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Allan Tang

Medicine and drugs: Option D

D.1 Pharmaceutical products

Lines of defense

First line of defense: barriers to prevent entry

Skin

Mucous membranes

Closures and secretions of natural openings such as lips, eyelids, ear wax etc.

Second line of defense: attack invaders

White blood cells engulf invaders (phagocytosis)

Blood clotting to prevent loss of blood and further invasions.

The inflammatory response

Third line of defense: immune system

White blood cells produce specific proteins called antibodies to recognize and destroy the

invaders

Memory cells enable the body to fight a repeat invasion of the same organism more effectively

Medicines vs. Drugs

Drug: a chemical that affects how the body works. This includes changes for the better and for the

worse. The term is sometimes associated with substances which are illegal in many countries, such as

cocaine, ecstasy and heroin.

The effects on the body of drugs include:

Alteration of the physiological state, including consciousness, activity level and coordination

Alteration of incoming sensory sensations

Alteration of mood or emotions

Medicine: a substance that improves health. Medicines, which may be natural or synthetic, therefore

contain beneficial drugs. Synthetic medicines also contain other ingredients, which are non-active but

help in the presentation and administration of the drug. The beneficial effect of a medicine is known as

its therapeutic effect.

The Placebo effect: Patients that receive therapeutic and healing effects from medicines that are

pharmacologically inert, when they believe they are taking an effective drug.

Methods of administering drugs:

Oral: taken by mouth: tablets, capsules, pills, liquids.

Inhalation: vapor breathed in; smoking: medications for respiratory conditions such as asthma.

Skin patches: absorbed directly from the skin into the blood: some hormone treatments like estrogen or

nicotine.

Suppositories: inserted into the rectum: treatment of digestive illnesses, hemorrhoids.

Eye or ear drops: liquids delivered directly to the opening: treatments of infections of the eye or ear.

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Parenteral – by injection:

Intramuscular – drug is injected into a muscle – many vaccines

Intravenous – fastest method of injection – drug if injected directly into the bloodstream – local

anesthetics

Subcutaneous – drug is injected directly under the surface of the skin – dental injections

Therapeutic effect – the intended physiological effect

Side-effect – unintended physiological effects

Sometimes side-effects can be beneficial: aspirin, taken for pain relief, helps prevent against

heart disease

Can be relatively benign: causing drowsiness, nausea or constipation.

Dosing Regimen – the amount of drug used for each does and the frequency of administration.

Many variables used to determine dosing regimen – age, sex, weight, diet, and environment.

Ideally, the dosage should result in constant levels of the drug in the blood, but it is almost

impossible without an intravenous drip.

Therapeutic Window - The range of a drug’s concentration in the blood between its therapeutic level

and its toxic level. Concentration in the bloodstream must remain within a certain range: above this

range, unacceptable side-effects may occur. Below this range there may not be effective therapeutic

outcomes.

Tolerance – when a person is given repeated doses of a drug, and they have a reduced response to the

drug. Higher doses are needed to produce the same effect.

Dependence or addiction – when a patient becomes dependent on the drug in order to feel normal and

suffers from withdrawal symptoms if the drug is not taken.

Discovery research

First stage in drug development involves identifying and extracting compounds that have been shown to

have biological activity and are known as lead compounds. Usually derived from plants, often have low

levels of activity. Microorganisms have rich sources of lead compounds.

Next, effectiveness of the lead compound is optimized by making and testing chemically related

compounds called analogues. Using combinatorial chemistry and high-throughput screening, scientists

test vast numbers of candidate medicines in a short time. Potential medicines then tested on animals.

Development research

Three Phases of human trial, each subsequent human trial involving more patients. In the Phase III, the

effectiveness of the drug is judged by the relative improvement in the patients who have received real

medications compared with those on a placebo.

D.2 Antacids

The stomach produces hydrochloric acid from the linings of the walls that kill bacteria and provide an

optimum environment for digestive enzymes. Some factors, such as excess alcohol, smoking, stress and

anti-inflammatory drugs can cause excess produce of acidic secretion known as gastric juice. This leads

to:

Acid indigestion: a feeling of discomfort from too much acid in the stomach

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Heartburn: acid from the stomach rising into the esophagus – often called acid reflux.

Ulcer: damage to the lining of the stomach wall, resulting in loss of tissue and inflammation.

Antacids

Weak bases which neutralize excess acid.

Work by neutralizing the hydrochloric acid, hence reliving the symptoms.

Antacids are usually weakly basic compounds (often metal oxides or hydroxides, carbonates or

hydrogencarbonates) that react with the acid to produce salt and water.

Examples: Aluminum hydroxide and Magnesium hydroxide.

Magnesium salt tends to act faster and acts as a laxative. Aluminum dissolves more slowly to

provide longer lasting relief.

Other antacids contain metal carbonates and hydrogencarbonates which react with the acid to

produce salt, water and carbon dioxide, which can cause bloating and flatulence.

o Using antifoaming agents can help avert this problem.

Some antacids contain alginates which float to the top of the stomach, which acts as a barrier to

prevent reflux into the esophagus.

D.3 Analgesics

Pain is only a symptom of a bigger problem such as an injury or disease, so long-term relief is dependent

on treating the underlying cause, while analgesics are only there to soothe the pain.

Pain receptors – Detect pain sensations and send nerve messages to the brain.

Prostaglandins – chemicals that stimulate pain receptors, which are released from cells damaged by

thermal, mechanical or chemical energy. Once released prostaglandins also mediate the inflammatory

response by causing the dilation (widening) of blood vessels near the site of injury. This can lead to

swelling and increased pain. Also may cause increased body temperature or fever.

Painkillers must intercept or block this pathway somewhere between the pain receptors and the

perception in the brain.

Mild analgesics

Including aspirin and non-steroidal anti-inflammatory drugs such as ibuprofen.

Act by preventing stimulation of the nerve endings at the site of pain.

They inhibit the release of prostaglandins from the site of injury and give relief to inflammation

and fever as well as pain.

They do not interfere with the functioning of the brain, so they are non-narcotics.

Aspirin

The active ingredient in willow bark that gave it the pain relieving ability was salicin, which is

converted to salicylic acid in the body.

1890, Bayer Company in Germany made an ester derivative of salicylic acid which was more

palatable and less irritating to the stomach, called aspirin.

o Today it continues to hold its place as most widely used drug in the world.

o Used to treat headaches, toothaches, and sore throat.

o Effective in reducing fever and inflammation.

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Aspirin reduces the ability of the blood to clot and this mkes it useful in the treatment of

patients at risk from heart attack and strokes.

o But, can be dangerous if taken by a person whose blood does not blot easily or before

surgery.

Negative side-effects: irritation and ulceration of the stomach, lead to bleeding. May become

more acute when ingested with ethanol. Also linked to Reye’s syndrome, rare and potentially

fatal liver and brain disorder.

Paracetamol

Acts by reducing the production of prostaglandins in the brain, but does not affect the

prostaglandin production in the rest of the body. So, not effective in reducing inflammation.

Safest of analgesics when taken correctly.

o Does not irritate the stomach and rare allergic reactions

But, overdoes or chronic use of paracetamol can cause severe and possibly fatal damage to

kidneys, liver and brain. Used with ethanol, it has toxic effects as well.

Strong analgesics

Including drugs related to morphine, known as opioids.

Bind to the so-called opioid receptors in the brain, which then blocks the transmission of pain

signals between brain cells and so alters the perception of pain.

They cause drowsiness and possible changes in behavior and mood, so are called narcotics.

Most effective pain killers for severe pain, but since they have side-effects and potential

problems with dependence, their usage must be monitored.

Opium

Opioids also known as narcotics, derived from the extract of poppy seeds.

Narcotic drugs derived from opium are primarily morphine and its derivatives.

We are considering three of these: codeine, morphine and diamorphine, known as heroin.

o These are powerful analgesics, acting on the central nervous system to block the

perception of pain.

o Adverse side-effects include:

Causing constipation

Suppressing the cough reflex

Causing constriction of the pupil in the eye.

Narcotic effects

The three drugs have increasing effect as analgesics, increasing narcotic effects and increasing

side-effects in the order: codeine morphine heroin

Codeine, morphine, and heroin have a common basic structure that accounts for their similar

properties, as well as some different functional groups.

o Benzene ring

o Ether

o Alkene

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Codeine

Therapeutic uses:

o Sometimes used in preparation with a non-narcotic drug such as aspirin or paracetamol

in the second stage of pain management ladder.

o Also used in cough medications and in the short-term treatment of diarrhea.

Structure contains: benzene ring, ether(2), alkene, alcohol (1), tertiary amine

Morphine

Therapeutic uses:

o Used in the management of severe pain, such as in advanced cancer

o Can be habit forming and can lead to dependence, so use must be regulated by a

medical professional.

Structure contains: benzene ring, ether, alkene, alcohol (2), tertiary amine

Diamorphine/Heroin

Therapeutic uses:

o Used medically only in a few countries legally for the relief of severe pain.

o The most rapidly acting and the most abused narcotic.

o Initially produces euphoric effects, but very high potential for causing addiction and

increasing tolerance.

o Dependence leads to withdrawal symptoms and many associated problems.

Structure contains: benzene ring, ether, alkene, ester-ethanoate (2), tertiary amine

The conversion of morphine into heroin involves an esterification reaction in which both its –OH

groups are converted into ethanoate (ester) groups by reaction with ethanoic acid. The loss of

two polar –OH groups means that heroin is less polar and so more lipid-soluble than morphine.

This enables it to cross the blood-brain barrier quickly, which is why it is faster acting than the

other opioid drugs. In the brain, it is hydrolyzed to morphine by reversing the esterification

reaction.

World Health Organization (WHO) Three step analgesic ladder.

1. Use mild analgesics.

2. Add a weak opioid such as codeine or tramadol.

3. In severe intractable pain, use strong opioids such as morphine, fentanyl or methadone.

Narcotic effects

In the short term, heroin induces a feeling of well-being and contentment, as it causes a dulling of pain

and lessening of fear and tension.

Long-term regular use leads to constipation, reduced libido, loss of appetite and poor nutrition.

Heroin users start to show dependence relatively quickly, so they cannot function properly without it,

and will start to suffer withdrawal symptoms.

Helping heroin addicts to break their dependence is slow and difficult.

Sometimes an alternative analgesic methadone is administered. This can reduce drug craving and

prevent symptoms of withdrawal.

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D.4 Depressants

Depressants

Drugs that act on the brain and spinal cord (Central Nervous System or CNS).

Changes the communication between the brain cells by altering the concentration or the activity

of chemicals called neurotransmitters.

Cause a decrease in brain activity that in turn influences the functioning of other parts of the

body such as the heart and the mechanisms determining breathing rate.

They include drugs also classified as tranquilizers, sedatives and hypnotics.

Dosage effect: Low to moderate dose:

Calmness

Relief from anxiety

Very relaxed muscles

High dose:

Slurred speech

Staggering gait

Altered perception

Sleep induced

Extremely high doses/lethal dose:

Respiratory depression

Coma/death

Description: Tranquilizer Sedative Hypnotic

Increasing dosage

Ethanol

Present in beer, wine, and hard liquor

Most widely used psychoactive drug and is legal in most countries.

Has antiseptic properties so can be used on skin before an injection or to clean a small wound.

o Rubbed into feet to prevent blistering

In low doses, it can help to create a mild excitement and users become more talkative, confident

and relaxed.

o Evidence that low doses of ethanol might have a beneficial effect on the circulation and

diminish cardio-vascular diseases. Has some mild anti-clotting effects.

Being a CNS depressant, ethanol changes behavior and adverse effects increase as dose

increases.

Short-term effects of ethanol abuse Long-term effects of ethanol abuse

Loss of self-restraint; memory, concentration and insight are impaired.

Loss of balance and judgement

Violent behavior

Dangerous risk-taking behavior

Dehydration

Vomiting, loss of consciousness, coma and death.

Dependence known as alcoholism, associated with withdrawal symptoms

Liver disease, cirrhosis, liver cancer

Coronary heart disease

High blood pressure

Fetal alcohol syndrome

Permanent brain damage

The polar –OH group enables ethanol to form hydrogen bonds with water, making it readily

soluble in aqueous solution.

o Also dissolves in lipids, which allows it to cross cell membranes easily.

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Following ingestion, ethanol passes quickly from the gut into the blood through stomach wall,

and then circulates to all tissues of the body.

90% of the ethanol load is broken down in the liver. Easily passes across the placenta to fetus.

Ethanol has the potential to increase the activity of other drugs when taken at the same time.

The effect is known as synergy.

o Synergistic effects can lead to very serious, even fatal, results.

o Some examples are:

With aspirin, ethanol can cause increased bleeding of the stomach lining and

increase risk of ulcers.

With other depressants such as barbiturates and sleeping pills, ethanol can

induce heavy sedation, possibly coma.

With tobacco, ethanol appears to increase the incidence of cancers, particularly

of the intestines and liver.

With many other drugs, ethanol can interfere with their metabolism by the liver,

which can cause greater and more prolonged drug effects.

Ethanol is a volatile compound and at body temperature in the lungs it establishes equilibrium

between being dissolved in the blood and released into the air in exhaled breath.

o The equilibrium constant Kc for this reaction has a fixed value at a particular

temperature so measurement of the ethanol in the breath can be used to assess the

blood alcohol concentration.

o A breathalyzer that contains crystals of potassium dichromate(vi), are orange, but

become green chromium(iii) ions as they oxidize the ethanol to ethanal and ethanoic

acid.

The extent of the color change is measure with a photocell to determine

ethanol concentration.

o More accurate technique infrared spectroscopy using an intoximeter.

Ethanol has absorption band at 2950 cm-1.

The size of the peak can be used to measure ethanol concentration when

compared to ambient air.

o Gas-liquid chromatography

Blood or urine is vaporized, injected into stream of inert gas. The ethanol gas

and other vapors move at different rates depending on boiling point and

relative solubility in the two phases. Each leaves the column holding the liquid

phase after a specific interval of time called retention time. A peak at retention

time that corresponds to ethanol can be used to confirm its presence.

Benzodiazepines

A major group of depressants that depress activity in the part of the brain that controls emotion

and used as tranquilizers in the treatment of anxiety disorders and related insomnia.

Used as sleeping pill and muscle relaxant.

Little side-effects other than dependence. Used for short term treatments.

Some example drugs are: diazepam (Valium) and nitrazepam (Mogadom)

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o Benzodiazepine implies, they contain both benzene rings and the diazepine structure,

which is a seven-membered heterocyclic ring containing carbon and two nitrogen

atoms.

Widely used anti-depressant drug is fluoxetine hydrochloride, or Prozac. It decreases levels of

serotonin, an important neurotransmitter in the brain. Used to treat depression and eating and panic

disorders.

D.5 Stimulants

Stimulants

A different class of drugs that affect the central nervous system

Function largely opposite to that of depressants. Increase the activity of the brain and the

person’s mental alertness.

o Used to prevent excessive drowsiness and allow greater concentration.

o They can help facilitate breathing by causing relaxation of the air passages.

o They may reduce appetite and so have been used as part of treatment for obesity

o They may cause palpitations or tremors to occur.

o When used in excess, they can cause extreme restlessness, sleeplessness, fits, and

delusions and hallucinations.

They alter the levels of neurotransmitters, chemicals that act as messengers in the nervous

system.

Adrenaline

The hormone that is released in times of stress and enables the body to cope with sudden

demands such as those imposed by pain, shock, fear, and cold.

The response, sometimes called the “fight or flight” reaction stimulates the pathways that:

o Increase the heart rate and blood pressure

o Increase the blood flow to the brain and muscles

o Increase the air flow to the lungs

o Increase mental awareness.

Similar in both its structure and physiological effects to a neurotransmitter called noradrenaline

which is responsible for communication in the part of the nervous system known as the

sympathetic nervous system.

Amphetamines

One major group of similar drugs that act to mimic and enhance the effects of adrenaline and

nonadrenaline.

Have a structure quite similar to that of adrenaline and noradrenaline.

Both adrenaline and amphetamine molecules are derivatives of the phenyl ethyl amine

structures.

Because of their role in stimulating the sympathetic nervous sytem, the amphetamines are

called sympathomimetic drugs.

In small doses: it increases mental alertness and physical energy.

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Side effects: dilation of pupils, decreased appetite, blurred vision, dizziness.

Regular use leads to tolerance and dependence, depression, and reduced resistance to

infections.

Modifications to amphetamine structure produce designer drugs, which are powerful and

addictive stimulants.

o Methamphetamine (speed or crystal meth) and ecstasy.

Nicotine

One of the most widespread and abused stimulants.

Obtained from tobacco plants.

Inhaled as smoke from cigarettes and cigars, but can be chewed as well.

Lipid-soluble molecule, nicotine able to cross blood-brain barrier, bringing rapid effects to brain

activity.

o Increases level of adrenaline, alters concentration of certain neurotransmitters.

Short-term effects of nicotine consumption Long-term effects of nicotine consumption

Increases concentration

Relieves tension and boredom

Helps to counter fatigue

Increases heart rate and blood pressure

Decreases urine output

High blood pressure

Increases risk of heart disease including angina

Coronary thrombosis

Increases the level of fatty acids in the blood which can lead to atherosclerosis and stroke

Over-stimulation of stomach acids which can lead to increased risk of peptic ulcers.

Nicotine is habit-forming, quickly leads to dependence or addiction.

Users will suffer withdrawal symptoms: nausea, weight gain, drowsiness, lack of concentration.

Caffeine

Present in coffee, tea, chocolate and colas.

Legal and unregulated, consumed by 90% of American adults.

Reduces physical fatigue and restores mental alertness.

Caffeine, like nicotine, contains heterocyclic rings (containing both carbon and nitrogen) and a

tertiary amine group. Also has two amide groups.

Acts as a respiratory stimulant increasing the rate of energy release within cells.

o Intensifies and prolongs the effects of adrenaline.

Consumption of caffeine in small amounts Consumption of caffeine in large amounts

Enhancement of mental energy, alertness and ability to concentrate

Acts as a diuretic, increasing the volume of urine; can cause dehydration

Can cause anxiety, irritability and insomnia

Can cause dependence; side-effects on withdrawal include headaches and nausea.

Helps absorb some analgesics and is often included in the formulation of headache pills and

other medications.

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D.6 Antibacterial

First example of a chimerical used to kill pathogens came from observations that certain dyes

used in the dyestuffs industry were able to kill some microorganisms.

1891, this led to the treatment of malaria using methylene blue.

Paul Ehrlich introduced concept of a “magic bullet”, chemical designed to kill specific disease but

not touch the host cells, successfully treated syphilis patients with arsenical drug.

Sulfonamide drugs like Prontosil in 1933, seemed to cure septicemia.

Penicillin

Chemicals, usually produced by microorganisms, which act against other microorganisms.

Alexander Fleming in 1928 worked on bacteria cultures.

o Noticed fungus or mold known as Penicillium notatum had contaminated some of his

cultures, so he was going to throw them away.

o But, he noticed that the mold had generated a clear region where no bacterial colonies

were growing.

Concluded that the mold produced something that specifically inhibited the

bacterial growth.

1940, Howard Florey and Ernst Chain successfully isolated penicillin as the antibacterial agent in

the mold.

o Used in human trials in 1941, helped during WWII, saved thousands of lives and they

won the Nobel Prize with Fleming.

Research moves to the United States, isolation and development of penicillin occurred.

Dorothy Hodgkin in 1945 using X-ray crystallography determined the structure of penicillin G,

the major constituent of the mold extract.

o Core structure is four-membered ring consisting of one nitrogen and three carbon

atoms and known as beta-lactam. This part of the molecule is known to be responsible

for its antibacterial properties.

By acting as an irreversible inhibitor of an enzyme, it prevents the development of cross-links in

bacterial cell walls, so weakening the walls and causing the bacteria to rupture and die during

their reproductive phase.

o Its action is effective against a wide range of bacteria responsible for infections in the

ear, nose, throat, and mouth, and wounds.

Penicillin G can be broken down by stomach acid and has to be injected directly into the blood.

o Different forms of penicillin have been developed by modifying the side chain (the part

denoted as ‘R’ in the structure) and these enable the drug to retain activity when

ingested in pill form.

Bacterial resistance

A major problem with the use of penicillin and other antibiotics.

Penicillin started to prove ineffective against some populations of bacteria.

o Now its known that theses resistance bacteria produce an enzyme, penicillinase, which

can open penicillin’s beta-lactam ring and render it inactive.

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Antibiotic resistance arises by genetic mutation in bacteria that would normally account for a

very small population.

o But the number of resistant organisms increases dramatically when antibiotic exposure

increases.

o Widespread resistant strains of bacteria threaten usefulness of antibiotics.

o Superbugs are bacteria which carry several resistant genes.

Resistance problem increasing because of its wide use of penicillin used in animals feeds to

lower disease in stock.

o This causes antibiotics to enter the human food chain, hence increasing the resistant

bacteria population.

Response to the challenge of antibiotic resistance include:

o Developing different forms of penicillin, with modified side chains able to withstand the

action of penicillinase.

o Controlling and restricting the use of antibiotics by legislation to make them

prescription-only drugs; also encouraging doctors not to over-prescribe.

o Education and encouragement of patients in the importance of completely the full

course of treatment with antibiotic, referred to as ‘patient compliance’; this is essential

to prevent resistant bacteria prolonging the disease or spreading into the community.

D.7 Antiviral

Virus

Small and simple structure

Contain only two components: Protein and nucleic acid(either RNA or DNA)

Has no cellular structure and are only capable of reproducing inside another living cell.

They take over the functioning of another cell (the host cell) and use it to carry out their own

reproduction.

o Host cell’s components are used in the assembly of new viral particles and the cell

eventually dies, releasing thousands of viral particles.

Treating viral infections is a challenge because they live within cells, so it’s hard to target them.

o Lacking cell structure of bacteria, they are not affected by antibiotics.

o They can multiply and spread throughout the body rapidly before symptoms arise.

o Viruses can mutate rapidly (making small changes in their genetic material) and this

changes their susceptibility to drugs.

Fighting against Viruses

Successful vaccination programs enable the body to prepare specific antibodies against a virus,

have reduced incidence of diseases such as cholera, polio and measles.

Some antivirals work by altering the cell’s genetic material (DNA) so that the virus cannot use it

to multiply.

Others clock enzyme activity within the host cell, which prevents the virus from reproducing.

o Progression of the disease will be halted and there will be relief from symptoms, but the

virus will not be completely eradicated. Symptoms can flare up.

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Amantadine

Antiviral drug that causes changes in the cell membrane that prevent the entry of virus into the

cells.

Best used as prophylactic (preventative) before the infection has spread widely, most effective

way to treat influenza.

AIDS

Cause by the human immunodeficiency virus (HIV).

Characterized by a failure of the immune system, so the body falls prey to life-threatening

infections like pneumonia and cancer.

Spread throughout the world, 40 million HIV positive.

HIV

Primarily infects vital white blood cells in the immune system. These cells are called CD4+ T cells.

The virus binds to specific receptor proteins on the cell surface and penetrates the cell.

HIV is a retrovirus (its genetic material is in the form of RNA, not DNA). It releases its RNA into

the cell and the enzyme reverse transcriptase controls the synthesis of viral DNA from the RNA.

o The viral DNA integrates into the cell’s own DNA and replicates when it divides.

o The virus is replicated inside the host cell and released in large numbers when it dies.

Three main reasons HIV is hard to defeat

o The virus destroys T-helper cells, the very cells in the immune system that should be

defending the body against the virus.

o The virus mutates rapidly, with more variations in HIV in a single patient than in

influenza virus worldwide in a year. Variations mean it “escapes” the immune response.

o Virus often lies dormant within host cell, so immune system doesn’t respond to it.

Antiretroviral drugs

Drugs to help fight against HIV.

Act at different stages in HIV lifecycle:

o One is to inhibit the enzyme reverse transcriptase, so it only affects the virus.

o The drug AZT or zidovudine works this way and was approved for AIDS treatment.

Effective in delaying progression.

Blocks transmission of HIV to fetus during pregnancy.

Other antiretroviral drugs:

o Block the binding of HIV to cell membranes

o Inhibit the assembly of new viral particles in the cell.

The variable nature of the virus within cells and the fact that immune response seems to act too

slowly in the HIV infection is the main problem.