Describe competitive inhibition

Occurs when an antagonist binds to the same active site of a receptor as the endogenous substrate, thus preventing it from binding

Describe non-competitive inhibition

Occurs when an antagonist binds to the receptor at a site other than the active site (i.e. allosteric site), which changes the shape of the active site and prevents the endogenous substrate from binding

True or False: Some medications affect multiple receptors.

True

What are a couple examples of drugs that affect multiple receptors?

1) Isoproterenol: mixed beta-1 and beta-2 agonist

2) Carvedilol: alpha-1, beta-1, and beta-2 antagonist

3) Vasopressors: stimulate alpha-1 and beta-1 receptors

How does clonidine affect the amount of NT released and available to the PNS?

Clonidine acts centrally as an agonist of the alpha-2 adrenergic receptors. Stimulation reduces release of Epi and NE and decreases sympathetic output

For Muscarinic Receptors:

Endogenous Substrate?

Agonist Action?

Drug agonists?

Antagonist Action?

Drug antagonists?

Endogenous Substrate: ACh

Agonist action: ↑ SLUDD

Drug agonists: pilocarpine, bethanechol

Antagonist action: ↓ SLUDD

Drug antagonists: atropine, oxybutynin

For Nicotinic Receptors:

Endogenous Substrate?

Agonist Action?

Drug agonists?

Antagonist Action?

Drug antagonists?

Endogenous Substrate: ACh

Agonist Action: ↑ HR, BP

Drug agonists: Nicotine

Antagonist Action: Neuromuscular blockade

Drug antagonists: Neuromuscular blockers (e.g. rocuronium)

For Alpha-1 Receptors (mostly peripheral):

Endogenous Substrate?

Agonist Action?

Drug agonists?

Antagonist Action?

Drug antagonists?

Endogenous Substrate: Epi, NE

Agonist Action: Smooth muscle vasoconstriction, ↑ BP

Drug agonists: Phenylephrine, dopamine (dose-dependent)

Antagonist Action: smooth muscle vasodilation, ↓BP

Drug antagonists: Alpha-1 blockers (e.g. doxazosin, carvedilol, phentolamine)

For Alpha-2 Receptors (mainly brain; central):

Endogenous Substrate?

Agonist Action?

Drug agonists?

Antagonist Action?

Drug antagonists?

Endogenous Substrate: Epi, NE

Agonist Action: ↓ release of Epi and NE, ↓BP, HR

Drug agonists: Clonidine, brimonidine (ophthalmic for glaucoma)

Antagonist Action: ↑ BP, HR

Drug antagonists: Ergot alkaloids, yohimbine

For Beta-1 Receptors (mainly heart):

Endogenous Substrate?

Agonist Action?

Drug agonists?

Antagonist Action?

Drug antagonists?

Endogenous Substrate: Epi, NE

Agonist Action: ↑ myocardial contractility, CO, HR

Drug agonists: dobutamine, isoproterenol, dopamine (dose-dependent)

Antagonist Action: ↓ CO, HR

Drug antagonists: Beta-1 selective blockers (metoprolol) and non-selective beta blockers (carvedilol, propranolol)

For Beta-2 Receptors (mainly lungs):

Endogenous Substrate?

Agonist Action?

Drug agonists?

Antagonist Action?

Drug antagonists?

Endogenous Substrate: Epi

Agonist Action: bronchodilation

Drug agonists: albuterol, terbutaline, isoproterenol

Antagonist Action: bronchoconstriction

Drug antagonists: Non-selective beta blockers (carvedilol, propranolol

For Dopamine Receptors:

Endogenous Substrate?

Agonist Action?

Drug agonists?

Antagonist Action?

Drug antagonists?

Endogenous Substrate: Dopamine

Agonist Action: Many, including renal, cardiac, and CNS effects

Drug agonists: Levodopa, pramipexole

Antagonist Action: Many, including renal, cardiac, and CNS effects

Drug antagonists: 1st Gen antipsychotics, (e.g. haloperidol), metoclopramide

For Serotonin Receptors:

Endogenous Substrate?

Agonist Action?

Drug agonists?

Antagonist Action?

Drug antagonists?

Endogenous Substrate: 5-HT

Agonist Action: Many, including platelet, GI, and psychiatric effects

Drug agonists: Triptans (e.g. sumatriptan)

Antagonist Action: Many, including platelet, GI, and psychiatric effects

Drug antagonists: Ondansetron, 2nd Gen/Atypical antipsychotics (e.g. quetiapine)

What is an enzyme?

Compounds that speed up (catalyze) a reaction

How do substrates interact with enzymes?

Can be agonistic or antagonistic and competitive or non-competitive

What NTs is MAO (monoamine oxidase) enzyme responsible for breaking down?

Catecholamines:

Dopamine

Epi

NE

5-HT

What occurs when multiple drugs work similarly at the same receptor or enzyme?

Additive effects, which can be detrimental

What AEs can occur due to additive effects with MAO inhibitors? Why?

Hypertensive crisis

Serotonin syndrome

Occurs due to excess catecholamine accumulation

Examples of drug classes that can cause additive effects with MAO inhibitors?

SSRIs

SNRIs

TCAs

Etc.

For the Acetylcholinesterase enzyme:

Endogenous effects?

Drug Inhibitors?

Drug Action?

Endogenous effects: breaks down ACh

Drug Inhibitors: donepezil, rivastigmine, galantamine

Drug Action: Inhibits acetylcholinesterase, resulting in ↑ ACh

For the Angiotensin-Converting Enzyme (ACE):

Endogenous effects?

Drug Inhibitors?

Drug Action?

Endogenous effect: converts angiotensin I to angiotensin II

Drug Inhibitors: ACE-inhibitors (e.g. ramipril, lisinopril)

Drug Action: inhibits conversion of angiotensin I to angiotensin II, resulting in ↓ vasoconstriction and ↓ aldosterone secretion

For the Catechol-O-methyltransferase (COMT) enzyme:

Endogenous effects?

Drug Inhibitors?

Drug Action?

Endogenous effects: Breaks down levodopa

Drug Inhibitors: COMT-inhibitor (entacapone)

Drug Action: Inhibits the COMT enzyme to prevent peripheral break down of levodopa, resulting in ↑ duration of action of levodopa

For the Cyclooxygenase (COX) enzyme:

Endogenous effects?

Drug Inhibitors?

Drug Action?

Endogenous effects: converts arachidonic acid to prostaglandins (cause inflammation) and thromboxane A2 (causes platelet aggregation)

Drug Inhibitors: NSAIDs (e.g. aspirin, ibuprofen)

Drug Action: Block COX enzymes to ↓ prostaglandins and thromboxane A2

For the Monoamine oxidase (MAO) enzyme:

Endogenous effects?

Drug Inhibitors?

Drug Action?

Endogenous effects: Breaks down catecholamines

Drug Inhibitors: MAO inhibitors (MAOIs): phenelzine, isocarboxazid, tranylcypromine, selegiline, rasagiline

Drug Action: Inhibits MAO which ↑ catecholamine levels

For the Phosphodiesterase (PDE) enzyme:

Endogenous effects?

Drug Inhibitors?

Drug Action?

Endogenous effects: Breaks down cGMP, a smooth muscle relaxant

Drug Inhibitors: PDE-5 inhibitors (e.g. sildenafil, tadalafil)

Drug Action: Competitively binds to the same active site as cGMP on the PDE-5 enzyme, preventing the breakdown of cGMP and prolonging smooth muscle relaxation

For the Vitamin K epoxide reductase (VKOR) enzyme:

Endogenous effects?

Drug Inhibitors?

Drug Action?

Endogenous effects: converts vit. K to the active form required for production of clotting factors

Drug Inhibitors: Warfarin

Drug Action: Inhibits VKOR enzyme which ↓ production of clotting factors II, IV, IX, and X

For the Xanthine Oxidase enzyme:

Endogenous effects?

Drug Inhibitors?

Drug Action?

Endogenous effects: Breaks down hypoxanthine into xanthine and then xanthine into uric acid

Drug Inhibitors: Xanthine oxidase inhibitor: allopurinol

Drug Action: Blocks xanthine oxidase enzyme which decreases uric acid production

What is structure-activity relationship?

the relationship between the molecular structure of a drug and its activity

Celecoxib structure

Has a sulfa group

Procaine structure

Lidocaine structure

What are the neutral functional groups?

Hydroxyl or alcohol (primary)

Ketone

Aldehyde

Amide

Nitrate

Nitro

Aromatic (Benzo) ring

Urea

Carbonate

Carbamate

Ether

Thioether

Hydroxyl functional group

Ketone functional group

Aldehyde functional group

Amide functional group

Nitrate functional group

Nitro functional group

Benzene ring

Urea functional group

Carbonate functional group

Carbamate functional group

Ether functional group

Thioether functional group

What are the acidic functional groups?

Carboxyl

Phenol

Imide

Sulfonamide

Carboxyl functional group

Phenol functional group

Imide functional group

Sulfonamide functional group

What are the basic functional groups?

Amine (primary and tertiary)

Imine

Amidine

Primary Amine functional group

Tertiary amine functional group

Imine functional group

Amidine functional group

Beta-lactam Ring

Define stability of a drug

the extent to which a product retains, within specified limits, and throughout its period of storage and use (i.e. the shelf-life), the same properties and characteristics it possessed at the time it was made

TL:DR the extent to which a drug retains is properties and characteristics compared to when it was made

What factors indicate compromised drug stability?

Changes in texture, color, smell, or development of precipitates

In terms of functional groups, what common causes may lead to drug degradation?

Reactions involving functional groups can lead to degradation and make a drug ineffective, unpalatable, and/or toxic

What are the 3 types of chemical reactions that cause most drug to become unstable or degrade?

1) Oxidation-reduction

2) Hydrolysis

3) Photolysis

What is oxidation?

loss of electrons

What is reduction?

gain of electrons

What is meant by "re-dox reaction"?

Oxidation and reduction reactions occur together, when one compound is oxidized the other is reduced

What is a common sign of oxidation for some drugs?

Color change

What color does Epi become when oxidized?

Amber-colored (yellow/orangish)

What is another common color drugs turn when oxidized?

pink/reddish

What functional group is highly oxidizable? What are drug examples?

Hydroxyl group directly bonded to an aromatic ring

Examples: Catecholamines

What does oxidation produce?

Free radicals

What catalyzes oxidation?

Heat

Light

Metal ions

What are methods to prevent oxidation of drugs?

Light protection: Amber glass/plastic

Temp. Control

Antioxidants (free radical scavengers): ascorbic acid (Vit. C), tocopherols (Vit. E)

Chelating Agents: chelate metal ions. Start with "ED-", EDTA

pH control: use of buffers

Define hydrolysis

Occurs when water causes cleavage of a bond in a molecule

What functional groups are most susceptible to hydrolysis? What component of these functional groups is the usual target of hydrolysis?

Ester, amides, and lactams (beta-lactam ring)

The carbonyl (C=O) component is most likely target of hydrolysis

What are methods to prevent/reduce hydrolysis?

Protect drug from moisture:

Desiccants (absorbents): absorb moisture that enter the container

Lyophilized powders (freeze-dried)

Manufactured as a less hygroscopic salt

Storage: avoid storing meds in bathrooms or humid places and close container lid tightly

Oxidation prevention can also reduce hydrolysis

What is photolysis?

Breakage of covalent bonds and drug degradation due to UV light exposure

Is photosensitivity common for drugs?

Yes