PChem Quiz 4 (L10-L12)

L10

drug administration

{oral administration} dosage form → [dissolution] drug in solution from GI tract (has lipid membrane) ← → [absorption] {parenteral administration} drug in general circulation

drug in gen circulation ← → [distribution] (only a fraction) site of action (biological activity)

drug in gen circulation ← → storage sites (protein binding or neutral effect)

drug in gen circulation ← → metabolism (liver**, blood, many cells where it becomes inactivated or activated) → excretion (via urine or feces, out of system)

ADME

(dissolution), absorption, distribution, metabolism, excretion

ADME for IV

NO absorption

ADME for IM and SQ

some absorption

physico-chemical properties that are related to drug action

• solubility

• degree of dissociation (pKa)

• partition coefficient → logP > 0

• resonance - induction

• H bonding

• chelation

• stereochemistry

• interatomic distance between functional groups

• isosterism

determined by the kind (type), number, and arrangement of atoms in a drug molecule

structurally non-specific drugs

• drugs that do not req any specific site of action; few percentage

• biological effect is closely related to physico-chemical properties rather than chemical structures

structurally non-specific drugs examples

• osmotic diuretics

  • has many OH, which bring water w urine

• gastric antacids

  • inorganic weak bases that neutralize HCl in stomach to tame down reflux

• general anesthetics

structurally specific drugs

• interact w a specific receptor/enzyme to initiate or block the transduction of a signal leading to the observed biological response

• ligands, agonists, antagonists, or inhibitors

• certain structural features appear to have greater influence on the overall biological effects than their physico-chemical properties

• small structural change causes a drastic difference in biologic activity

structurally specific drugs examples

• diff R groups

  • DNA vs anti-cancer drug

  • neurotransmitter vs drug to induce cholenergic activity

  • drug that inc BP vs drug that dec BP

• size of R groups vary which changes binding pocket

role of chemical bonding interactions

• a biological response is the result of the interaction of a drug w a functional or organized group of molecules

• relatively weak forces yet strong enough must be involved in the drug-receptor complex

• high degree of structural specificity w complimentary groups on the receptor

drug-target interactions

**in order of how common in a drug

1. hydrogen bond → 2-5 kcal/mol

   1. O, N, F are strong EN atoms for H bond donors and acceptors

2. ionic (charge-charge) → 5 kcal/mol

3. ion (charge) - dipole → 1-7 kcal/mol

4. dipole-dipole → 1-7 kcal/mol

5. hydrophobic → 1-4 kcal/mol

6. reinforced ionic (ionic + H bond) → 10 kcal/mol

7. covalent (strongest) → 50-150 kcal/mol

   1. ex: aspirin on COX1 & COX2 enzymes; alkylating agents

8. van der waals → 0.5-1 kcal/mol

steric factors and pharmacological activity

3D structure of a compound plays an important role in binding of a drug to the receptor

3 major types of steric factors that influence pharmacological activity

• optical and geometric isomerism

  • chirality

  • cis/trans for double bonds and ring systems

• conformational isomerism

• isosterism

  • groups that share the same number of total or valence electrons and exhibit similar physical or chemical properties

thalidomide

• R → has calming and sleep-inducing properties

• S → causes teratogenic effects

• was used in pregnant women for morning sickness in germany

  • not brought into US

• found to and found to have teratogenic effects in humans, rabbits, and monkeys but not rodents

• taken off the market in 1961

• now used for cancer - multiple myeloma and erythema nodosum leprosum (ENL) - due to vasculogenesis inhibition properties; still has BBW

• administration of drug epimerizes in vivo under biological conditions

L11

OTC inorganic drugs

come from mineral origin

• fluorides and iodides

• gastric antacids

• germicides

fluorides

prevent tooth decay

• makes teeth more resistant to decay

• makes it stronger

• inhibit bacteria’s ability to digest teeth carbohydrates

found in municipal H2O → H2SiF6, Na2SiF6 (0.7 ppm)

found in toothpaste → NaF, Na2FPO3 (1000 ppm)

mechanism:

converts OH of Ca5(PO4)OH into F

too much F → fluorosis which causes white spots on teeth

iodides

prevent iodine deficiency (affects abt 30% of world population)

• goiter → enlargement of thyroid gland

• mental retardation

iodine → needed for T3, T4 thyroid hormones

food source: seafood, dairy, eggs

NaI, NaIO3

antacids and acid reducers

uses

• heartburn

  • acid reflux disease or GERD (acid reflux happening more than 2x a week)

• dyspepsia

  • pain or an uncomfortable feeling in the upper middle part of stomach

• ulcers

  • cells are exposed to stomach acid (HCl)

antacids examples

inorganic weak bases that neutralize stomach acid immediately

→ bc NaOH is too strong and corrosive

• Al(OH)3, MgCO3 → Gaviscon

• CaCO3 → maalox, Tums, Pepcid

• CaCO3 + Mg(OH)2 → mylanta, rolaids

• Mg(OH)2 (milk of magnesia) → ex-lax milk of magnesia

  • bc Mg(OH)2 does not dissolve in water

• NaHCO3 + citric acid → alka-seltzer heartburn relief

  • effervescence: put it in water which gets rid of separation barrier and then bubbles and releases CO2

  • 1.94 g : 1 g → 4.44 : 1 = molar ratio

  • mostly excess NaHCO3 and Nacitrate

• bismuth subsalicylate → kaopectate, pepto-bismol

  • weak base, antibacterial, antiinflammatory → salicylate (similar root to aspirin)

  • pink color from food dye NOT API - marketing

H2 blockers

organic drugs that produce a slower reaction; often used for GERD

• slows production of HCl

ex:

• cimetidine → tagamet HB 200

• famotidine → pepcid AC

• ranitidine → zantac 75

PPI - proton pump inhibitor

organic drugs that produce a slower reaction; often used for GERD

• stops production of HCl

ex:

• omeprazole → prilosec

combination products antacids

have properties of both organic and inorganic drugs

ex:

• famotidine + CaCO3 + Mg(OH)2 → pepcid complete

germicide

a substance capable of killing a wide variety of microorganisms

• antiseptic → used on skin

  • ex: wounds

• disinfectant → used on equipment

  • ex: table, surgical tools

oxidizing germicide

substance w germicidal effect on most organisms through oxidation

• irreversibly alters microbial proteins

• most have little or no action on bacterial spores

• makes germ cell walls leaky + kills them

hydrogen peroxide

powerful ox agent

2 H2O2 → [catalase] O2 + 2H2O

drop on cut → bubbles out O2 due to catalase

drop on table → nothing

preparations

• pharmaceutical grade → 3% (10 vols)

  • 1 volume H2O2 = 10 volume (mL) O2

• food grade → 6% (20 vols)

• contact lens solution → 3%

• mouthwash → 4.5%

metal peroxides

• slower decomposition

• usually solid

• used to disinfect cosmetics

• ex: CaO2, MgO2, Na2O2

organic peroxides

used as antiseptic + disinfectant

• ex:

  • peroxyacetic acid

  • benzoyl peroxide

    • used for free-radical rxn initiation

  • cumyl and tert-butyl peroxides

    • used for free-radical rxn initiation

ozone (O3) as oxidizing germicide

powerful ox agent; unstable at high conc

• in lower atmosphere → tm causes irritation to airways

• in upper atmosphere → protects us from UV radiation from sun

convenient

• produced from 2O3 → 2O2

• electricity used to create O3 by splitting O2 in municipal water treatments

• convenient use + storage

sodium hypochlorite (NaOCl) as oxidizing germicide

bleach; inorganic compound used as disinfectant in hospitals and dentisry

• household bleach - 3-6%

  • 1:10 or 1:100 dilution until 0.05%

• needs to be diluted or it can be corrosive; disinfect w alcohol after

hypochlorous acid as oxidizing germicide

HOCl

• used in water treatment

• Cl2 + H2O → HCl + HOCl

• need storage for Cl and not made on site

L12

Iodine as oxidizing germicide

weakest oxidizing agent; low solubility in water

• pink; can stain skin

tincture of iodine

2% I2 + 2.4% KI in 47% ethanol/H2O

• used since 1908

• produces I3-

KI/I2

5% I2 + 10% KI = Lugol’s solution

novel iodine antiseptics

PVPI - povidone-Iodine

• addition of I2 to polymer polyviylpyrrolidone

• 9-12% iodine

OTC betadine solution (10%)

betadine surgical scrub (7.5%)

permanganates as oxidizing germicide

magenta-rose color in solution; can stain

• in highest oxidation form

• diluted to 0.1% solution and then to 0.01%

oxidation potential ranking (strongest to weakest)

• fluorine gas (F2)

  • strongest oxidizing agent

  • never used bc too strong and corrosive

• hydroxyl radical (·OH)

  • product of H2O2

• ozone (O3)

• hydrogen peroxide (H2O2)

• permanganate (MnO4-)

• hypochlorous acid (HOCl)

  • formed when Cl is bubbled into water

• chlorine (Cl2)

• hypobromous acid (HOBr)

  • not rly used bc Br- can cause toxicity

• chlorine dioxide (CO2)

• iodine (I2)

  • weakest

  • most often used

neurotransmitter reqs

• synthesized and stored in presynpatic neuron

• released into synpase by presynaptic neuron due to stimulation

• produce a response in postsynaptic cell

• elimination mechanism that deactivates neurotransmitters

• receptor at postsynaptic cell that relate in pharmacologic activity

neurotransmitter receptors

• ligand-gated ion channels

• G protein-coupled receptors

neurotransmitter metabolism

• reputake → neurotransmitters in synapse are taken back into storage by presynaptic cell

• metabolism of neurotransmitters

• diffusion → of conc out of the site of the receptor

  • ineffective

  • uncontrollable

7 main neurotransmitters

• acetylcholine

  • unique structure

• Norepinephrine (R=H), epinephrine (R=CH3)

  • catecholamine (benzene w diol)

  • monoamine

• dopamine

  • catecholamine (benzene w diol)

  • monoamine

• serotonin

  • largest MW 176

  • monoamine

• histamine

  • monoamine

• GABA

  • smallest MW 103

  • amino acid

• glutamate

  • amino acid

MW → 100-180; smaller than most drugs which have MW 200-500

acetylcholine structure

functional groups

• ester

• quaternary amine

  • + charge dipole interacts w water

  • high water solubility as synapse is aqueous

acetyl + choline

acetylcholine function

• used in CNS and PNS

• used between neurons

• used in preganglionic neurons in autonomic NS

  • + parasympathetic postganglion as well

• inhibitory + excitatory

acetylcholine synthesis

AcetylCoA + choline → [choline acetyltransferase] acetylcholine

acetylcholine elimination

• no reuptake

• happens in synapse

• t ½ = 1-2 milliseconds

acetylcholine → [acetylcholine esterase (AChE)] acetic acid + choline

acetylcholine receptors

• nicotinic cholinergic receptors (nAChR)

  • ligand-gated ion channels

  • faster

  • stimulated by ACh + nicotine

• muscarinic cholinergic receptors (mAChR)

  • GPCRs

  • slower

acetylcholine + organophosphates/nerve gases

parathioh insecticide

• when these organophosphates are ingested, you get phosphoyl AChE bc AChE attacks phosphate

• pseudo-irreversible due to longer t ½

nerve gases

• VX

• Soman

• Sarin

• can have ACh build-up in periphery that can cause muscle spasms

acetylcholine organophosphates antidotes

• atropine → mAChR antagonism

• pralidoxime (2-PAM) → reverts AChE back