p-chem quiz 4

1. Dosage dissolves

2. Drug enters GI tract as solution —> absorbed

3. Enters general circulation (blood)

4. Distributed to site of action or storage sites

5. OR immediately metabolized or excreted (“first pass metabolism”)

Overview of Oral Administration

can re-enter bloodstream

• as a metabolite (pro-drug)

• after it reaches site of action

Why are all but excretion reversible?

different absorption site, bypasses first-pass metabolism

Parenteral Administration: IM and SQ

NOT ABSORBED, travels directly into bloodstream

Parenteral Administration: IV

• water solubility

• degree of dissociation (pKa)

• partition coefficient (K): oil to water solubility

• resonance

• hydrogen bonding

• chelation

• stereochemistry

• interatomic distance between groups

• isosterism

Physio-chemical properties related to drug action

kind, number, and arrangement of atoms in a drug molecule

What determines physico-chemical properties?

Structurally Non-Specific Drugs

Drugs that do not require any specific site of action

Biological effect relies on physico-chemical properties

Osmotic diuretics, Gastric antacids, general anesthetics

Examples of structurally non-specific drugs

Structurally Specific Drugs

interact with a specific receptor/enzyme to initiate/block signal transduction (ligands, agonists, antagonists, inhibitors)

rely on certain structural features

biological response

result of the interaction of a drug with a functional or organized group of molecules

1. Covalent (STRONGEST)

2. Reinforced Ionic

3. Ionic / charge-charge

4. Charge-dipole

5. Hydrogen bond

6. Dipole-dipole

7. Hydrophobic

8. Van der Waals (WEAKEST)

Bond strength ranking of chemical bonding interactions

1. Optical and geometric isomerism (R VS S, cis VS trans)

2. Conformational isomerism (sigma bond can rotate)

3. Isosterism: change in atom/functional groups

3 major types of steric factors that influence pharmacological activity

1. Fluorides and iodides

2. Medicinal agents for the control of pH: Gastric Antacids

3. Oxidating Germicides

Examples of Inorganic Substances as Medicinal Agents

Fluorides

prevent tooth decay by:

• promoting tooth remineralizatiob

• make teeth more decay resistant (better resistant to acid dissolutin)

• inhibit plaque bacteria

Hydroxyapatite in teeth gets replaced with F to become fluoroapatite, which is more resistant to acid dissolution

How does fluoride help prevent tooth decay?

H2SiF6 and Na2SiF6: found in municipal water

NaF and Na2FPO3: found in toothpaste

Examples/sources of fluorine

• Iodine is needed to produce thyroid hormones T3 and T4

• Iodine deficiency can lead to

  • goiter: enlargement of thyroid gland

  • mental retaradation

Why is it important to prevent iodine deficiency?

NaI and NaIO3

Where is Iodine found?

antacids and acid reducers

OTC relief for heartburn and acid reflux (usually weak bases that neutralize HCl in stomach)

• heartburn: acid reflux disease or GERD

• Dyspepsia: pain/discomfort in upper middle part of stomach

• Ulcers: cells are exposed/irritated by stomach acid

3 conditions antacids help with

Al(OH)3, MgCO3, CaCO3, Mg(OH)2

Examples of Antacids (weak bases)

composed of NaHCO3 and citric acid

• In tablet, 2 separate forms

• Reaction forms when dissolved: in H2O, forms CO2 bubbles

What is unique about Alka-Seltzer?

has both anti-bacterial and anti-inflammatory activity

dyed pink for branding purposes

What is unique about Bismuth Subsalicylate?

H2 blockers and PPIs

Examples of Organic drugs that work better for GERD, but take longer to produce effects

H2 blockers

inhibit stomach acid production

proton pump inhibitors

blocking proton pump to prevent acid production

oxidizing germicide

a substance that can kill a wide variety of organisms by oxidation, which irreversibly alters microbial proteins

• Peroxides

• Ozone

• Halogens and their Oxo Compounds

General categories of oxidating germicides

hydrogen peroxide

• used to clean wounds

  • Catalase converts H2O2 —> H2O + O2

  • Catalases on skin catalyzes decomposition of H2O2, releasing O2 bubbles

  • Wound is cleaned and bacteria is healed

• can also sterilize heat-labile medical equipment

Metal Peroxides

peroxides used in pharmaceutical products, disinfectants, detergents, toothpaste

SLOWER decompositon than H2O2 —> better at producing oxidizing effects

CaO2, MgO2, Na2O2

Examples of metal peroxides

Organic Peroxides

peroxides that are used as antiseptics/disinfectants

• can also initiate free radical chain reactions

Peroxyacetic acid, Benzoyl Peroxide, Cumyl and tert-butyl peroxides

Examples of organic peroxides

Ozone

powerful oxidizing agent, far better than dioxygen

decomposes and is unstable at high concentrations

used to bleach surface and kill microorganisms in air/water

• Sodium hypochlorite

• Hypochlorous Acid

• Iodine

• Permanganates

Examples of Halogen Germicides

Sodium hypochlorite (NaOCl)

Bleach: used as a disinfectant in hospitals/dentistry

can destroy standard steel because can be corrosive, must wash off and finish with alcohol

hypochlorous acid (HOCl)

• Cl2 gas + H2O → H2O and HOCl

  • Cl2 used to disinfect air and municipal water

• Keep at low concentration in pipes to kill bacteria

Iodine

WEAKEST of all oxidizing germicides, One of only halogens that is relatively safe

not soluble enough in water, must increase using different techniques

pink color

used in antiseptics

I2

Tincture of iodine: 2% I2 + 2.4% KI —> I3-

KI/I2: 5% I2 + 10% KI (Lugol’s solution)

Novel Iodine Antiseptics: Povidone-Iodine —> Polyvinyl pyrrolidone (PVPI)

• used in organic polymers

• dissolve in H2O

• OTC Betadine solution/surgical scrub —> 1% I2

Forms of iodine

permanganates (KMnO4)

• must dilute to 0.01% for use

• will stain skin/clothes (magenta)

• can be reduced to lower oxidation states

• used as antiseptic

1. Fluorine (STRONGEST)

2. OH radical

3. Ozone

4. H2O2

5. Permanganate

6. HOCl

7. Cl2

8. HOBr

9. ClO2

10. Iodine (WEAKEST)

Ranking of Oxidation Potential from strongest to weakest

1. synthesis and storage in presynaptic neuron

2. released into synapse due to stimulus

3. produce response in postsynaptic cell

4. elimination mechanism: deactive neurotransmitter

5. receptor at post-synaptic cell

5 criteria of neurotransmitters

1. Reuptake: taken back to presynaptic cell for storage in vesicle

2. Metabolism: enzymes break down

3. Diffusion: decreased concentration where receptors are

Types of elimination mechanisms for neurotransmitters

• located in CNS and PNS

• cholinergic neurons

• sympathetic and parasympathetic

• can be inhibitory or excitatory

• associated with Alzheimer’s (decreased ACh into CNS)

Function of Acetylcholine

Acetyl CoA + Choline —> Acetylcholine

by choline acetyltransferase

Synthesis of Acetylcholine

Acetylcholine —> Acetic Acid and Choline

by acetylcholine esterase (AChE)

choline: taken back to presynaptic neuron to be reused

Elimination of Acetylcholine (metabolism)

nicotinic cholinergic receptors (nAChR)

muscarinic cholinergic receptors (mAChR)

2 main classes of acetylcholine receptors

nicotinic cholinergic receptors (nAChR)

ion channels that bind nicotine

muscarinic cholinergic receptors (mAChR)

GPCRs that bind muscarine

• prevent metabolism of acetylcholine in presynaptic cleft

  • build up acetylcholine —> muscle spasms

• If reaching synapse, will phosphorylate acetylcholine esterase, causing the increase in ACh and overactivation of postsynaptic cells

How do organophosphates and nerve gases work on Acetylcholine?

Parathion: Insecticide

Example of organophosphate

VX, Soman, Sarin

Examples of Nerve Gases

Atropine and 2-PAM

2 antidotes of organophosphates and nerve gases

atropine

bind to muscarinic receptor, preventing acetylcholine from binding —> STOP muscle spasms

2-PAM

recover unphosphorylated enzyme to remove phosphate from acetylcholine

• must be done within 24 hours of exposure