Mohammed N. Sabir

5/16/2017 1

3rd Pharmacy – N.41

A group of alkaloids

in which the

nitrogen atom is not

hetercyclic

(Protoalkaloids) also called atypical alkaloids.

5/16/2017 2

Most are derivatives

of Phenylethylamine

5/16/2017 3

Examples on alkaloids

belongs to this class:-

1-Ephedrine

2-Cathinone

5/16/2017 4

3-Colchicine

4-Capsaicine

5/16/2017 5

1-Ephedra (ma huang)

The overground part of

Ephedra sinica (Ephedrales

or Ginetaceae)

In Chinese:

ma = astringent

huang = yellow

5/16/2017 6

This plant has been used in

Chinese herbal medicine

since 5000 years ago;

While in modern medicine since

1923.

5/16/2017 7

The plant is indigenous to

China and to many parts in

Asia including Kurdistan

Region-Iraq.

5/16/2017 8

The plant is a shrub with

about 50-100cm height.

5/16/2017 9

The major alkaloid is Ephedrine (-)-Erythro-α-[1

(methylamino)ethyl]benzyl alcohol

Production is either by extraction from the plant or chemical

synthesis.

5/16/2017 10

Chemical synthesis from benzylhydroxymethyl ketone and methylamine.

5/16/2017 11

Ephedrine occur as white

needle-like crystals soluble in

water, alcohol, chloroform,

ether and petroleum ether.

5/16/2017 12

It is structure similarity to the

endogenous catecholamines

makes it potent

sympathomimetic agent,

stimulating both α and β-

adrenergic receptors.

5/16/2017 13

5/16/2017 14

Ephedrine and

Pseudoephedrine are mixed

action adrenergic agonists.

5/16/2017 15

Medicinal uses (Ephedrine sulphate and Ephedrine. HCl)…

o Bronchodilator.

o Allergy.

o Cough suppressant.

o Increase BP during shock.

o Vasoconstrictor.

o Decrease inflammation and mucus secretion.

5/16/2017 16

Adenylate cyclase

ATP c-AMP

PKA (c-AMP dependent PK)

Ca++

Na+

Ca++

Beta adrenergic activity

PharmacologicAction

5/16/2017 17

Alpha 2 adrenergic activity

PharmacologicAction

Adenylate

cyclase

ATPc-AMP

PKA

(c-AMP dependent PK)

Ca++

Na+

Ca++

5/16/2017 18

5/16/2017 19

beta2Muscle

beta2Muscle

Tissue Receptor Subtype

Heart beta1

Adipose tissue beta1beta3?

Vascular Smooth

Airway Smooth

5/16/2017 20

5/16/2017 21

5/16/2017 22

5/16/2017 23

At large doses:-

1-

2-

3-

4-

5-

6-

Hypertension

Headache

Dizziness

Palpitation

Vomiting

Toxicities ofEphedrine

Nervousness and insomnia(CNS-effects)

5/16/2017 24

Available as (Ephedrinesulfate & Ephedrine HCl)

Pharmaceutical dosageforms:-

1-Tablets

2-Oral liquid dosage forms

3-Inhalations

4-Injections

Clinical uses:-

5/16/2017 25

Ephedrinederivatives

5/16/2017 26

Compounds with lessα-receptor affinity

N-MethylephedrineNorephedrine

5/16/2017 27

Colchicine

Is the dried ripe seed of

Colchicum automnale

(Fam: Liliaceae)

5/16/2017 28

Colchis = refers to the plant

flourishes

Autumnale = refers to the

Season where the plant

bloom

5/16/2017 29

The plant is indigenous to Europe and North Africa

The Arabs recommended the use of the corn for

Gout.

Colchicum contains the Colchicine (0.6-0.8%).

5/16/2017 30

Colchicine is a weak base and almost

lacks basicity since it does not react

with acids as other alkaloids do,

however; it is precipitated by the

detecting reagents.

5/16/2017 31

Biosynthesis

5/16/2017 32

- Inhibition of leucocyte migration.

- Reduction of lactic acid production.

- Decrease deposition of uric acid.

- Reduction of phagocytosis leading to decrease

the severity of inflammation.

Mechanism of action

5/16/2017 33

Colchicine is also antimitotic agent through affecting the

chromosomes of the cell, in which it will still divided but

without the formation of the spindle fibers and subsequent

cell division.

5/16/2017 34

For such activity, colchicine has been used in

investigation for its anticancer activity in

animals.

5/16/2017 35

Pathophysiology of Gout

Uric acid, the end product of purine

metabolism, is considered a waste product and

serves no known physiologic purpose in

humans.

5/16/2017 36

lacking the enzyme Urate-oxidase (Uricase), which further

degrades uric acid to allantoin, a substance that is more

water soluble and more readily excreted by the kidneys.

5/16/2017 37

5/16/2017 38

Uricase

Excessive uric acid accumulation contributes to

hyperuricemia (defined as an elevated serum uric

acid (sUA) level above 7mg/dl in men and above

6mg/dl in women)

5/16/2017 39

It is considered to be the principle cause of

gouty arthritis which describes acute and chronic

clinical manifestations caused by the deposition

of monosodium urate crystals in articular and

extra articular tissues.

5/16/2017 40

5/16/2017 41

Urate crystals

-Asymmetric swelling within joint on a radiograph

-First metatarsophalangeal joint

is tender or swollen

-Hyperuricemia

-Maximal inflammation

developed within 1 day

-Monoarthritis attack

-More than one acute arthritis

attack

5/16/2017 42

-Redness observed over joints

-Subcortical cysts -Unilateral

first metatarsophalangeal

joint attack

-Unilateral tarsal joint attack

5/16/2017 43

Recent research has identified hyperuricemia as an

independent risk factor for metabolic syndrome,

coronary artery disease, and chronic kidney disease.

5/16/2017 44

Gout refers to disease that occurs in response to

the presence of crystals of monosodium urate

(MSU) in joints, bones, and soft tissues.

5/16/2017 45

Consist of the fresh leaves of

Catha edulis (Celastraceae)Khat

5/16/2017 46

The plant is a tree native to

tropical East Africa.

The plant part that is rich

with the alkaloid is the leaf.

5/16/2017 47

Fresh leaves contains more

alkaloids when compared to

the old ones which contains

the less active metabolite

(+)-norephedrine.

5/16/2017 48

5/16/2017 49

The leaves are Chewed

habitually by the

inhabitants.

Inhibiting the sensation of

hunger and fatigue.

5/16/2017 50

5/16/2017 51

The WHO does not classify Khat a

habitual drug that cause

addiction, however; France

consider it as one of the

narcotics.

5/16/2017 52

Catha edulis contains

phenylalkylamine alkaloid (-)-

cathinone.

5/16/2017 53

Cathinone actions are analogues to (+)-amphetamine

including:-

Induction of catecholamine release from storage sites (CNS

stimulant action).

5/16/2017 54

Psychological effects include

▪Euphoria

▪Anxiety

▪Increased

▪Alertness

libido

▪Concentration

5/16/2017 55

- Energy

- Self-esteem

- Self-confidence

- Sociability

- Irritability

5/16/2017 56

- Aggression

- Psychomotor agitation

- Repetitive and obsessive behavior

- Paranoia

5/16/2017 57

With chronic and/or high doses, amphetamine psychosis

can occur.

5/16/2017 58

Capsaicin…

Derived from Capsicum annuum (Solanaceae)

Chili pepper.

5/16/2017 59

Used topically as circulatory stimulant and

analgesic for arthritis , neuropathy, neuralgia

and as anesthetic.

Also used in psoriasis to decrease itching and

inflammation.

5/16/2017 60

It binds selectively to a protein capsaicin receptor (CR)

on the membranes of pain and heat-sensing neurons.

CR is a heat-activated calcium channel that opens

between (37 – 45)°C .

Upon binding it causes the channel to open below 37°C, which is

why capsaicin is linked to the sensation of heat.

5/16/2017 61

Prolonged activation causes depletion of

presynaptic substance P.

Neurons that do not contain capsaicin receptors

will be unaffected.

5/16/2017 62

A study in 2003 showed that capsaicin

regulate blood sugar levels through

affecting carbohydrate breakdown after meals.

5/16/2017 63

Oil of Capsicum

Oil of Capsicum derived from chili pepper (Capsicum spp.)

5/16/2017 64

Medicinal uses:-

1- Analgesic (topical ointments, dermal patches) in

concentrations 0.025-0.25%.

2- In nasal sprays as decongestant anti-inflammatory.

3- In arthritis.

4- Neuralgia.

5- Reduce itching and inflammation (as creams in

psoriasis).

5/16/2017 65

Purinebases

- Include alkaloids derived from

immidazole ring, the nucleotides

(xanthine bases)

5/16/2017 66

Those which retaintherapeutic activities are:-

1-Caffeine (1,3,7-trimethylxanthine)

2-Theophylline (1,3-

dimethylxanthine)

3-Theobromine (3,7-

dimethylxanthine)

5/16/2017 67

Base Numbering

structures of the five major purine (R) and pyrimidine (Y)

bases of nucleic acids in their dominant tautomeric forms

and with the IUPAC numbering system

Source: Blackburn and Gait, Nucleic acids in chemistry and biology, Oxford University Press New York 1996.5/16/2017 68

Methylxanthines

are biosynthesized from Aspartic

acid, Glycine, Glutamine

5/16/2017 69

5/16/2017 70

1- Caffiene

5/16/2017 71

A purine alkaloid belongs to xanthine

class.

White crystalline powder with bitter

taste.

5/16/2017 72

Caffeine is found in

varying quantities in

the seeds, leaves, and

fruit of some plants

like (Camelia sinensis,

Coffea arabica)

5/16/2017 73

5/16/2017 74

5/16/2017 75

ServiceSize

CoffeesCaffeine (mg)

200) (16 oz. = 266)

Starbucks Brewed Coffee (Grande) 16 oz. 320

Dunkin' Donuts regular coffee 16 oz. 206

Coffee, generic instant 8 oz. 93 (range: 27-173)

Starbucks Espresso, doppio 2 oz. 150

Starbucks Espresso, solo 1 oz. 75

Espresso, generic 1 oz. 40 (range: 30-90)

Starbucks Espresso decaffeinated 1 oz. 4

Einstein Bros. Espresso 1 oz. 75

Starbucks Frappuccino Blended Coffee Beverages, average 9.5 oz. 115

Coffee, generic decaffeinated 8 oz. 5 (range: 3-12)

Starbucks Vanilla Latte (Grande) 16 oz. 150

Einstein Bros. regular coffee 16 oz. 300

Coffee, generic brewed 8 oz. 133 (range: 102-

5/16/2017 76

Teas Service Size

8 oz.

Caffeine (mg)

53 (range: 40-120)Tea, brewed

Snapple, Lemon (and diet version) 16 oz. 42

Snapple Raspberry (and diet version) 16 oz. 42

Nestea 12 oz. 26

Arizona Iced Tea, green 16 oz. 15

Snapple, Kiwi Teawi 16 oz. 10

Snapple, Just Plain Unsweetened 16 oz. 18

Arizona Iced Tea, black 16 oz. 32

Snapple, Peach (and diet version) 16 oz. 42

Starbucks Tazo Chai Tea Latte (Grande) 16 oz. 100

5/16/2017 77

Chocolates/Candies/Other Service Size Caffeine (mg)

Hershey's Special Dark ChocolateBar

1.45 oz. 31

Hershey's Kisses 41g (9 pieces) 9Hot Cocoa 8 oz. 9 (range: 3-13)

Hershey's Chocolate Bar 1.55 oz. 9

Jolt Caffeinated Gum 1 stick 33

5/16/2017 78

Over-The-Counter Drugs Service Size Caffeine (mg)

Vivarin 1 tablet 200

Anacin (Maximum Strength) 2 tablets 64Excedrin (Extra Strength) 2 tablets 130

NoDoz (Maximum Strength) 1 tablet 200

5/16/2017 79

Theophylline Thebromine

5/16/2017 80

Mechanisms of action

Competitive nonselective phosphodiesterase

inhibitor, thereby increasing intracellular c-AMP,

and inhibiting TNF-α and leukotriene synthesis,

thus reducing inflammation and innate immunity

5/16/2017 81

Nonselective adenosine receptor antagonist,

antagonizing A1, A2, and A3 receptors which is

responsible for its cardiac effects

5/16/2017 82

Antibiotics

Mohammed N. Sabir

Pharmacognosy II, Third Year

15-May-17 1

15-May-17 2

Lecture outline…

• Introduction & History

• Development trends

• Screening for Antibiotics

• Commercial production of antibiotics

• Increasing commercial yield

• Recovery & Isolation

• Manipulation of the formulation

• Rational antibiotic therapy

• Classification of antibiotics

Introduction and History… Moldy breads & soy bean curds

15-May-17 3

15-May-17 4

Pyocynase (first commercial antibiotic)

15-May-17 5

Alexander Fleming and

Penicillin

1928

Development of antibiotics… - Screening

- Isolation of mutant M.O.

- Isolation of metabolites

- Chemical modification

- In vitro assessment

15-May-17 6

Screening for antibiotics… Method of screening

15-May-17 7

Screening for antibiotics should be:- Simple

Rapid

Cheap

15-May-17 8

15-May-17 9

Actinomycetes

15-May-17 10

Cycloheximide or Phenol 1 :140

Disinfectant soil sample

15-May-17 11

Inhibition zones

Commercial production of antibiotics… Requirements for production

15-May-17 12

15-May-17 13

Production involves large

fermentation tanks…

The Vegetative growth cultures

are kept through lyophilisation…

15-May-17 14

Advantages of large standard inoculum…

1- Reduce incubation time.

2- Decrease the chance for contamination.

3- Provide optimal nutritional and environmental

conditions for growth.

15-May-17 15

NH3N

Mycelial N2

Sugar (Glucose + Lactose)

pH

0 20 40 60 80 100 Time (Hours)

0

400

80

0

Pe

nici

llin

Conc

./ m

l

Nitr

ogen

gm

/l , S

ugar

gm

/100

ml

0

1

2

3

Penicillin

Increasing commercial yield… Factors that affect Quantity and Quality of production

15-May-17 16

15-May-17 17

Bacillus subtilis provide optimal yield of Bacitracin when

the C/N = 15

At lower or higher ratios the yield is less or produce

undesirable antibiotics.

15-May-17 18

Phenyl acetamide and ampicillin… Phenyl acetic acid and penicillin G… Acyl moieties and Penicillin-V…

15-May-17 19

Increasing Commercial Yield

-Specialized penicillins are prepared by semisynthetic processes.

-Mercaptothiazole in cultures of Streptomyces aureofacciens

enhances production without being incorporated to the AB

structure.

15-May-17 20

Mercaptothiazole and tetracycline…

15-May-17 21

Addition of enhancers…

15-May-17 22 15-May-17 Pharmacognosy II - Antibiotics 22

In penicillin production Lysine inhibits the antibiotic

production.

Sugar Amonia

Α-amino adipic acid

-ve feedback (inhibition or repression)

15-May-17 23

Biosynthetic pathway for penicillin-G

Recovery & isolation…

15-May-17 24

15-May-17 25

Purity of the product will decrease the toxicities, example:-

Vancomycin when purified, the nephrotoxicity will be decreased.

15-May-17 26

-Masking microbial contamination for ABs (to be used

as injectable):-

1. Appropriate treatment before testing sterility.

2. Microfiltration.

Manipulation of formulations… Chemical and physical Why we do formulation changes?

15-May-17 27

Rational antibiotic therapy… Causative agent…

Sensitivity tests…

15-May-17 28

15-May-17 29

Susceptibility tests are performed either by Kirby-Bauer

testing or by turbidity testing to determine a MIC.

15-May-17 30

Criteria for ideal antibiotic...

Patient factors for selecting antibiotics…

Classification of antibiotics…

15-May-17 31

Cell-wall synthesis inhibitors…

15-May-17 32

14-May-17 1

Pharmacognosy II - Antibiotics

Classification of antibiotics…

Katzung & Trevor’s Pharmacology 2005®

Cell wall structure…

www.chemie.uni-hamburg.de

Peptidoglycan…

en.wikipedia.org

www.sigmaaldrich.com

www.3dscience.com

Mechanisms of resistance:-

1- Through changing the structure of PBPs.

2- Through production of β-lactamases (plasmid

mediated).

3- Through changing the structure of Porin.

Chemistry of betalactams…

Piperacillin Ticarcillin

Vancomycin