Med Chem

Creation of drugs:

1) molecular target

2) clinical trials

3) regulatory review

Ways to administer drugs:

1) Orally

2) Rectally

3)Inhalation

4) Injection

5) Topical

Injection types:

Intravenous- into blood, by passes stomach content (most effective)

Intramuscular- into the muscle (large volumes can be injected and when immediate response is not required)

Subcutaneous- under the skin (slow absorption)

Bioavailability

the fraction of the administered dose that reaches the bloodstream

What effects bioavailiblity?

• higher solubility = more bioavailability

• Functional groups

• Polarity-

  • nonpolar good at passing blood-brain barrier (Ex. esters, ether, phenyl rings)

  • Polar- good at entering the blood stream (Ex. hydroxyl, carboxyl, amino groups)

Tolerance

The body's adaptation to a drug, which causes a need for a higher dosage in order to achieve the original effect

Addiction

when the dependency on a drug leads to withdrawal symptoms if its withheld.

Dosage Regime

refers to the specific quantity of the drug to be taken at one time, and the frequency of administration

First-pass effect

pharmacological phenomenon in which a medication undergoes metabolism at a specific location in the body cause bioavailability to become reduced

Therapeutic window

describes the dosage range between a minimum effective therapeutic concentration, and the minimum toxic concentration

wide range is most desirable

Therapeutic index (TI = TD50/LD50)

ratio of the dose that produces toxicity to the dose that produces a clinically effective response in a population

• Low TI VERY DANGEROUS

• High TI less dangerous

Receptors

often proteins, binding of the drug inhibits normal biological activity, so development of the disease is interrupted

Inhibitors

binds to an enzyme and blocks its activity

ED50 (effective dose)

is the dose producing the therapeutic effect in 50% of the population

LD50 (lethal dose)

the dose that is lethal for 50% of the population

TD50 (toxic dose)

the dose that is toxic for 50% of the population

Non-steroidal anti-inflammatory drugs (NSAIDs)

are medicines that are widely used to relieve pain, reduce inflammation, and bring down a high temperature

Analgesics

pain reliever

Mild analgesics

block the sensation of pain at the source (aspirin)

or block Prostaglandins

Prostaglandins

hormone like cells that release from cells damaged, allowing the body to detect pain

mediate the inflammatory response by causing dilation of blood vessels

Inflammatory response

the immune system's response to harmful stimuli, such as pathogens, damaged cells, toxic compounds, or irradiation

Antipyretic

fever reducer (aspirin)

Anticoagulant

“blood thinners”, prevents the clotting of blood (aspirin)

Aspirin

-derivative of salicylic acid - esterified to become less irritable to the body

Effects:

• Analgesic

• Anti-inflammatory (relief from swelling)

• Antipyretic

• Anticoagulant

• can cause bleeding when taken with alcohol

• allergic reactions

• Reye’s disease in children

Functional Group:

• Carboxylic acid

• phenyl group

• ester

combine it with NaOH or NaHCO3 to form an ionic salt which increases solubility - increases bioavailability

Paracetamol/ acetaminophen

Effects:

• Antipyretic

• Analgesic

• NOT AN ANTI-INFLAMMATORY

• Can cause liver damage and kidney damage

• overdose

• increase tolerance

• skin reactions

Functional groups

• Hydroxyl

• phenyl group

• amide

less side effects than aspirin and has narrower therapeutic window

Ibuprofen

Similar properties to aspirin ( only has carboxylic acid)

• is not a blood thinner

• antipyretic

IR Spectrum of aspirin and salicylic acid

Similarities:

C-O( alcohol/ ester)

C=O ( carboxylic acid)

O-H( carboxylic acid)

C-H

Differences:

Aspirin has an ester group and salicylic acid has an OH group attached to the benzene ring

recrystallization

• used on aspirin

• purifying a substance by causing it to crystalize from a hot saturated solution

Synergy

An interaction between two or more drugs that causes the total effect of the drugs to be greater than the sum of the individual effects of each drug.

Antibiotics

chemicals produced from microorganisms that act against other microorganisms

Bacterocidal

kills bacteria directly

Bacteriostatic

inhibits bacteria’s cell division

Penicillin G

administered by injection because its not acid resistance

Penicillin V

taken orally because acid resistance

Cloxacillin

penicillinase and acid resistant

Beta-lactam

90 degree Four-membered ring containing a cyclic amide group, most active part, responsible for its antibacterial properties

the 90-degree bond angles can easily break and bind to the transpeptidase disrupting the formation of the cell wall, causing the cell to burst

What in penicillin is unique?

5 ring sulfur and beta-lactam ring

Disadvantages of overprescription (penicillin):

• destruction of harmless bacteria in digestive tract

• leads to genetic resistance

• makes penicillin less effective

Reasons to modify side chains of penicillin

• become more resistnat to stomach acid

• increase tolerance to penicillinase

• prevent deactivation by penicillinase

Trans-peptidase

a bacterial enzyme that cross-links the peptidoglycan chains to form rigid cell walls

Penicillinase

enzyme produced by resistant bacteria, that can open penicillin ring and render it inactive

Opiates (strong analgesics)

prevent transmission of pain impulses at the brain, rather than the source

Narcotic

sleep inducing, effects mood and behavior

Blood-brain barrier

• protects the brain by restricting chemicals that can enter the blood

• nonpolar

• the more lipid soluble the more likely a substance can enter the brain

Semi-Synthetic

derivatives of natural antibiotics with slightly different but advantageous characteristics

esterase

a group of hydrolases that have wide substrate tolerances and are able to catalyze a broad spectrum of reactions even in organic solvents

active metabolite

are the active forms of drugs after they have been processed in the body

• codeine is converted into morphine in the body and it is the morphine that binds much more strongly to the opioid receptors than codeine, producing an analgesic effect

• omeprazole/esomeprazole are converted into different forms that are able to bind to proton pumps

• aspirin is converted into the active form – salicylic acid.

Codeine

0.5 % raw opium (prepared from morphine)- methylation

Effects

• Used with OTC drugs

• cough medication

• treatment of diarrhea

• dizziness, anxiety, mood change, confusion

Functional Groups:

• 2 methyl Ethers

• phenyl

• 1 hydroxyl -makes it less polar allowing it to cross more easily

• Alkenyl

• Tertiary amine

Morphine

10 % raw opium

Effects

• relief of severe pain

• better bioavailability (100%) when inserted through IV

• Addictive, Anxiety, mood change, allergic reaction

Functional Groups

• Ether

• Alkenyl

• 2 Hydroxyls (slightly polar)- limits ability to cross blood-brain barrier

• Tertiary amide

• phenyl

Heroin (diamorphine)

Synthesized from morphine (acetylation twice)

Effects:

• relief of server pain (illegal in many places)

• Addictive, anxiety, fear, mood changes, withdrawal

Functional Groups

• 2- esters - least polar ( can move across barrier easiest)

• ether

• tertiary amide

• phenyl

Methadone

reduces drug craving and withdrawal symptoms

Parietal Cells

maintain the pH in stomach (1-2) by releasing HCl

Dyspepsia

acid indigestion- uncomfortable feeling in stomach

Heartburn- acid rises to esophagus

Ulceration- damage the lining

What causes dyspepsia?

excess alcohol, smoking, caffeine, and stress which leads to increase acid buildup

Histamine

activates the partietal cells that release gastric juices

H2- receptor antagonist (Zantac/ ranitidine)

Zantac interacts with H2 receptors; prevents histamine interacting with H2 receptors; prevents secretion of acid into stomach

-does not really prevent healing of ulcers

Proton pump inhibitor (omeprazole or esomeprazole)

reduce the production of acid by blocking the enzyme in the wall of the stomach that neutralizes acid

-inhibit initial producing of HCl

-prevents and heals ulcers

Antacids

weak bases that neutralize acids

-strong bases can not be used ( to corrosive)

Types of antacids:

Magnesium Compounds  may cause diarrhea

Aluminum Compounds may cause constipation and they also may interfere with the adsorption of phosphates in the formation of bones. 

Carbonates may generate carbon dioxide leading to bloating and flatulence.

Formulas for antacids

CaCO₃  + 2 HCl = CaCl₂ + H₂O  +  CO₂

  NaHCO₃ + HCl = NaCl  + H₂O  +  CO₂

  Al(OH)₃ + 3 HCl = AlCl₃ + 3 H₂O (best)

  Mg(OH)₂ + 2 HCl = MgCl₂ + 2 H₂O

  MgO +  2 HCl = MgCl₂ + H₂O

Buffers

resist changes in pH of a solution upon the addition of small amounts of acid or base

pH equations

Alginates

float on the stomach contents to form a neutralizing layer preventing reflux of stomach acids up into the esophagus.  Hence they help to prevent acid reflux or heart burn.

Anti-foaming agents

such as simethicone(dimethicone) prevent the formation of gases and reduce flatulence

Superbugs

strains of bacteria that are resistant to several types of antibiotics.

Viruses

are submicroscopic, non-cellular parasitic, infectious particles that can only reproduce inside a living host cell

reproduce rapidly with mutations( change in genetic material)

Bacteria

reproduces by cell division/ fission, living cell, and has a cell wall

Virus reproduction

1. Virus attaches to host cell
2. Viral DNA injected into cell
3. Viral DNA replicated using metabolic processes of host
4. New protein coats for viruses are made
5. Mature virions assembled in cell
6. Cell ruptures and releases mature viruses

prophylactic

prevents disease

How the body fights viruses

- Helper T-Cells (white blood cells) - fight infections- must recognize viral/abnormal cells before new viruses are released
- A secondary viral infection is fought by memory B-cells releasing antibodies to mark viruses

Antivirals

medications that help your body fight off certain viruses that can cause disease.

Use of antiviral medicines

1.Alter the genetic material within the cell, ex: acyclovir prevents cold sore replication

2.Inhibit the activity of enzymes within the host cells that are needed to make new viruses, ex: indinavir – prevents HIV protease to make new viruses

3.Prevent them from binding to the host cell surface and gaining access into the host

4.Prevent the virus from leaving the host cell so it cannot infect others

Latent Viruses

viruses that inject their genetic material into a host cell, but the material is not expressed until a later date

Influenza

common viral disease

contains RNA, RNA polymerase and a lipid envelope with neuraminidase (NA) and hemagglutinin (HA) proteins.

Hemagglutinin (H)

allows viruses to bind to host cells at sialic acid (glycoprotein)

Neuraminidase (N)

breaks down mucous surrounding cells allowing it access to target cells

>After viruses replicate in the host cell the NA must break the link between sialic acid so the virus can break free from the cell

If the NA fails to work, the virus is unable to infect other host cells

Oseltamivir (Tamiflu)

• neuraminidase inhibitors

• They bind to the active site of the NA enzyme and prevents it from Un anchoring the virus from the cell

• Contains: ester, carbonyl group

• taken orally

• total synthesis makes a lot of waste

• Uses shikimic acid (synthetic route)

shikmic acid

is renewable and can be extracted from Chinese star anise (low yielding process and star anise not always available) or from glucose fermentation using genetically modified bacteria (uses low temperatures and an aqueous medium – greener process).​

zanamivir (Relenza)

• neuraminidase inhibitors

• bind to the active site of the NA enzyme and prevents it from unanchoring the virus from the cell

• Contains alcohol, carboxyl

• dry powder for oral inhalation since it is highly polar and cannot pass through the cell membrane

retrovirus

type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell

can mutate much easier

HIV

>infects T-cells due to specific receptor proteins on their surface to which the virus attaches to gain entry. 

>Once inside the viral enzyme, reverse transcriptase converts RNA into DNA so it is integrated into the cell’s DNA.

>T-cells then make more HIV viruses or remain latent, copying the viral DNA whenever they replicate.

Death of T-cells occurs when viruses leave, causing a weakened immune system

AZT (azidothymidine)

early anti-retroviral drug designed to target the reverse transcriptase enzyme, preventing DNA synthesis.

Multi-drug resistance (MDR)

bacteria have developed, so “cocktails” of antibiotics need to be prescribed to hopefully combine their effects to overcome the infections.

Radioactive isotopes

• used in medicine as a form of treatment and diagnosis.​

• decay by emission of alpha particles, beta particles, or gamma rays (called ionizing radiation).​

Ionizing radiation

• causes the formation of ions (by ejection of electrons) when they interact with matter.​

• can damage cells, usually due to the damage caused to DNA.​

Low-level waste (radioactive waste)

has low activity and usually contains isotopes with short half lives. And includes gloves, clothing, tools, syringes, excrement

small amt of radiation for a short time

stored on site or shipped to a central site until safe OR incinerated OR buried underground in individual concrete lined vaults (up to 500 years).​

intermediate-level radioactive waste

a category that is sometimes used but not universally.​

High-level waste ​

has high activity and usually contains isotopes with longer half-lives. And includes fuel rods and other materials from nuclear reactors.

kept underwater in storage ponds and then transferred to dry casks and stored in concrete bunkers.  Permanent store is a major problem since the future and stability of the containers is unknown.​

Waste Solvent

used as mediums in which many reactions occur, in the extraction and purification of compounds and contribute about 80-90% of the mass of substances used in pharmaceutical production and make a large contribution to the energy used, and to the cost.​

toxic to humans

Ways to make waster solvent greener:

prevention of solvent use is paramount; using a solvent that is recyclable or reused is preferable; energy use to purify the solvent is considered, and disposal method for solvents is also considered (incineration, underground injection, reuse, etc.) ​

the release of antibiotics into the environment

• 1. incorrect disposal of unwanted medicines, ex. Flushing them down the toilet​

• 2. agriculture – drugs given to animals will be present in animal waste that enters groundwater, rivers, and lakes​

• Water treatment does remove some of the materials but long term exposure to man can result in damage.​

• Antibiotics can damage aquatic organisms and also increases the resistance of bacteria to antibiotics

Green Chemistry

approach to chemical research and industrial processes that seeks to minimize the production of hazardous substances and their release to the environment.​

12 Principles of Green Chemistry:

• 1. Prevention – it is easier to prevent waste than clean it up or treat it​

• 2. Atom economy – synthetic methods should try to maximize incorporation of all materials into the final product (less waste)​

• 3. Less hazardous chemical synthesis – design use to generate substances that possess little to no toxicity to humans or environment​

• 4. Designing safer chemicals – products should do what they are designed to do and minimize their toxicity​

• 5. Safer solvents and auxiliaries – Use of ancillary materials should not be used or made innocuous when used​

• 6. Design for energy efficiency - Energy requirements for processes should be assessed for environmental and economic impact (attempt to occur at ambient temperature and pressure)​

• 7. Use of renewable feedstocks – a raw material or feedstock should be renewable whenever technically and economically practical.​

• 8. Reduce derivatives – unnecessary derivations should be minimized or avoided as they generate added waste.​

• 9. Catalysis – Catalytic reagents are superior to stoichiometric reagents​

• 10. Design for degradation – Chemical products should be designed to break down into innocuous products that do not persist in the environment.​

• 11. Real time analysis for pollution prevention – methodologies need to be developed for real time monitoring and control of hazardous wastes​

• 12. Inherently safer chemistry for accident prevention – choose substances to minimize accidents, releases, fires, and explosions.

chiral auxiliary

stereoisomers -have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms in space.

causes different functions / effects

breathalyzer (ethanol)

the ethanol is oxidized, reduces the dichromate causing a color change from orange to green

Percent error formula

| Actual - experimental / actual| X 100

ABSOLUTE VALUE

Half life equation

Nuclear chemistry