LUCID "Chemistry 1002 Chapter 19"

Chemistry 1002 Chapter 19
Pharmacology

Introduction

Although the mass media are always bombarding us with the notion of the desirability of a "drug-free" world, the use of drugs by modern man is probably the single most important reason that the average life expectancy of people living in advanced cultures (currently about 72 years) has nearly doubled in recent times (since the birth of microbiology, about 300 years ago).

Show Fig. 19.1, Table from old text.

Pharmaceuticals

I. Antibiotics

A. Sulfa Drugs

B. Penicillins

C. Cephalosporins

D. Tetracyclines

II. Antivirals

A. Nucleotide Mimics

B. Protease Inhibitors

C. Vaccines

1. Antigens

2. Attenuated Virus

III. Hormone Regulators

A. Agonists

B. Antagonists

IV. Neurochemicals ([Ag/Antag]onists)

A. Acetocholine

B. Norepinephrine

C. Dopamine

D. NMDA (N-methyl-D-aspartate)

E. Seratonin

F. Adenosine

G. GABA (gamma-aminobutyric acid)

V. Analgesics

A. Opiates

B. NSAIDS

C. Others (acetaminophen)

VI. Influenza/Allergy Relief

A. Decongestants

B. Antitussives

C. Expectorants

D. Antipyretics

E. Antiinflammatory

F. Antihistamines

VII. Cardiovascular Drugs

A. Cholesterol Antagonists

B. Diuretics

C. Vasodilators

D. Beta Blockers

E. Calcium Channel Blockers

F. Clot Dissolvers

VIII. Chemotherapy (anticancer)

A. Alkylating Agents

B. Antimetabolites

ANTIBIOTICS

Effective against certain types of bacterial but not against viruses.

Technically only antibacterials synthesized by other bacteria are antibiotics (ie. not sulfa drugs), but current usage of term has come to include all antibacterials.

Kill bacteria by disrupting:

cell wall synthesis, folic acid metabolism, cytoplasmic membrane, DNA replication, transcription, or protein synthesis.

Sulfa Drugs.

Kill bacteria by mimicking PABA (para-aminobenzoic acid) used by bacteria to synthesize folic acid (coenzyme used to make nucleic acids). Humans don't need PABA to make folic acid; we consume folic acid in diet.

PROBLEM 40.

How do sulfa drugs kill bacteria and not humans?

@ They disrupt folic acid synthesis in bacteria. We don't make folic acid.

Penicillins.

Disrupt cell wall synthesis in some (Gram-positive) bacteria. Bacteria make tough polymeric walls around themselves to hold in cell contents under pressure (typically about 30 psi). These walls constructed of modified polysaccharide material crosslinked by oligopeptide. Penicillins specifically disrupt the creation of peptide crosslinks by bacteria attempting to create cell walls.

PROBLEM 8.

How does penicillin kill bacteria?

@ Disrupts cell wall synthesis.

Cephalosporins.

Cephalosporins kill bacteria in fashion similar to penicillins, but have broader spectrum of activity (active against both Gram-positive and Gram-negative bacteria).

Tetracyclines.

Kill bacteria by inhibiting protein synthesis. Disable bacterial ribosomes, which are protein synthesis machines. Animal cell protein-making ribosomes different from bacterial ribosomes, so tetracyclines don't harm humans. Tetracyclines have an extremely broad spectrum of activity against bacteria.

ANTIVIRALS

Very few drugs exist which have any broad spectrum activity against viruses. Most antivirals are "vaccines" (directed against specific viruses).

Difficult to operate against range of viruses without killing healthy human cells since viruses function mostly via cell's own machinery; have very little machinery of their own. General-purpose antivirals which have been developed mostly nucleotide mimics (ie. AZT). These disrupt synthesis of new DNA (ie. replication); give cell or virus bad DNA-synthesis feedstocks.

These disruptive to virus producing DNA and healthy cells trying to replicate and repair own DNA. Theory is that healthy cells don't need to make new DNA often, so nucleotide mimics should be more disruptive to virus activity than healthy cell activity.

Show Fig. 19.3 retrovirus cycle (HIV).

Viruses come in two flavors, DNA viruses and retroviruses (RNA viruses). DNA viruses have a more difficult job than retroviruses. After they insert DNA into host (make "provirus") they must cause host to make enzymes which exclusively replicate provirus DNA thousands of times to make DNA for new viruses (not normal for cell to replicate DNA frequently).

Retroviruses contain an enzyme, reverse transcriptase, which does transcription in reverse, producing DNA product from virus RNA template rather than other way around. Although it is wierd for cell to make DNA from RNA it only needs to do this once.

Once provirus DNA is made and incorporated into human DNA (enzyme called "integrase" responsible for this) thousands of copies of RNA genome made by cell from provirus DNA during normal course of transcription.

Retroviruses much more primitive (and deadly) than DNA viruses because they don't need much baggage to succeed (KISS always works best). They can mutate to escape host immune system and still succeed at causing disease. DNA viruses sophistocated enough that mutations much more likely to make them ineffective. Retroviruses cause cancers and AIDS in a variety of different animals.

PROBLEM 9.

What's a retrovirus?

@ An RNA virus.

NUCLEOTIDE MIMICS

Defective monomers for DNA synthesis useful as drugs for stopping activity involving too much DNA replication (virus activity and cancer). These drugs are highly toxic because they poison normal dividing cells (tissue repair) as well as virus-infested cells and cancerous cells.

PROTEASE INHIBITORS

Designed specifically to interfere with protein synthesis by HIV provirus. HIV makes single long superprotein molecule which must be cut into 9 pieces by HIV protease in order to become the 9 proteins which used to make new HIV viruses.

VACCINES

Vaccines are made from outside envelope of virus or whole crippled virus. They not able to infect cells well, and so they serve as practice target material for immune system to train on until real virus comes along. Vaccines made from virus envelope components are viral antigen vaccines and vaccines made from crippled whole virus called attenuated virus vaccines.

Vaccines train immune system vs. very specific viruses. If viruses mutate too much (HIV) vaccines fail.

Hormone Regulation

Hormones are organic molecules synthesized in specific organs (called "glands") which regulate vast array of body functions. Examples: Metabolic rate, heartbeat, alertness/sleep, all sexual/reproductive functions, muscle building (natural anabolic steroids), blood sugar regulation/metabolism, blood clotting, blood pressure, muscle function, allergic reaction, urination.

New drugs constantly developed which either enhance (agonists) or hinder activity (antagonists) of specific hormones to achieve specific objectives (ie. thyroid agonists increase BMR, antagonists help control hyperactivity in Graves' disease).

Hormones act by binding to receptors (protein or sugar) outside cells, causing "signal" to go through membrane and initiate "cascade" inside cell. Often involves "G proteins" inside cell.

Neurochemicals

Neurochemicals are drugs that enhance (agonists) or inhibit (antagonists) activity of hormone-like biochemicals (neurotransmitters) which stimulate or inhibit "firing" of neurons by binding to receptors on the neurons. Sedatives, anaesthetics, stimulants, and hallucinogens usually neurochemicals.

Neurotransmitters bind to receptors like hormones, but not made in glands.

Neurotransmitters made in neurons. Neurons (nerve cells) have three parts, a central part called the "soma," a long protruberance which carries electrical nerve impulse resulting in release of neurotransmitters from its tip, called the "axon," and a large number of stringy long protruberances which stick out everywhere and try to catch neurotransmitters from other neurons, called "dendrites."

Neurotransmitters are manufactured in the soma of neuron, transported to the tip of the axon, and released when the neuron "fires." Dendrites from one or more other neurons in the vicinity catch these neurotransmitters, and the neurotransmitters may cause these other neurons to fire and release their neurotransmitters to be caught by still other neurons, etc.

After a dendrite has caught a neurotransmitter molecule it breaks it down and releases the parts into the space between the neurons. The neuron may or may not fire before it decomposes the neurotransmitter depending on a variety of biochemical conditions (presence of other types of neurotransmitter molecules, etc.). The broken down neurotransmitter molecule is swallowed by the soma of a neuron in the area, turned back into a functional neurotransmitter molecule, transported to the tip of this neuron's axon, and the cycle repeats itself.

Neurotransmitter receptor sites located on neuron dendrites. Some dendrites have receptors for many different neurotransmitters. Commonly known neurotransmitters: acetylcholine, norepinephrine, dopamine, NMDA (neurostimulants), seratonin, adenosine, and GABA (neurodepressants). These control mood, coordination, sleep, involuntary activity (breathing, heartbeat), energy level, emotion, etc.

PROBLEM 13.

Which biochemicals bind to receptors?

@ Hormones and neurotransmitters.

Blood-Brain Barrier.

Neurochemicals designed to be agonists or antagonists of neurotransmitters which have receptors in brain neurons must be designed not only to bind to receptors better than natural neurotransmitters, but also to pass across "blood-brain barrier."

Antidepressant and other psychiatric drugs normally are agonists for the neurotransmitters seratonin, norepinephrine, and dopamine. These most widely known to involve mood.

PROBLEM 27.

What class biochemicals are seratonin, dopamine, and norepinephrine?

@ Neurotransmitters.

Analgesics

Painkillers. Work by variety of mechanisms. Most powerful analgesics are "opiates", which are neurochemicals (antagonists for peptide neurotransmitters called "endorphins." The most widely used mild analgesics (ie. aspirin, ibuprophen, naproxen, etc.) are called NSAIDs (Non-Steroidal AntiInflammatory Drugs). NSAIDs are hormone regulators. They kill pain associated with inflammation (ie. some headaches, allergy pain, etc.) by blocking hormones which cause inflammatory prostaglandin synthesis.

Other mild analgesics like acetaminophen (Tylenol) are neurochemicals, but mechanism of action not understood.

Influenza/Allergy Relief

Over-the-counter (OTC) drugs used for symptom relief of allergies and colds are mixtures of several different drugs, most of which are agonists or antagonists for various hormones.

Decongestants. Reduce swelling in nasal, sinus, and bronchial tissues.

Antitussives. Control coughing.

Expectorants. Help you get rid of sticky flem by thinning it, enabling you to "hock that lugi."

Antipyretics. Reduce fever.

Antiinflammatory drugs. Reduce pain associated with swelling.

Antihistamines. Reduce allergic reactions.

PROBLEM 10.

What are these drugs for?

Analgesics - Pain relief.

Antipyretics - Fever reduction.

Antibiotics - Bacterial infections.

Antihistamines - Allergy relief.

PROBLEM 35.

What are these drugs for?

Antihistamines - Allergy relief.

Analgesics - Pain relief.

Decongestants - Reduce swelling in breathing passages.

Antitussives - Control coughing.

Expectorants - Get rid of mucus.

Cardiovascular Drugs

Mostly used to treat heart disease and/or high blood pressure, which are often related problems.

Cholesterol Antagonists. Lower serum cholesterol, typically by interfering with synthesis of cholesterol by liver enzymes. For some reason, when liver cholesterol synthesis is inhibited body produces less low-density ("bad") lipoprotein. This minimizes atherosclerotic plaque formation (plaques block arteries delivering oxygen and glucose to heart muscle). Example: Lovastatin.

Diuretics. Increase urination frequency. This causes body to lose very water-soluble metal ions (ie. sodium). Lowering sodium level lowers blood pressure (thins blood). Example: Dyazide.

Vasodilators. Widen veins so blood flows more easily through them lowering blood pressure between heartbeats more; heart doesn't have to work against as much back pressure. Help relieve "angina" (pain caused by overworking an oxygen-deprived heart). Example: Lanoxin.

Beta Blockers. Antagonists for adrenaline and norepinephrine receptors on heart muscle cells (norepinephrine is a hormone rather that neurotransmitter here). These two hormones cause heart to beat faster (more frequently) and use oxygen faster. Beta blockers (ie. Inderal) block the hormone receptor sites and prevent hormones from causing rapid heartbeat.

Calcium Channel Blockers. Calcium ions flowing into heart muscle cells cause them to contract somewhat during resting period between heartbeat (using oxygen during rest period). When they contract further during heartbeat they squeeze the heart chamber closed more than they would if no calcium present, but exert more pressure to do so and use up more oxygen (can worsen angina). Calcium channel blockers block channels which calcium uses to get into heart cells but not escape channels. This results in less calcium in cells. Example: Procardia.

Clot Dissolvers. Dissolve atherosclerotic plaques and other blood clots on emergency basis to enable coronary blood flow to increase and get oxygen to heart during heart attack. Example: TPA (Tissue Plasminogen Activator).

PROBLEM 36.

What are these drugs for?

Cholesterol lowering drugs: Atherosclerosis.

Vasodilators: Angina or hypertension (high blood pressure).

Diuretics: Hypertension.

Calcium channel blockers: Angina.

Chemotherapy Drugs

Technically, chemotherapy means treating any kind of disease with drugs, but current usage seems restricted to cancer.

Chemotherapy (against cancer) currently works against cells which are reproducing (dividing), but not against cells which are carrying out other functions. Most cells in body (other than skin cells) do not need to divide often except to repair damage. Cancer cells reproduce at uncontrolled rate and spread throughout body. Chemotherapy drugs are toxic because they kill both healthy cells and cancer cells, but kill more cancer cells than healthy cells since cancer cells divide more often.

Alkylating Agents. Designed to bind to nitrogen atoms of DNA bases, these interfere with DNA replication during cell division. Can actually cause cancer as well as fighting it by causing DNA damage. Example: cyclophosphamide.

Antimetabolites. Less brutal than alkylating agents, designed to shut down enzymes involved in DNA replication without damaging DNA. Example: Methotrexate.

PROBLEM 11.

What are these drugs for?

Vasodilators: Angina or hypertension.

Alkylating agents: Cancer.

Beta blockers: Angina.

Antimetabolites: Cancer.

PROBLEM 15.

What classes do these drugs belong to?

Lovastatins: Cholesterol antagonists.

Methotrexates: Antimetabolites.

Chlorphenirimines: Antihistamines.

Pseudoephidrines: Decongestants.