INTRODUCTION Presenter:

MAHEYA MIDHAT KHANDepartment Of PharmacyJinnah University For women, Karachi.

DEFINITION

the term “alkaloid” (alkali-like) is commonly used to designate basic heterocyclic nitrogenous compounds of plant origin that

are physiologically active.

Deviation from Definition:

Basicity: Some alkaloids are not basic e.g. Colchicine, Piperine, Quaternary alkaloids.

Nitrogen: The nitrogen in some alkaloids is not in a heterocyclic ring e.g. Ephedrine, Colchicine, Mescaline.

Plant Origin: Some alkaloids are derived from Bacteria, Fungi, Insects, Frogs, Animals

New Definition:

Alkaloids are cyclic organic compounds containing nitrogen in a negative state of oxidation with limited distribution among living

organisms.

ORIGIN AND HISTORY The term alkaloid was coined by Meissner, A German

Pharmacist, in 1819. The mankind has been using alkaloid for various

purposes like poisons, medicines, poultices, teas and etc. The French chemist, Derosne in 1803, isolated Narcotine. A significant contribution to the chemistry of alkaloids in

the early years of its development was made by the French researchers Pierre Joseph Pelletier and Joseph Bienaimé Caventou, who discovered quinine (1820) and strychnine (1818).

Several other alkaloids were discovered around that time, including xanthine (1817), atropine (1819), caffeine (1820),coniine (1827), nicotine (1828), and cocaine (1860).

Nomenclature:

Trivial names should end by "ine". These names may refer to: From plant generic name (Atropine)

From specific plant species (Cocaine)

From the common name of Drug (Ergotamine)

From physiological activity (emetine)

From the name of discoverer (Pelletierine)

From the prominent Physical character (Hygrine)

Distribution and occurrence:

Rare in lower plants. Dicots are more rich in

alkaloids than Monocots. Families rich in Alkaloids:

Apocynaceae, Rubiaceae, Solanaceae and Papaveracea.

Families free from Alkaloids: Rosaceae, Labiatae

Distribution in Plant:

All Parts e.g. Datura. Barks e.g. Cinchona Seeds e.g. Nux vomica Fruits e.g. Black

pepper Latex e.g. Opium Leaves e.g. Tobacco

Forms of Alkaloids:

• Free bases• Salts with Organic acids e.g. Oxalic, acetic

acids• Salts with inorganic acids e.g. HCl, H2SO4.• Salts with special acids: e.g. Meconic acid in Opium

Quinic acid in Cinchona • Glycosidal form e.g. Solanine in Solanum.

Function in Plants

• They may act as protective against insects and herbivores due to their bitterness and toxicity.

• They are, in certain cases, the final products of detoxification (waste products).

• Source of nitrogen in case of nitrogen deficiency.

• They, sometimes, act as growth regulators in certain metabolic systems.

• They may be utilized as a source of energy in case of deficiency in carbon dioxide assimilation.

EFFECTS OF ALKALOIDS ON HUMANS:

High Biological Activity Produce Vary Degrees Of Physiological

and Psychological Responses – Largely by interfering with Neurotransmitter

In large doses- highly toxic – fatal In small doses – many have therapeutic

value

Muscle relaxant, Pain killers, tranquilizers, Mind altering drugs, Chemotherapy

Physical Properties:

I- Condition:• Most alkaloids are crystalline solids. • Few alkaloids are amorphous solids e.g. emetine.

• Some are liquids that are either: Volatile e.g. nicotine and coniine, or Non-volatile e.g. pilocarpine and hyoscine.

II- Color:The majority of alkaloids are colorless but some are

colored e.g.:• Colchicine and berberine are yellow. • Canadine is orange.

• The salts of sanguinarine are copper-red.

Physical Properties:

III- Solubility: Both alkaloidal bases and their salts are soluble in

alcohol. Generally, the bases are soluble in organic solvents and

insoluble in water Exceptions: Bases soluble in water: caffeine, ephedrine, codeine,

colchicine, pilocarpine and quaternary ammonium bases. Bases insoluble or sparingly soluble in certain organic

solvents: morphine in ether, theobromine and theophylline in benzene.

Salts are usually soluble in water and, insoluble or sparingly soluble in organic solvents.

Chemical Properties:I- Nitrogen: Primary amines R-NH2 e.g.

Norephedrine

Secondary amines R2-NH e.g. Ephedrine

Tertiary amines R3-N e.g. Atropine

II- Basicity: R2-NH > R-NH2 > R3-N

According to basicity Alkaloids are classified into:

Weak bases e.g. Caffeine

Strong bases e.g. Atropine

Neutral alkaloids e.g. Colchicine

III- Oxygen: Most alkaloids contain Oxygen and are solid in nature e.g.

Atropine.

Some alkaloids are free from Oxygen and are mostly liquids e.g. Nicotine, Coniine.

Effect of heat:

Alkaloids are decomposed by heat, except Strychnine and caffeine.

Reaction with acids:

1- Salt formation.

2- Dilute acids hydrolyze Ester Alkaloids e.g. Atropine

IV- Stability:

COOH

R-CHNH2 R-CH2NH2 RN=CH RNH-CH-R’ CH2R’’ Schiff Base Alkaloid

COOH Transamination R’-CHO

R’-CHNH2 -CO2

Alkaloid Biosynthesis

Mannich Condensation

H-C-H R”carbonion

Amino Acids Schiff Base Alkaloid

-H2OCO2

Isolation of Alkaloids

• Process remained unchanged >1,000 years

Plant Material

Acid solutionEtOAc: neutral/weakly basic alkaloids

1) Methanol2) Concentrate3) Partition EtOAc/2% acid

Petroleum ether extracts non-polar fats and waxes

Residue: polar material

Wash with petroleum ether

Basic aqueous solution of quaternary alkaloids

1) Ammonia2) Partition with EtOAcEtOAc: basic alkaloids

Purification of Alkaloids

• Gradient pH as alkaloids are basic• Volatile alkaloids: distillation• Crystallisation

• Fractional or acid/base pair

• Chromatography• HPLC, GC, TLC and CC

Precursors of Alkaloids:Alkaloids

OrnithineTropane

Pyrrolidine

Pyrrolizidine

Tyrosine

Benzyl-iso-Quiniline

Tryptophan

Indole Quinoline

Lysine

Quinolizidine Piperidine

N

N

CH3

nicotine

from ornithine

N

O

N

O

strychnine

from tryptophan

O

HO

NCH3

HO

morphine

fromtyrosine

N OH

H3C

Lycopodine

from lysine

CLASSIFICATION OF ALKOLOIDS

TRUE ALKOLOIDS

True alkoloids derived from amino acids Heterocyclic ring with nitrogen Highly reactive substances in low doses

also Bitter taste with white appeareance Form water soluble salts

examples: cocaine,morphine,nicotine,dopamine etc.

NICOTINE

Nicotine is a potent

 parasympathomimetic

 alkaloid found in the

 nightshade family of plants (Solanaceae) and a stimulant drug .

 It is made in the roots of and accumulates in the leaves of the nightshade family of plants.

Nicotine is a hygroscopic, colorless oily liquid that is readily soluble in alcohol, ether or light petroleum. It is miscible with water in its base form.

nicotine forms salts with acids that are usually solid and water soluble.

Nicotine is optically active, having two enantiomeric forms. The naturally occurring form of nicotine is levorotatory (−)-nicotine. The dextrorotatory form, (+)-nicotine is physiologically less active than (–)-nicotine. (−)-nicotine is more toxic than (+)-nicotine. 

CHEMISTRY

SAR

Initially causes nausea and vomiting by stimulating vomiting center in brain stem and sensory endings in stomach. This becomes tolerant.

Stimulates hypothalamus to produce antidiuretic hormone, causing fluid retention.

Reduces activity coming in from muscles, producing relaxation.

Increases heart rate, blood pressure and contractility; but carbon monoxide in smoke combines with oxygen better than hemoglobin, so it decreases oxygen carrying capacity (suffocates cells).

PHARMACOLOGICAL EFFECTS

Nicotine is quickly and thoroughly distributed in the body, to brain, placenta, all body fluids (including breast milk).

Liver metabolizes 80–90 percent before excretion by kidneys. Elimination half-life is ~2 hours. The major metabolite of nicotine is cotinine, which is

basis for tests.

Uses: The primary therapeutic use of nicotine is in

treating nicotine dependence in order to eliminate smoking with the damage it does to health. 

Nicotine medicines release a sufficient amount of nicotine into the body to help stop your craving to smoke

Believe it!

smoking (almost certainly due to nicotine) reduces risk of Parkinson’s disease reduces risk of Alzheimers

schizophrenics on neuroleptics smoke in very large numbers – why?

nicotine also can be neuroprotective (against ETOH WD neurotoxicity for example) suppress certain autoimmune diseases

Doses: In lesser doses (an average cigarette yields about 2 mg of absorbed nicotine), it stimulant 

the nicotinic receptor(cholinergic), while high amounts (50–100 mg) can be harmful and blocks the receptors.

Side effects: Feeling sick (nausea)

Being sick (vomiting)

Indigestion (dyspepsia)

Headache

Dizziness

Dry mouth

Increase in saliva in the mouth

Throat irritation

Cough

Rash

Swelling (oedema)

Nasal irritation

Nose bleeds (epistaxis)

Nasal irritation

Watery eyes

Feeling thirsty

Stomach discomfort

Ear sensations

Inflammation of the blood vessels (vasculitis)

Nightmares

Chest pain

Shortness of breath (dyspnoea)

Sweating

MORPHINE

MORPHINE Morphine is the most abundant opiate

found in opium, the dried latex extracted by shallowly scoring the unripe seedpods of the Papaver somniferum poppy. Morphine was the first active principle purified from a plant source and is one of at least 50 alkaloids of several different types present in opium.

Morphine  is an opioid analgesic drug. Morphine has a high potential for addiction; tolerance and psychological dependence develop rapidly, although physiologicaldependence may take several months to develop. 

Morphine was first isolated in 1804 by Friedrich Sertürner, which is generally believed to be the first ever isolation of a natural plant alkaloid in history.

Sertürner originally named the substance morphium after the Greek god of dreams, Morpheus (Greek: Μορφεύς), for its tendency to cause sleep

CHEMISTRY Morphine is a benzylisoquinoline alkaloid with two

additional ring closures. It has:

A rigid pentacyclic structure consisting of a benzene ring (A), two partially unsaturatedcyclohexane rings (B and C), a piperidine ring (D) and a tetrahydrofuran ring (E). Rings A, B and C are the phenanthrene ring system. This ring system has little conformational flexibility.

Two hydroxyl functional groups: a C3-phenolic OH (pKa 9.9) and a C6-allylic OH

An ether linkage between C4 and C5,

Unsaturation between C7 and C8,

A basic, 3o-amine function at position 17,

5 centers of chirality (C5, C6, C9, C13 and C14) with morphine exhibiting a high degree of stereoselectivity of analgesic action.

Structure activity relationship

USES

Relief of pain caused by heart attack or myocardial infarction.

Relief of the severe bone and joint pain associated with sickle cell crisis.

Pain relief before, during and after surgery.

General anesthsia to sedate a patient. A cough suppressant in cases where

cough is severe enough.

MECHANISM OF ACTION

Opioid receptors

As morphine binds to opioid receptors, molecular signalling activates the receptors to mediate certain actions.

There are three important classes of opioid receptors and these are:

μ receptor or Mu receptors - There are three subtypes of this receptor, the μ1, μ2 and μ3 receptors. Present in the brainstem and the thalamus, activation of these receptors can result in pain relief, sedation and euphoria as well as respiratory depression, constipation and physical dependence.

κ receptor or kappa receptor - This receptor is present in the limbic system, part of the forebrain called the diencephalon, the brain stem and spinal cord. Activation of this receptor causes pain relief, sedation, loss of breath and dependence.

δ receptor or delta - This receptor is widely distributed in the brain and also present in the spinal cord and digestive tract. Stimulation of this receptor leads to analgesic as well as antidepressant effects but may also cause respiratory depression.

ADR

dizziness drowsiness nausea vomiting stomach pain and

cramps diarrhea loss of appetite weight loss

dry mouth sweating weakness headache agitation nervousness mood changes confusion

PROTO-ALKALOIDS

1. ADRENALINEGeneral Characteristics Features:

• Have no nitrogen as part of heterocyclic ring

• Derived from amino acids like Phenylalanine, Tyrosine

• Physiologically active compounds

• Examples: Adrenaline, Ephedrine, Colchicines, Mescaline

Biosynthesis of PROTO-ALKALOIDS

SHIKIMATE PATHWAY

SHIKIMATE PATHWAY

Shikimic Acid

Chorismic Acid

Prephenic Acid

Phenylalanine

TyrosineProto-AlkaloidsE.g. Ephedrine, Epinephrine etc.

ADRENALINE (Epinephrine)

Adrenaline is a hormone and a neurotransmitter• As a hormone it is synthesized by adrenal medulla of kidney

• As a neurotransmitter it is released by some sympathetic nerve endings.

CHEMICAL STRUCTURE

Adrenaline is one of a group of monoamines called the catecholamines. It is produced in some neurons of the central nervous system, and in the chromaffin cells of the adrenal medulla from the amino acids phenylalanine and tyrosine

(R)-4-(1-Hydroxy-2-(methylamino)ethyl)benzene-

1,2-diol

ADRENALINE Mechanism Of Action

“Fight” OR “Flight”

Response of ADRENALIN

E

Blood flow to skeletal muscles

increases

Intestinal muscle relax

Breathing rate

increases

Heart rate

increases

Pupil dilate

Blood pressure

in arteries

increases

Blood sugar level

increases

Clinical Use of

ADRENALINE

Anaphylaxis

Cardiac Arrest

Asthma

Local Anesthetic

s

STRUCTURE-ACTIVITY RELATIONSHIP

HO

OH

OH

HNR

STRUCTURE-ACTIVITY RELATIONSHIP

HO

OH

OH

HNR

CATECHOL

STRUCTURE-ACTIVITY RELATIONSHIP

HO

OH

OH

HNR

AMINE

STRUCTURE-ACTIVITY RELATIONSHIP

HO

OH

OH

HNR

ALKYL GROUP

HOOH

OH

HNR

Series Of Compound From ADRENALINE

OH

OH

HOHN

H

ADRENALINENORADRENALINE

HOOH

OH

HNR

Series Of Compound From ADRENALINE

OH

OH

HOHN

CH

ADRENALINE ISOPRENALINE

CH3

CH3

HOOH

OH

HNR

Series Of Compound From ADRENALINE

OH

OH

OHHN

C

ADRENALINE SALBUTAMOL

CH3

CH3

CH3

Let’s talk about Ephedrine

EphedrineA phenethylamine found in EPHEDRA SINICA. PSEUDOEPHEDRINE is an isomer. It is an alpha- and beta-adrenergic agonist that may also enhance release of norepinephrine. It has been used for asthma, heart failure, rhinitis, and urinary incontinence, and for its central nervous system stimulatory effects in the treatment of narcolepsy and depression.

2D structure of Ephedrine

3D structure of Ephedrine

Chemical properties of EphedrineChemical Names  Ephedrine,

2-(methylamino)-1-phenylpropan-1-ol; Benzyl alcohol, alpha (1-methylaminoethyl)

Formula:  C10H15NO

Molecular Weight 165.2322 g/mol

Boiling Point 260 deg C at 745 mm Hg

Melting Point 38.1 deg C

Solubility In water, 56,900 mg/L at 25 deg C ; 63,600 mg/L at 30 deg Celcius

Density 1.0085 g/cu cm at 22 deg C

Chemistry of EphedrineEphedrine exhibits optical isomerism and has two chiral centres, giving rise to four stereoisomer. By convention, the pair of enantiomers with the stereochemistry (1R, 2S and 1S,2R) is designated ephedrine, while the pair of enantiomers with the stereochemistry (1R,2R and 1S,2S) is called pseudoephedrine. Ephedrine is a substitute amphetamine and a structural methamphetamine analogue. It differs from methamphetamine only by the presence of a hydroxyl (OH).

Stereoisomer of Ephedrine

SAR Ephedrine and pseudo ephedrine are the diastereomers Among the optical isomers of ephedrine and pseudo ephedrine only D(-) ephedrine can significantly block the adrenergic receptors there by lowering blood pressure.

04/15/2023Stucture-activity relationship

On R1 -substitution on Amino Nitrogen= CH3 (the activity of both alpha and beta receptor is maximal when R1 is Methyl.)

On R2- Substitution alpha to basic Nitrogen to Carbon 2 = CH3 (such substitution slows metabolism by MAO but has little over all effect on duration

of action)

On R3- Substitution on Aromatic Ring = H, (provides excellent receptor activity on both alpha and beta receptor)

Receptor Activity= on alpha and beta adrenergic receptors

ephedrine is less polar than the other compounds, and crosses the

blood brain barrier far better than the catecholamine do.

Because of its ability to penetrate the CNS, ephedrine has been used as a stimulant, and exhibits side effects

related to its actions in the brain.

Mechanism of Action

Ephedrine is a sympathomimetic amine - that is, its principal mechanism of action relies on its direct and indirect actions on the adrenergic receptor

system, which is part of the sympathetic nervous system. Ephedrine increases post-synaptic

noradrenergic receptor activity by (weakly) directly activating post-synaptic α-receptors and β-

receptors, but the bulk of its effect comes from the pre-synaptic neuron being unable to distinguish between real adrenaline or nor adrenaline from

ephedrine. 

Uses

Diseases of the respiratory tract with mild bronchospasms in adults and children over the age of six.

Spinal anesthetics during delivery

Used for breathing problems, asthma and nasal swelling/congestion caused by a cold or allergies.

Ephedrine is the active ingredient in ephedra or huang. It belongs to a class

of medications called sympathomimetics. It works like a naturally occurring

substance (adrenaline) that your body makes when it thinks it is in danger. It is a central nervous system stimulant that

increases your heart rate/blood pressure, narrows your blood vessels

(vasoconstriction), and opens up the lungs (bronchodilation).

Side effects

Nervousness Headache

ConfusionDeliriumhallucination, Pallorhypertension tachycardia, Palpitation Sweating, vomiting Anorexia

Restlessness Anxiety Tension Tremor Weakness Dizziness Vertigo

Nervous system

Nervous system side effects associated with large doses of ephedrine have included nervousness, insomnia, vertigo, and headache. 

Cardiovascular

Cardiovascular side effects associated with large doses of ephedrine have included tachycardia and palpitation. Hypertension, stroke, and myocardial infarction.

Gastrointestinal

Gastrointestinal side effects have included nausea, vomiting, and anorexia.

Genitourinary

Urinary retention has mainly been reported in male patients with prostatism.

Genitourinary side effects have included dysuria and urinary retention.

Psychiatric

Psychiatric side effects associated with prolonged abuse of ephedrine have included symptoms of paranoid schizophrenia. Suicide and psychotic episodes have also been reported.

PSEUDO-ALKALOIDS

Caffeine:

“Anger - a better alternative to caffeine.” ― Ilona Andrews, Magic Rises

INTRODUCTION

Caffeine (1,3,7-trimethylxanthine) is a purine alkaloid that occurs naturally in coffee beans .Caffeine is an alkaloid from methylxanthines called 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6,-dione or 1,3,7-trimethylxanthine.Some physiological effects associated with caffeine administration include central nervous system stimulation, acute elevation of blood pressure, increased metabolic rate, and diuresis.Caffeine is rapidly and almost completely absorbed in the stomach and small intestine and distributed to all tissues, including the brain.It is found in varying quantities in the seeds, leaves fruits of some plants, where it act as a natural pesticide.Beverage containing coffee such as coffee, tea soft drinks, & energy drinks.

HISTORY 1st use of caffeine as early as 600,000 BCE .

1820 - Caffeine was first isolated from coffee by German chemist Friedlieb Ferdinand Runge,.

1821 - . Pelletier coined the term "caffeine" from the French word for coffee (café), and this term became the English word "caffeine".

1821 - Pure caffeine extracted from coffee.

1880 - Caffeinated soft drinks appear.

1903 - Researchers remove caffeine from beans ‘without destroying the flavor’.

1923 - Decaffeinated coffee is introduced to the United States.

1940 - The US imports 70 percent of the world coffee crop.

1962 - American per-capita coffee consumption peaks at more than three cups a day.

1995 - Coffee becomes the worlds most popular beverage (overtaking tea ) .

Which Foods and Beverages Contain CaffeineTable 1. Caffeine source and amount of caffeine content

Coffee contain caffeine and theophylline

Theophylline is a dimethylxanthines that have two rather than three methyl groups 3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione; 1,3-dimethylxanthine,

Is considerably weaker than caffeine and having about one tenth the stimulating effect of either. It has a stronger effect on the heart and breathing than caffeine. For this reason it is often the drug of choice in home remedies for treating asthma bronchitis and emphysema. The theophylline found in medicine is made from extracts from coffee or tea.

Why do people become addicted to caffeine?

A person who drinks 1 cup of coffee a day over seven days will build a tolerance to this amount of caffeine. This person will have to consume 2 cups of coffee to feel the same effects as before but again will build a tolerance to that amount of caffeine. Over time this cycle will lead to an addiction to caffeine and will have negative side effects on the body. 

Caffeine as a Drug

The behavioral effects of caffeine can be characterized principally as a reduction in fatigue and boredom, as well as a delay in the onset of sleep.

Recent evidence suggests that caffeine might lower the risk of developing Parkinson’s disease in men.

A comparable protective role in women is currently uncertain.

© Copyright 2011, Pearson Education, Inc. All rights reserved.

Caffeine as a Drug

Health risks from moderate consumption of caffeine are not clinically significant, except for the adverse effects on fetal development during pregnancy, the development of bone loss among the elderly, a possible adverse effect on the cardiac condition of patients already suffering from cardiovascular disease, and the aggravation of panic attacks among patients with this disorder. © Copyright

2011, Pearson Education, Inc. All rights reserved.

Mechanism of Action

Caffeine's primary mechanism of action is as an

antagonist of adenosine receptors in the brain.

Adenosine in the Brain

In the brain neurons are transmitting electrical energy.

When activity is too high adenosine molecules stop the neuron cells from firing.

Caffeine blocks adenosine receptors with its own molecule preventing the adenosine molecule from binding.Brain activity remains at its excited state and can even increase in activity because adenosine is unable to slow it down.

Similar chemical struct = mimicking behavior

The binding of Adenosine to an adenosine receptor causes the receptor to undergo a shape change which triggers a biochemical cascade. The end result is the opening of ion channels and the slowing of activity.

The binding of caffeine to a adenosine receptor causes a shape change that does not initiate a biochemical cascade. Instead, neuronal activity remains the same or increase.

Adenosine Caffeine

Adenosine Receptor

Adenosine Receptor

Caffeine Extraction Processes

Super critical Fluid Extraction Microwave-assisted extraction ultrasonic extraction heat reflux extraction

Health Benefits of Caffeine

Caffeine helps ward off Alzheimer’s. In Japan researchers have shown that caffeine

increases memory. Caffeine detoxes the liver and cleanses the

colon when taken as a caffeine enema. Caffeine can stimulate hair growth on balding

men and women. Caffeine relieves post work-out muscle pain

by up to 48%. Caffeine can ease depression by increasing

dopamine in the brain.

Caffeine increases stamina during exercise. Caffeine protects against eyelid spasm. Caffeine may protect against Cataracts. Caffeine may prevent skin cancer. A new

study out of Rutgers University found that caffeine prevented skin cancer in hairless mice.

People who consume caffeine have a lower risk of suicide.

Caffeine may reduce fatty liver in those with non-alcohol related fatty liver disease. This study comes out of Duke University.

Negative Side Effects of Caffeine

Effects on Heart Rate and Blood Pressure

Osteoporosis Diabetes Loss of sleep Fertility and miscarriage Hormonal Effects

Fig. 5. Main symptom of caffeine overdose

Caffeine products

Scitec Caffeine capsuleAlpecin Caffeine Shampoo

Plantur 39 Caffeine Tonic

Alert energy caffeine gum

Nestle Nescafe gold coffee

Cocacola Beverage

Awake caffeinated chocolate

Decaffeinated products

Nescafe decaf coffeeTassimo nabob decaf coffee

Zevia caffeine free cola

Twinings pure green tea

Conclusion

The good and bad of caffeine

Caffeine is part of modern life. Regular coffee drinkers include the majority of adults and a growing number of children. The recommendation for most people is to enjoy one or two cups of coffee a day, which will allow you to capitalize on its health benefits without incurring health drawbacks. Extensive recent research has put forth that coffee is far more healthful than it is harmful. Very little bad and a lot of good come from drinking it.

 

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