Drugs: Comprehensive Study Notes

Drugs

Introduction

Pharmacology: Derived from Greek words "Pharmacon" (drug/medicine) and "loges" (learning/science).
- Science dealing with drugs, their nature, actions, mechanisms, pharmacokinetics, therapeutic uses, preparations, and administration.
Drug: From the French word "Drogue" (dry herb).
- Any chemical substance altering body functions at the molecular level.
- Used for diagnosis, prevention, or treatment of disease.
- Substance that kills germs or affects body function/structure.
Pharmacodynamics: What drugs do to the organism.
- Studies of biological and therapeutic effects and mechanisms of action.
Pharmacokinetics: What happens to drugs inside the body.
- Studies of absorption, distribution, metabolism, and excretion (ADME) of drugs and their mathematical relationships.
Drug Nomenclature: Drugs are named in 3 ways:
- Full chemical name.
- Nonproprietary name (official or approved).
- Proprietary name (trademark) - commercial property of a pharmaceutical company.
- N.B: Generic name refers to a class or a genus of compounds, e.g. sulphonamides or barbiturates. However, "generic" is often misused to mean "nonproprietary".
Sources of Drug Information: Pharmacology textbooks, medical journals, and pharmacopoeias.
- Pharmacopoeia: Official book containing a selected list of widely used drugs and medicinal preparations.
  - Descriptions of physical properties and tests for identity, purity, potency, and safety.
  - Description of standard preparations and average adult doses (70 Kg weight).
  - Introduces drugs according to therapeutic usefulness.
  - Many nations publish their own pharmacopoeia (B.P., U.S.P., Egyptian P., etc.).
Psychoactive drug: A drug that alters sensory perceptions, mood, thought processes, or behavior.
Legal (licit) drugs: Drugs that can be manufactured, distributed, and sold legally.
Illegal (illicit) drugs: Drugs that cannot be manufactured, distributed, or sold legally and usually lack recognized medical value.
Psychological dependence: A psychological state of mind characterized by a desire to continue taking a drug even though clinical signs of physical illness may not be apparent.
Drug use: A general term to describe drug-taking behavior.
Drug misuse: Inappropriate use of a prescription or nonprescription drug.

Sources of Drugs

Plant: Morphine, digoxin, quinine, and pilocarpine.
Animal: Insulin, thyroxine, vaccines, sera, vitamins.
Mineral: Salts, bases, acids (magnesium sulfate, iron salts).
Synthetic: Sulfonamides, aspirin, procaine, and chloroquine.
Microorganisms: Antibiotics (penicillin, streptomycin).
Genetic Engineering (Recombinant DNA technology): Insulin, growth hormone, colony-stimulating factors, erythropoietin, interferons, rtP-A.

Drug Abuse, Drug Dependence, and Addiction

Drug Abuse

Excessive non-medical or social drug use.
Non-medical drug use: Continuous or occasional use to achieve one's well-being, whether by choice or compulsion.
Drug abuse (=drug misuse): Any use of an illegal drug or legal drug detrimental to one's health or the health of others.
"Non-medical drug use": Use of any drug in a manner deviating from approved medical or social patterns.
Two principal forms:
- Continuous use when there is a true dependence for e.g. opioids, alcohol.
Drugs used for non-medical purposes are often classified into two groups:
1. Hard drugs:
  - Drugs liable to disable the individual as a function member of society, by inducing sever psychological and physical dependence.
  - Examples: Heroin, morphine, alcohol, and cocaine.
2. Soft drugs:
  - Less dependence-producing drugs.
  - May produce psychological dependence, but little or no physical dependence.
  - Examples: Sedatives, tranquilizers, amphetamine, cannabis, alcohol, to caffeine and hallucinogens.

Drug Dependence

A state arising from repeated, periodic, or continuous administration of a drug, resulting in harm to the individual and sometimes to society.
The subject feels a desire, need, or compulsion to continue using the drug.
Feels ill if abruptly deprived of it (abstinence or withdrawal syndrome).
A state of chronic intoxication due to repeated drug use.
Detrimental to individual and society.
Compulsion to continue drug intake.
Usually occurs with drugs that affect mood and behavior.
Dependence may be:
- Psychological dependence: Emotional distress if the drug is withdrawn.
- Physical dependence: Accompanies psychological dependence in some cases. Physical illness if the drug is withdrawn.

Addiction

The most severe form of dependence where compulsive craving dominates the subject's daily life.
Characterized by:
1. Overpowering desire or need (compulsion) to continue taking and obtain the drug.
2. Tolerance or tendency to increase the dose of the drug.
3. Psychological and physical dependence.
4. Withdrawal symptoms (abstinence syndrome).
5. Detrimental effect to the individual and society.

Types of Drug-Dependence (WHO classification)

Opiate type (Opioids): Severe psychic dependence. Physical dependence develops quickly. Tolerance is marked. Cross-tolerance occurs with related drugs. Naloxone induces abstinence syndrome.
Alcohol-barbiturate type:(Alcohol, barbiturates benzodiazepines) Severe psychic dependence. Physical dependence develops slowly at high doses. There is tolerance and cross tolerance.
Amphetamine type: (Amphetamine, dexamphetamine, methylphenidate, methylamphetamine): Severe psychic dependence, slight physical dependence, and rapid tolerance. Psychosis occurs during use.
Cocaine type: Like amphetamine, but tolerance does not occur.
Cannabis type: (Hashish, marihuana): Some psychic but doubtful physical dependence. No characteristic abstinence syndrome. Tolerance is slight.
Hallucinogen type: (LSD, mescaline, psilocybin, phencyclidine): Like cannabis dependence.
Nicotine (Tobacco; snuff): Strong psychic slight physical dependence.
Volatile compounds: (Acetone, toluene, $CCl_4$, petrol, paint thinners, hair lacquer): Psychic and slight physical dependence with tolerance.

Natural Products

Alkaloids

Complex basic nitrogenous substances.
Insoluble in water, but their salts are soluble.
Alkaline in reaction.
Contain N, C, H; most containO₂. Those containing O₂ are solids (xanthine bases, atropine, eserine). Those not containing O₂ are liquids (nicotine, lobeline, and pilocarpine).
Precipitated by alkaloidal reagents (tannic acid, picric acid, phosphotungstic acid, heavy metals, Mayer's reagent).
Possess optical activity.
Very potent drugs.

Glycosides

Ether-like combinations between sugar and an organic group (genin or aglycone).
Glucoside if the sugar is glucose.
Not alkaline in reaction and do not form salt with acid.
On hydrolysis, split at the ether linkage liberating sugar and aglycone.
The genin or aglycone is the active part.
Sugar increases solubility, GIT absorption, accessibility, and fixation to cells.
Examples: Cardiac glycosides, rutin.

Oil

Fixed oils:
- Esters of fatty acid with glycerol.
- Used as demulcents (olive oil), emollients to soothe skin and mucous membranes, laxatives (castor oil), and vehicles for fat-soluble substances.
Volatile oils:
- Volatile, alcohol-soluble, odorous principles found in plants.
- Used to correct drug taste and smell, as plain muscle relaxants (antispasmodics), local anesthetics in toothache (oil of clove), carminatives to relieve distension and flatulence, counterirritants in rheumatic pains (methyl salicylate), and as reflex CNS stimulants.

Resins

Oxidation products of volatile oils.
Examples: Podophyllum resin used in the treatment of malignant warts.

Gums

Secretory substances from plants.
Used to suspend insoluble substances in water, prepare emulsions from oils, and as laxatives.
Examples: Gum arabic, agar, psyllium seeds.

Tannins

Plant constituents that have a bitter taste and astringent action on mucous membranes (precipitate surface proteins).
Used to stop diarrhea (tannic acid).

Antibiotics

Substances produced by living microorganisms (bacteria, yeast, and fungi) that can kill or inhibit the growth of other microorganisms.

Alkaloids (Detailed)

Introduction

Many of the earliest isolated pure compounds with biological activity were alkaloids.
The term alkaloid or alkali-like was first proposed by the pharmacist, W. Meissner in 1819.
Alkaloid definition:
- A plant-derived compound.
- Contains nitrogen in a heterocyclic ring.
- Is basic.
- Is of limited distribution in the plant kingdom.
- Complex molecular structures.
- Manifest significant pharmacological activity.
Widely distributed bases of plant origin (methyl, trimethyl, simple alkylamines, cholines, and betaines) are not classified as alkaloids; they are designated as biological-amines or proto-alkaloids.
Phenyl alkylamines are also classified among biological amines.
The distinction is arbitrary.
Alkaloids usually have a complex structure with the nitrogen atom involved in a heterocyclic ring.
Thiamine is not regarded as an alkaloid due to its almost universal distribution in living matter.
Colchicine is classed as an alkaloid due to its particular pharmacological activity and limited distribution in the plant world.

Occurrence and Distribution in Different Organs of the Plant

About 1000 alkaloids are known, belonging to about 100 families, 500 genera, and 1200 species.
Not equally distributed among the plant kingdom.
Nearly absent in Algae and in the lower groups of plants, with the exception of one or two families of the fungi.
Fungal examples include ergot and various mushrooms.
Streptomyces sp. produce the antibiotic alkaloids chloromycetin (chloramphenicol) and erythromycin.
Alkaloids are of common occurrence in the monocotyledons (Amaryllidaceae and Liliaceae).
Majorities are in the dicotyledons.

Alkaloids of the Pyridine Group

Five subgroups:
- A: Alkaloids having pyridine group alone, e.g., Trigonelline.
- B: Alkaloids having pyridine with other nitrogenous ring, e.g., Tobacco Alkaloids.
- C: Tetrahyropyridine Alkaloids, e.g., Areca Alkaloids.
- D: Piperidine Alkaloids, e.g., (1) pepper Alkaloids, (2) Conium Alkaloids, (3) Lobelia Alkaloids and (4) Pomegranate Alkaloids.
- E: Pyridone Alkaloids, e.g., Ricinine.

A. ALKALOIDS HAVING PYRIDINE GROUP ALONE

Trigonelline:
- The betaine of 1- Methyl nicotinic acid.
- Occurs in coffee beans and other plants.
Crystalline compound that dissolves in water, giving a neutral solution.
When heated with HCl at 260°C, it decomposes into methyl chloride and nicotinic acid.
$Trigonelline + HCl \xrightarrow{260°C} Methyl Chloride + Nicotinic Acid$

B. ALKALOIDS HAVING PYRIDINE WITH OTHER NITROGENOUS RING: Tobacco Alkaliods.

TOBACCO
- Introduction
  - Tobacco consumption is increasing in countries of the Eastern Mediterranean Region.
  - Globally, approximately three million people die every year from tobacco consumption (expected to increase to ten million people every year by the year 2025).
  - Increase due to population growth, rising income, affordability, increased smoking among girls and women, lack of awareness, advertising, and insufficient tobacco-control funding.
- Tobacco Use Spreads
  - Over 60 species of Nicotiana, but only two major ones: Nicotiana tobacuum and Nicotiana rustica.
    - Nicotiana tobacuum: Major species grown today in over 100 countries, is large leafed. Most importantly, tobacuum was indigenous only to South America, so the Spanish had a monopoly on its production for over a hundred years.
    - Nicotiana rustica: A small-leaf species and was the plant existing in the West Indies and eastern North America when Columbus arrived.
TOBACCO ALKALOIDS
- The leaves of the tobacco plant (Nicotiana tobacum L., Family Solanaceae) contain several alkaloids, of which nicotine constitutes about three-quarters of the total alkaloid content.
  *The leaf contains about 4-6% of nicotine.
- Other volatile liquids are nor-nicotine and anabasine, as well as the non-volatile liquid alkaloids nicoteine and nicotyrine, and the solid tobacco alkaloid, nicotelline.
Preparation of Tobacco Alkaloids
- Powder + water + HCl:
  - Extract concentrated + NaOH. And steam distillation
    - Liquid in distillation flask
      - Extract with benzene and evaporate
        Residue (nicotine, nicotyrine)
        Dissolve in ether and concentrate
        Distillate (nicotine, anabasine, nornicotine)
        Neutralize with acid and concentrate
        Add NaOH.
        Extract with ether.
        ↓
        Evaporate ether. 5- Add to residue Hcl cold $NaNO_2$solution.
        Crystals
        Mother liquor
        oily nitroso-derivative
        aq. Layer+NaOH
        Nornicotine evaporate
        of (anabasine, Nicotelline), Extract with ether, heat with HCL, add NaOH & steam Distillate extract with ether & evaporate Separate by fractional distillation under vacuum. nicotine]
        Nicotelline (Solid)
        Nicoteine
NICOTINE
- *The formula for nicotine Is $C{10}H{14}N_2$
It includes three double bonds.
Mol. Wt.: 162.23
Density in natural state: 1.0097
Introduction:
Boiling point: 264 °C
*
Melting point: - 79 °C
Nicotine is one of more than 4.000 chemical found in the smoke from tobacco products such as cigarettes, cigars and pipes. It is the primary component in tobacco that acts on the brain.
Smokeless tobacco products, such as snuff and chewing tobacco also contain many toxins as well as high levels of nicotine.
There are many species of tobacco plants; the tabacum species serves as the major source of tobacco products today.
Nicotiana tobacum:
(ni co she ann a toe back um) species of tobacco widely cultivated for smoking and chewing products.
Nicotiana rustica:
(Russ tick a) less desirable species of tobacco not widely grown in the United States.
Properties of nicotine:- or what is nicotine?
Nicotine is one of the most frequently used addictive drugs.
Chemical properties:
- Pure nicotine is a colourless liquid alkaloid, b.p 264°C, it turns brown when burned and acquires the odor of tobacco when exposed to air. It is soluble in alcohol, ether or petroleum ether. Its miscibility with water at the temperature rang of 60-210 °C is limited, but it is miscible with water in all proportion below and above this temperature range. The salts of nicotine are readily water soluble.
  Exposure of nicotine to ultraviolet light may convert it to nicotine oxide, nicotinic acid and methylamine.
  Where it is found?
  Nicotine is found in cigarettes or any tobacco products.
  How is it obtained?
  Nicotine is obtained from tobacco plant or leaves, which are used in, for example, cigarettes.
  Other properties:
  A colorless poisonous alkaloid, $C{10}H{14}N_2$. derived from the tobacco plant and used as an insecticide. It is substance in tobacco to which smokers can become addicated. Nicotine is not a highly reactive compound. It is mainly used in cigarettes.
Tests of Identity of Nicotine:
1. An aqueous solution of nicotine, on the addition of a solution of paradimethylamino-benzaldehyde in chloric acid, gives a rose-red colour, which changes gradually to violet colour.
2. On shaking an aqueous nicotine solution with 5ml. of .5g vanillin in 100ml conc. HCl a red colour is given.
3. On adding one drop of formaldehyde to little nicotine and leaving for 12 hours and then treating with a drop of nitric acid, a red colour is developed.
4. On treating a solution of nicotine in ether with an equal volume of an etherial solution of iodine, an oily precipitate of nicotine periodide $BHI.I_2$ will gradually crystallize out in the form of ruby red needles showing blue colour in reflected light.
The Prevalent form of Nicotine:
- Cigarette smoking is the most prevalent form of nicotine addiction in the world. Most cigarettes of market today contain 10 milligrams (mg) or more of nicotine.
- Through inhaling smoke, the average smokers takes in 1 to 2 mg nicotine per cigarette.
- Nicotine is absorbed through the skin and mucosal lining of the mouth and nose or by inhalation in the lungs.
- Cigarette smoking, for example, results in rapid distribution of nicotine throughout the body reaching the brain within 10 seconds of inhalation.
  The composition of tobacco smoke:-
  The composition of tobacco smoke is complex (about 500 compounds have been identified in it) and varies with the type of tobacco and the way it is smoked. The chief pharmacologically active ingredient is nicotine.
  Smoke of cigars and pipes is alkaline (pH 8.5) and nicotine is relatively unionized and lipid soluble so that it is readily absorbed in the mouth. Cigar and pipe smokers thus obtain nicotine without inhaling (they also have a lower death rate from lung cancer).
  Smoke of cigarettes is acidic (pH 5.3) and nicotine is relatively ionized and insoluble in lipids. Desired amounts of nicotine are only absorbed if it is taken into the lungs where the enormous surface area for absorption compensates for the relative lipid insolubility. Cigarette smokers therefore inhale (they have a high rate of death from lung cancer). The amount of nicotine absorbed from tobacco smoke varies from 90% in those who inhale to 10% in those who do not.
  Tobacco smoke contains 1-5% carbon monoxide and heavy smokers may have as much as 15% of their haemoglobin as
carboxyhaemoglobin, which cannot carry oxygen. This is sufficient to reduce exercise capacity in patients with angina pectoris. The plasma t of carboxyhaemoglobin is about 4 hrs so that heavy smokers with angina pectoris who reduce their cigarette consumption by only a few cigarettes a day will not achieve any useful reduction in carboxyhaemoglobin. Chronic carboxyhaemoglobinaemia causes polycythaemia.
*Substance (polycyclic hydrocarbons and N-nitroso compounds) carcinogenic to animals has been identified in tobacco smoke condensates from cigarettes, cigars and pipes.
*
Is nicotine addictive?
- Yes, nicotine is addictive. Most smokers use tobacco regularly because they are addicted to nicotine. It is well documented that most smokers identify tobacco as harmful and express a desire to reduce or stop using it, and nearly 35 million of them make a serious attempt to quit each year. Unfortunately, less than 7 percent of those who try to quit (=stop) smoking can achieve their aim.
- Atypical smoker will take 10 puffs on a cigarette over a period of 5 minutes that the cigarette is it lit.
  Scientists can see the dramatic effect of cigarette smoking on the brain and are finding a marked decrease in the level of monoamineoxidase (MAO) A and B, (it is an important enzyme that is responsible for breaking down dopamine, since dopamine acts as transmitters).

So, researches have shown that nicotine decreases the MAO levels, and that due to increasing the levels of neurotransmitter dopamine in the reward circuits of the brain.

So, the smoker has a desire to continue smoking (why?) to sustain the high dopamine levels. That explain why the smokers have a desire for repeating the use of drug (the smoking).
Absorption and metabolism of nicotine:
- Inhalation is very effective drug-delivery system, with 90% of inhaled nicotine being absorbed. The physiological effects of smoking one cigarette have been mimicked by injecting about 1 mg of nicotine intravenously.
  *Nicotine is primarily deactivated in the liver, with between 80% and 90% being modified before excretion through the kidneys.
Nicotine's Effect on the Body
Adrenal glands are stimulated causing a release of glucose in blood.
Affect the CNS. The heart beat faster, blood vessels constrict or become smaller, and both of BP and respiration increases.
Suppresses insulin output from pancreas, so, smokers are slightly hyperglycemic (hyperglycemia).
Since nicotine causes the heart to beat much faster, blood vessels constrict, blood pressure rises. It also stimulates nerves in muscles, but this quickly gives way to kind of paralysis.
In small doses, nicotine causes tremors while in large doses, causes, convulsions.
Small doses stimulate breathing, while large ones have the opposite effect.
At first, the smoking of nicotine sharpens thinking but soon the user feels tired and let down
Nicotine excites the vomiting reflex both in the brain and in the nervous of the stomach
Nicotine also acts on the brain to produce addiction. So it is the cause of continued tobacco use by any person.
Nicotine also affects the brain as both a stimulant and a sedative.
The average cigarette contains about 1.5% nicotine or about (6-8) milligrams of nicotine.
So, the principal use of nicotine is an insecticide, commonly used in the form of a 40% solution of nicotine sulfate in various formulations.
Repeated exposure to nicotine due to the development of