TOPIC FINAL: ANTINEOPLASTIC AGENT the factor that can contribute to its development; certain

NEOPLASMS or Cancer (NEO- “NEW”) virus, exposure to radiation, and as well as when you have
● Neoplasms or neoplasia – uncontrollable or abnormal limited antioxidant, nutrient this factor can initiate, promote
growth or spread of tissue or the formation of tumors. or lead to the progression and abnormal growth of tissue
● New or unusual growth of tissue, tumors- abnormal eventually become malignant or cancerous. In addition, it can
swelling in a tissue or in a body part or organ of the body be in the genetics.
● It’s also determined by biopsy procedure where they are: • Based on psychology and oncologist they conclude
● May be benign – still not invading, not destroying the that the main culprit for developing of cancer is the
tissue by which it originate, does not affect, spread the food.
other part of the body or tissue kung saan siya nag grow GOALS
dun lang siya; encapsulated pa attach to tissue or Goal for treatment it depends in the type, stage of cancer that
malignant (cancer) - in the sense it's already destructive, the patient has or diagnose with,
its invaded, destroy the tissue that surround it, it also Curative
spreading into the blood stream sa blood vessel and ● Total eradication of cancer cells
through lymphatic system or immune system of the ● Lower tumor cell burden at which level host
body. So kapag nag spread to other organ or other sight immunological defenses may keep the cells in control
of origin is metastasis (blood, lungs, bones).
Palliative
● Alleviation of symptoms, decrease tumor size, control
growth
● Avoidance of life-threatening toxicity
● Increased survival and improved quality of life
● Its not to cure the cancer but rather at least lessen the
symptoms, to become tolerable to patient (symptoms,
pain, discomfort experience by the patients, at least
livable his/her days)

Adjuvant therapy
● Attempt to eradicate microscopic cancer after surgery
Carcinoma- it’s the cancer of epithelium; in the surface
● Example: when the breast of patient been removed it still
● Sarcoma- cancer in connective tissue (bone, muscle)
check if there are strain or residue of the cancer cells but
● Leukemia- cancer in the bone marrow; affected are RBC.
it can be eradicated through this therapy
● Lymphoma - cancer in the lymph nodes
● Myeloma- cancer in the Immune system
Salvage Chemotherapy (salvage means to save)
● Example: Lymphocytic leukemia – affect both the bone
● an attempt to get a patient into remission, after previous
marrow and the blood system; then affected also the
therapies have failed
lymphatic system
● Last resort for management; in the case when all the
available method are conducted but still no
ORIGIN OF THE CANCER
improvement to patient or the cancer still progress. Use
of Aminediyl life threatening drug – drugs that still in
clinical trial but given permit by the FDA to be use for
patient with imidine life threatening disease- patient who
has a life-threatening period or has a certain time.
● Example: The fault in our star (novel)

NeoAdjuvant
• Chemotherapy is given to decrease the tumor burden
before definitive therapy (surgery, radiation)
• PCOL: the patient is subjected to KISS therapy or in
the anti-thyroid agent for certain period or week like,
the minimum period is like 2 week or 1 month to 6
months. The patient will subject to KISS or Saturated
Solution of Potassium Iodide or anti thyroid agent for
Carcinogenesis can be cause by several factors one or the the objective of this is to reduce the tumor size. If the
other can contribute; possibly in not just cause for the cancer patient has hypothyroidism or to achieve new thyroid
to develop but one way to other can contribute to its state means to become normal the size of the thyroid
occurrence. Like example when expose or repeatedly expose before to subject in surgery.
to chemicals that are “carcinogenic”- its cancer generating or
cancer producing agent or chemical or can cause by the excess Remission
nutrient in the body or excess form of energy example is the • Oncologists prefer to use the term complete
unsaturated fats; it’s not also mean when you expose to response or remission to indicate a patient with no
carcinogenic agent is magkakacancer ka kaagad hindi it’s only evidence of disease after treatment.
 • Not necessary cure or not literal the patient is cancer TUMOR CELL PROPERTIES
free but there is no evidence of the disease.
• Example the cancer survivor they are not cure in the
cancer rather under remission sila. Example yung iba
after how many years, 10-15 years bumabalik pa yung
cancer sometimes mas malala pa and sa ibang part of
the body pa.

LOG KILL HYPOTHESIS

● According to the log-kill hypothesis, chemotherapeutic Metaphase since they inhibit the microtubular formation. If
agents kill a constant fraction of cells (first order kinetics), they stop the formation of microtubules there will be a
rather than a specific number of cells, after each dose problem in the metaphase stage. Diba sa metaphase stage
nagaalign yung mga chromosomes in the equatorial region
and then they will become pulled by spindle fiber
microtubules to each pole of the cells kapag nasira ang
microtubules magkakaproblem how metaphase progress in
the next stage.
CYCLINS
● During the entire cycle, movement from one phase to the
next is driven by proteins known as cyclins and their
associated cyclin-dependent kinases (CDK)

The size of tumor will determine if symptomatic or

asymptomatic or lethal or fetal the tumor burden. The have a surveillance system in DNA synthesis for example
DNA polymerase that proof reads kung tama yung DNA base
Usual if less than 1 gram the tumor the patients still pairing, kung meron bang irepair, mutations, kung magre’
asymptomatic. But when the tumor is in 1 gram – above its replicate or transcribe translate si proteins magiging defective
detectable na (or kung sa breast yan nakakapa na yan ng
patient) it is symptomatic. Behind the cancer cells is the body or rather than cancer cells
overcome the surveillance of the body or etong mga repair
If the patient tumor is on 1kg it can be fatal or lethal na. system natin.
 (2) the ethyleneamines; triethylenemelamine, thiotepa
Notes:
• The development of half of all Cancers is thought to result (3) the alkyl sulfonate; busulfan
from misfolding of p53 – refers to the protein of the body
refers to guardian of the cells; if the cells have damage it will (4) the nitrosoureas; carmustine lomustine
repair; if to damage it will signal apoptosis- program cell
death or suicide. (5) the triazenes; dacarbazine
So, in can cancer cell may misfolding na nangyayari sa p53 so
walang nagyayaring repair that taking place, or nawawala ang ALKYLATION OF DNA BASES
program cell death

AUTOCRINE SIGNALING
● The ability of some cells to synthesize their own growth
factors – mode that tell the cells if it will undergo
apoptosis or not .

Cancer therefore...
Is the FAILURE of cells to undergo apoptosis, (programmed cell
death) – IMORTAL

CELL CYCLE

Guanine then bind the agent to alkylate guanine the guanine

not be able to go replication and further reaction necessary for
the cells.
NITROGEN MUSTARDS
● Mechlorethamine
● Cyclophosphamide
● Ifosfamide
● Melphalan
● Chlorambucil

Dialkylating agents- one mustard molecule can alkylate two

nucleophiles (Example: Mechlorethamine)

CELL CYCLE NON- SPECIFIC AGENTS

- They don’t specifically act upon in certain stage in
the cell cycle.
Alkylating Agents
● Alkylation of DNA is thought to lead to cell death
● Literally they bind or attach to DNA by alkylating the DNA
by virtue of nitrogen ang kanilang component or ang
kanilang electron withdrawing group, para si DNA di na
makakapagreplicate so syempre pag di na nakapag
replicate si DNA, hindi na rin siya makakapagtranscribe ,
translate, di na makakapag synthesize ng protein, di na
makakaproduce si cells ng kailangan nya metabolite
leading to inhabitation of cell proliferation or cell
reproduction and eventually lead to cell death.

● DNA is unable to replicate→→X cell proliferation cell

death

Alkylating Agents
Mechlorethamine (living group si chloride; so si chloride ang
(1) the nitrogen mustards; mechlorethamine; igigiveup nya or irerelease nya so that yung knya
cyclophosphamide; ifosfamide; melphalan; pharmacophore or central nucleus will be retain and the living
chlorambucil group will be vacant to alkylate the DNA base)
Mechlorethamine is to reactive, flammable and not ideal for
oral administration.

Aziridine is the intermediate product of Mechlorethamine ,

one way to another it contributes to its toxicity and this can be
managed though by administration of Na thiosulfate. MESNA - 2-MERCAPTOETHANESULFONATE
NITROGEN MUSTARDS: CHLORAMBUCIL MELFALAN
Na thiosulfate is a strong nucleophile so si sodium thiosulfate
ang magiging role nya is sulfate coming form it can replace or
can take the place rather nung nileave ni chloride to act as
antidote in Mechlorethamine toxicity; to converting
Mechlorethamine to polar and readily excretable metabolite.

CYCLOPHOSPHAMIDE

● CHRONIC LYMPHOCYTIC LEUKEMIA

● ACUTE LYMPHOBLASTIC LEUKEMIA

ACTIVE PART: PHOSPHARAMIDE MUSTARD that become also

Aziridine
That can alkylate the DNA by forming DNA cross linkage
● TOXIC: Arcolein – (Also of Chloroform)
● Hydroxylation in the liver (same with chloroform it BOTH:
hepatotoxic) prone in covalent binding specifically to - It slows down the reaction in the formation of
liver cell or tissue) Aziridine, making oral administration possible for
them
- Responsible in the activity is the Phenyl Ring
- Living Group- Chloride
- also interfere and damaging the cells; the DNA the
damage induces cell cycle arrest and cellular
apoptosis. It will activate/ accumalates the P53 ni
Chlorambucil and Melfolan
- Activate BAX – BCL2 apoptosis promoter not direct
abbreviation of BAX

ETHYLENE IMINES: THIOTEPA

Cyclophosphamide need activation of CYP enzymes

In cases of extravasation (drug escapes from the tumor into

the underlying tissue) ....

For toxicity a strong nucleophile is given.

● Sodium thiosulfate
● The resulting adduct has increasing water solubility

- Free form azolidine, its employed in bladder cancer

- Its more reactive at low Ph
 Desulfuration Hydrolysis – h2o

Triethylenephosphoramide

Triethylene
thiophosphoramide
)

Aziridine

ALKYL SULFONATES

APPLIED IN BRAIN TUMOR

CARMUSTINE-BCNU (Bis-Chloroethyl
nitrosourea)

- Need: 4-5 alkyl substituents – optimal for LOMUSTINE- CCNU (Chloroethyl-

antineoplastic activity Cyclohexyl nitrosourea)
- Leaving Group: Sulfone
- If less than to 4 to 5 to short the alkyl in the center of These two agents can cause
sulfone, the sulfone will not be removed and the Myelosuppression is the dose limiting
bond will become strong between alkyl group and effect or bone marrow suppression. Pag
sulfone. If di mareremove si sulfone it will not alkylate nagkaroon neto baba yung production
the DNA. mucosite , white blood cell, red blood
- If masyado naman mahaba ang ating alkyl group cells and even mga thrombocyte or clotting factor
hindi naman makakaattach at hindi din maa’alkylate
ng DNA. It must be 4-5 carbon lang dapat. The rest of Nitrosureas can cross blood brain barriers because
- Fatl pulmonary Fibrosis, “busulfan lung” of excellent CNS penetrating activity.

NITROSUREAS
● Undergo spontaneous non-enzymatic degradation with TRIAZENES
the formation of the 2- chloroethyl carbonium ion from Dacarbazines/ Procarbazine
diazohydroxide formed ● Undergoes N-demethylation (liver, CYP450)
● Liberates isocyanate that attach carbamoyl groups to the ● Forms Diazomethane
lysine residues of proteins- inactivate DNA ● Can inhibit MAO and aldehyde dehydrogenase (causing
disulfiram-like reaction---cannot metabolize alcohol

ANTIMETABOLITES
● Purine Analogs
● Pyrimidine Analogs
● Folic Acid Analogs

They refer to antimetabolite because they mimic purine and

pyrimidine nitrogen bases and as well as folic acid to disrupt
or inhibit upon particularly DNA synthesis or S phase of the cell
cycles to act upon or to cause activity against neoplasms or
cancer.
2-ethyl carbon group
● Though we have to take note: that for all antimetabolite s MERCATOPURINE
Myelosuppression is the dose- limiting toxicity for all
drugs in this class.
Diba sa alkylating agents we only have nitrosoureas
Carmustine and lomustine with this dose limiting toxicity. But
for this group agent lahat sila dose limiting toxicity nila si
Myelosuppression

PURINE ANALOGS
● Mercaptopurine
● Thioguanine
● Azathioprine
● Pentostatin
● Hypoxanthine and guanine

▪ Major pathway for inactivation is through S-

Methylation by (TPMT. Thiopurine-S-methyl
transferase) and by oxidation through XO- Xanthine
Oxidase.

- So, in other hand kung TPMT ang nagiging by product

ni mercaptopurine after S methylation after oxidation
mercaptopurine converted to Thiouric acid which the
idea that uric acid trigger in gouty arthritis.
- Ideal if taas ang uric acid pwede bigyan ng Anti-gout
or substance that will inhibit uric acid; but take note:
- Mercaptopurine should not be given with Allopurinol
why? Since Allopurinol yes, its anti-gout medication
that would intent to lower the uric acid level yun nga
lang will have a drug interaction in Mercaptopurine in
Thioguanine and Mercaptopurine they acted upon by HGPRT relation to mechanism of action of Allopurinol.
is the Hypoxanthine, guanine phosphoribosyl transferase - Allopurinol inhibits (-) Xanthine Oxidase. Since
meaning the transfer of phosphate group to the ribose of this Xanthine Oxidase inactivates Mercaptopurine so kug
compound. walang xanthine oxidase malelessen yung activation
ng mercaptopurine or the elimination in the body
HGPRT acting upon to thioguanine to mercaptopurine will magaccumalate yung toxic metabolite in
converted to T-GMP (Thioguanosine monophosphate) and T- mecaptopurine therefore increase yung potency or
IMP (Thioinossine monophosphate) so when they are now yung activity and as well as toxicity mercaptopurine
phospho- related they will accumulate to inhibit inosinate
oxygenase ▪ Azathioprine, a derivative of 6- Mercaptopurine, is
used as an immunosuppressive agent. It is a hetero
The Inosinate Oxygenase if it inhibited again will affect or act derivative of 6-Mercaptopurine
upon the DNA or the S phase during cell cycle.
▪ Vidarabine (D-arabinose from D-ribose)
Again, they metabolize first by HGPRT to become T-GMP and
T-IMP accumulate the inhibit the Inosinate Oxygenase ▪ Fludarabine (addition of fluorine in D- ribose)

Inosinate Oxygenase needed to purine synthesis or for the ▪ Cladribine (chlorine incorporated in the adenine)
synthesis of guanine as well as adenine; though thioguanine
and mercaptopurine take note that resistance may happen for
three reasons:

1. Decrease on enzyme of HGPRT or decrease in

HGPRT- kasi kailangan muna nilang mactivate by
HGPRT para mainhibit yung inosinate oxygenase,
syempre kapag mababa yung level ng HGPRT or
walang HGPRT so affected ang kanilang activity.
2. Decrease by Drug Transport – so kung nagkaroon ng
modification sa structure nila, in term on transport
mechanism involving in this drug it will cause also
resistance
3. Increase Degradation by alkaline phosphatase
 PYRIMIDE ANALOGS • Fluorouracil (5-FU) is used in the treatment of cancer. It
● Fluorouracil is a pyrimidine analog. 5-FU has been in use against
● Floxuridine cancer for about 40 years, acting principally as a
● Cytarabine (cytosine arabinoside) thymidylate synthase inhibitor. Thymidylate synthase is
● Gemcitabine an enzyme important in the synthesis of pyrimidine for
DNA replication.
- So, they analog of either Cytosine, Uracil or Thymine.
FLUOROURACIL (5-FU) • 5-FU is the first choice for the treatment of colon cancer
- Analog of Uracil PRODRUG OF 5-FU

- This also an anti-fungal agent and in addition they

have Anti neoplastic captivity.
- 5-Fluorourocil actual have an activity that would - To reduce the catabolic INACTIVATION of 5-FU by
block the conversion of Uridine (Hydrogen in position
DPD (Dihydropyrimidine dehydrogenase) product
number 5). Pyrimidine base present in DNA is
like the following are produced. Para atleast pag
thymidine so uridine needs to be converted to
pasok ni Capecitabine and Tegafur in the body it
thymidine to utilize in DNA synthesis. So there is by would not recognize by Dihydropyrimidine
which method which uridine converted to thymidine .
dehydrogenase to be metabolize or to be inactivated .
So, the 5-flurourocil inhibits the particular
So if for nasa circulation na siya nakapag by pass na
mechanism by inhibiting the Thymidylate synthase.
sa first pass effect dun lang siya magiging 5-
- Si binoblock nya yung enzymes thymidylate synthase
flurouracil, so atleast marereduce natin yung
to block the convertion of uridine to thymidine.
inactivation ni 5-fluoracil
- the Fluorine also incorporated in structure here uracil
- In addition Tegafur is heating to birds in one stone
making fluorouracil causing in increasing by acidity kasi si tegafur iniinhibit nya rin si DPD, so
thereby binding more strongly in thymidylate
nakkapagtago na siya as 5-flurouracil naiinhibit nya
synthase.
pa yung enzymes that would supposedly inhibit 5-
• Fluorouracil is converted into a ‘fraudulent ‘nucleotide.
flurouracil or inactivate 5-flurouracil.
Instead of having FUMP to UTP, uridine
monophosphate hanggang sa maging Triphosphate na CYTARABINE
maiincorporate to RNA para mag protein synthesis so it
would acts like UMP or uridine monophosphate so
● Cytarabine (Ara-C) was discovered in Europe in the
magiging Fluorodeoxyuridine monophosphate
1960s. It gained FDA approval in June 1969. Cytosine
hanggang maging FUTP pero mainincorporate into RNA
arabinoside is an antimetabolic agent with the chemical
pero dahil defective kasi peke lang so walang or
name of 16-arabinofuranosylcytosine. Its mode of
maiinhibit din yung protein synthesis.
action is due to its rapid conversion into cytosine
• So two mechanism by which inhibits DNA as well as
arabinoside triphosphate, which damages DNA when the
Protein synthesis. cell cycle holds in the S phase.

- It also a fraudulent DNA base siya so it would like act

cytosine; (fake so it would disrupt and damage the
DNA synthesis)
 - The difference between the two instead of amino
acid group or Folic acid it has methyl group
substituting hydrogen in amino making it tertiary
amine instead of secondary amine.
- And then the replacement of oxygen in folic acid with
again amino group thereby increasing the basicity of
methotrexate.
MTX
● DIHYDROFOLATE REDUCTASE inhibitor
● PSEUDO IRREVERSIBLE (Higher pH-alkaline)
● Folate acid inhibition kills cells in the S phase
Toxicity in Methotrexate is associated with myelosuppression;
Leucovorin is given to prevent toxicity in normal cells. Given 6-
24 hours after treatment with MTX)

- In combination with daunorubicin or thioguanine for

the treatment of acute nonlymphocytic leukemia CYTOTOXIC ANTIBIOTIC

GEMCITABINE ● Daunorubicin
● Gemcitabine (Gemzar). As with fluorouracil and other ● Doxorubicin
analogues of pyrimidines, the drug replaces one of the ● Dactinomycin
building blocks of nucleic acids, in this case cytidine, ● Idarubicin
during DNA replication. ● Valrubicin
● It is given iv, and is the first line treatment for small lung ● Bleomycin
cancer ● Mitomycin
● Fluorination of the sugar moiety ● Plicamycin
● Also inhibit the ribonucleotide reductase ● Streptozocin
- They derive in Streptomyces Species
- disrupt DNA function and cell division

MOA:
• Intercalation
▪ Planar molecule inserts itself between base
pair of DNA
▪ (-) Topoisomerase
Example: Guanine and cytosine; Adenine and thymine sisiksik
FOLIC ACID ANALOGS
sila dyan sa base pairs kung magkakaroon ng intercalation,
● Methotrexate
mutation ang katumbas; The intercalation among DNA pairs
will now affect or inhibit the Topoisomerase – this
METHOTREXATE topoisomerase is responsible in unwinding the DNA nee ded
for transcription. Transcription is DNA to RNA diba iunwind
yung DNA portion lang naman iunwind para matranscribe at
makakuha ng certain genes para maging Mrna. Pero kung
naiinihibit young topoisomerase yun lang affected ang
magiging transcription process.
• Alkylation
• Strand Breakage

Literally they are being study or discovered in antibiotics but

they too toxic parang maging antibiotics lang so the
researchers lead to discovered them as antineoplastic agent.
BLEOMYCIN
- Isolated from Streptomyces verticillius
- Naturally occuring as Cu-chelates

Intercalates between
G-C base pairs

- Dihydrofolate reductase what converts folate to

tetrahydrofolate, so pano nya nabloblock ang DNA
synthesis yung tetrahydrofolate is folic acid is needed
or thymidine and purine synthesis.
 - Binding to DNA followed by single strand or double ANTHRACYCLINES
strand cleavage
- ROS formation from BLEO-IRON complex.

Mode on inactivation is through Hydrolysis through Bleomycin RED

Hydrolase it is found in low concentration in concentration in
the skin and lungs. Thus reddening of the skin, skin darkening
(hyperpigmentation) and PULMONARY TOXICITY occurs.

ACTINOMYCINS
● Isolated from Streptomyces sp.

Structure: planar
oxidized anthracene
nucleus fused to a
cyclohexane ring
that is subsequently
connected to an
amino sugar

● Streptomyces peucetius
● It intercalates into DNA and decreased synthesis of both
DNA and RNA
Inhibition of topoisomerase II > Strand breakage >
Apoptosis

*Take note that all ACTINOMYCINS has pharmacophore ● Doxorubicin: is the prototype and also widely use
Phenoxazone antineoplastic agent
DACTINOMYCIN ● Daunorubicin is dehydroxylated (instead of having
Specific at G1 and S phase alcohol in R2, hydrogen)
Penta peptide lactone
● Idarubicin: it is a dimethoxy analog of daunorubicin but
● INTERCALATES the dimethoxylation of the Idarubicin it contributes to its
between the less cardiotoxic activity
base pairs of ● Epirubicin is the ethermer difference is in R3- hydroxyl
DNA and group.
inhibits
topoisomerase Doxorubicin, Daunorubicin, Epirubicin, Valrubicin –
II CARDIOTOXIC BECAUSE OF DIMETHOXY ANALOG
● Particularly at
guanine-
cytosine ROS formed in Anthracyclines
● Streptomyces • Oxidation of cellular components or of
parvulus 3-phenoxazone,-1,9-dicarboxylic acid Anthracyclines result from the intercalation of base
pairs.
• ROS are formed
• REDOX recycling (ROS) -> cardiotoxicity

• Chelation of iron
Dexrazoxone (Totect)

Mitoxantrone
• Intercalation by chromophore
• (-) Topoisomerase II → strand breakage →apoptosis
• Not a substrate for reductase enzymes
- Lack of activation (side chain)
- Reduced cardiotoxicity
 PLANT PRODUCTS - Vinorelbine – semi- synthetic; employed in
Epipodophyllotoxins – from mayapple (mandrake) lung cancer
• Etoposide - Vinblastin – most active
• Teniposide - Vinkristin – is irreversibly binds in
microtubular
Camptothecins – from Cantoteca - Adverse Effect: neuropathy
• Irinotecan
• Topotecan TAXANES
● First isolated from bark of Western/ Pacific yew (Taxus
Vinca Alkaloids- from Periwinkle (Cantharanthus Roseus) brevifolia)
• Vinblastine ● NIH screening of plant extracts 1960s (but during their
• Vincristine discovery less potent ang mga naeextract from taxol. So
• Vinorelbine they modified the structure of taxol to come up in
Taxanes – From taxus tree Paclitaxel and this time is the texacxel
• Paclitaxel ● Mechanism: Different binding site compared with vinca
• Docetaxel alkaloids
- Middle of b-tubulin sub unit
- Paclitaxel – for breast and ovarian cancer
REVIEW ON MITOSIS
- Docetaxel – breast cancer particularly the
- All Plant product will act upon Mitosis stage
metastasize
particularly metaphase stage; they suppress
EPIPODOPHYLLOTOXINS
microtubule (sinisra nila yung mga
● The epipodophyllotoxins are semisynthetic derivatives of
microtubule that also need for spindle fiber
na kailangan natin during mitosis; so pag podophyllotoxin, which is isolated from the mayapple
naiinihibit nila ang metaphase walang (mandrake) root and functions as an inhibitor of
microtubule function.
anaphase, walang telaphase and walang two
daughter cells
● Topoisomerase II
● S and G2 phases of the cell cycle ; Halos lahat ng cell cyle
ang ininhibit nya
ETOPOSIDE
● Affects DNA topoisomerase II (not intercalating)
● Forms a ternary complex with topoisomerase II and DNa
● DNA strand breakage
Antimitotic agents bind to microtubuli ● Leukemia posttreatment
Supression of microtubuli dynamics
Metaphase arrest

● Mitotic spindle fails to form properly → chromosomes do

not move to metaphase plate →anaphase fails to
occurs→ cell undergoes apoptosis
VINCA ALKALOIDS
- Cantharanthus Roseus
4-hydroxy

The removal of 4-hydroxyl group in podophyllum toxin is not

applicable since its important in activity of etoposide to inhibit
topoisomerase II
Teniposide - Derivative from Etoposide; has a thiophene
structure which replace the methyl group in etoposide which
make Thiophene makes it 10 times more potent than
etoposide

CAMPTOTHECINS
Binds to microtubuli-Supression of microtubuli dynamics ● Type I Topoisomerase inhibitors: These chemotherapy
agents are extracted from the bark and wood of the
Metaphase arrest
Chinese tree Camptotheca accuminata. They work by
Depolymerization of microtubuli high conc.
-
 forming a complex with topoisomerase DNA. This in turn ● NEPHROTOXICITY- much less common with
suppresses the function of topoisomerase. CARBOPLATIN compared with Cisplatin

C7, C9, C10 – Incharge of ARSENIC TRIOXIDE

intercalation ● Active form: dimethyl arsenic acid (not employed since
arsenic is toxic)
● For promyelocytic leukemia
- Produces DNA fragmentation characteristic
of apoptosis

HYDROXYUREA
● Active against cells at S phase
Inhibition of ribonucleotides (to deoxyribonucleotides)
▪ (-) Ribonucleotide diphosphate reductase
● Camptothecins which includes irinotecan and topotecan ● Complexes with the IRON portion of the subunit
are commonly used type I topoisomerase inhibitors, first ● GUANAZOLE- same action
discovered in the late 1950s. ▪ ACTIVE FORM: DIAMINOTRIAZOLE
● Well absorbed after oral administration
● Intercalators
● Main toxicity is bone marrow depression expressed as
leukopenia, anemia, and occasionally thrombocytopenia
MISCELLANEOUS COMPOUNDS
● Gastrointestinal Toxicity
● Cisplatin
● Carboplatin
L-ASPARAGINASE
● Hydroxyurea
● Asparaginase
● Pegaspargase ● L-ASPARAGINE – nutrient for tumor cells
● Altretamine ● Inhibition of the nutrient
● Mitoxantrone ● Produced through recombinant DNA on E. coli (or Erwinia
caratovora)
● Gallium Nitrate
● Arsenic Trioxide ● PEGASPARGASE- alternative polymeric
● Bexarotene monomethoxypropylene glycol (if allergic and
● Sargramostim hypersensitive si patient)
● Filgrastim
ALTRETAMINE
PLATINUM CONTAINING ● METABOLIZED TO: pentamethylamine
▪ Platinum complex- inhibitor of DNA polymerase ● SURAMIN- may also inhibit angiogenesis and induce
- like alkylating agents normal cellular differentiation by increasing tissue
- displacement of chloride ions by N, O glycosaminoglycans
● Employed in resistant ovarian cancer
Original: cis-dichlorodiammineplatinum II (cisplatin)
SAGRAMOSTIM/ FILGRASTIM
CISPLATIN ● Granulocyte-macrophage colony stimulating factor (GM-
● CARBOPLATIN- cis isomer CSF)
● OXALIPLATIN- oxalate containing ligand ● For bone marrow recovery (patient with leukemia)
● ORMAPLATIN- six ligands (4 chlorides, 1,2- ● DIFFERENCES IN THE CONSTRUCT
diaminocyclohexane)
HORMONES
Reproductive system related cancer: Ovarian, Breast,
Testicular, Prostate cancer some of which are something
to do with hormones. (One of the reasons why cancer
being developed because some cases it over production)
● MITOTANE
● DROMOSTANOLONE
● TESTOLACTONE
● MEGESTROL ACETATE
● TAMOXIFEN CITRATE
● TOREMIFENE CITRATE
● FLUTAMIDE
● NILUTAMIDE
● BICALUTAMIDE
● CISPLATIN- is used in combination with Bleomycin and ● ESTRAMUSTINE
Vinblastine for metastatic testicular tumors ● LEUPROLIDE ACETATE
● TRIPTORALEN PAMOATE
● GOSERELIN ACETATE Bind to cytosolic androgen receptors and block the effects of
● ANASTRAZOLE testosterone and androgens.

- STEROID HORMONES including estrogens, GLUCOCORTICOIDS

androgens, progestins and glucocorticoids ● PREDNISONE- receptor mediated apoptosis
act at the level of transcription - Suppression of Pituitary gland
- Prostate CA
- The depression of the genetic template
operation, which stimulates the cellular MITOTANE
process ● Selective for only one gland
● CYTOTOXIC
- Some neoplasms are hormone dependent

ESTROGEN

Ethinyl estradiol

AROMATASE INHIBITORS
Estrogen dependent. Breast cancer
Inhibit estrogen biosynthesis

Since aromatase enzymes is what convert cholesterol to

estrogen
ANTIESTROGEN

● TAMOXIFEN is an antiestrogen that has been used

successfully in the treatment of postmenopausal women.
(Ovarian or breast cancer)
● BINDS TO ESTROGEN RECEPTOR competitive inhibitor of
estrogen.

● TOREMIFENE- analog of TAMOXIFEN differing in the

presence of Chlorine
● TESTOSTERONE propionate-for Breast Cancer
● TESTOLACTONE- no androgenic side effects
● PROGESTERONE- AGAINST neoplasms stimulated by
estrogens
Antiandrogen
TRIFLUOROMETHYLANILINE
- FLUTAMIDE
- NILUTAMIDE
- BICALUTAMIDE
WEEK 14- ANXIOLYTIC AND ANTIPSYCHOTIC AGENTS: ZDI/CJJ

ANXYIOLYTIC AGENT
GABA A RECEPTOR MODULATOR
- Or those act upon to the GABA receptors to
modulate the activity of the GABA which is
an inhibitory transmitter which is
responsible for causing CNS depression
activities, and those group of drugs upon
GABA receptors will include:
- Benzodiazepine, non-BZD, Barbiturates,
Gen, anesthetics

MELATONIN RECEPTOR AGONIST

- Ramelteon
Sedative Hypnotics which also employed as
ATYPICAL AZASPIRODECANEDIONES Anxiolytics agents, basically when you said Sedative
- Buspirone this agent would cause calming effects to the
patients when we say Hypnotics agent substances
MISCELLANEOUS that induce sleep to a patient.
- Chloral hydrate, Meprobamate,
Gluthetimide Anxiolytics – referred to anti-anxiety medication
and under this group for pharmacologic
SEDATIVE /Hypnotics classification is the Benzodiazepines and
AGENTS THAT ACT UPON GABA RECEPTOR: Barbiturates that acts upon the GABAergic systems
1) Benzodiazepines (BZDs): or GABA receptors.
- Alprazolam, diazepam, oxazepam, triazolam

2) Barbiturates:
- Pentobarbital, Phenobarbital

3) Alcohols:
- Ethanol, chloral hydrate, paraldehyde,
trichloroethanol

4) Imidazopyridine Derivatives:
- Zolpidem

5) Pyrazolopyrimidine
- Zaleplon

6) Propanediol carbamates:
The GABAergic Synapse basically, the GABA
- Meprobamate
channels or receptor rather activated by increase of
influx of Chloride ions cause the activation of GABA
7) Piperidinediones
receptors. The influx of Chloride ions technically
- Glutethimide
causes the hyperpolarization then this
hyperpolarization cause relaxation on the post
8)Azaspirodecanedione
synapse. Then the relaxations eventually lead to
- Buspirone
inactivation of CNS or brain activity causing
collectively CNS Depressions. This two agent
benzodiazepines and Barbiturates will affect the
influx of chloride ions by the channels; by affecting
the GABA receptors.
WEEK 14- ANXIOLYTIC AND ANTIPSYCHOTIC AGENTS: ZDI/CJJ

- 1963, diazepam (Valium) – Popular until

today.

Benzodiazepines metabolize by CYP3A4 enzymes

system and 2C19. And had replace the Barbiturates
in terms of popularity for benzodiazepines sub cure
drug interaction and low abuse potential.

MOA: increasing the frequency of the opening of

Chloride channels.
PHARMACOKINETICS
- lipophilic
- can cross BBB, placenta, mammary gland
- ↑lipophilic -> ↑ CHON binding
- Pentameric Structure composed of Alpha,
↓ duration of action
Beta, Delta, and Gamma Subunits
- Major player in Inhibitory Synapses
METABOLISM
- Binding of GABA causes the channel to
- N-dealkylation
open and Cl- to flow into the cell with the
- oxidation at carbon alpha to C=O and C=N
resultant membrane causing
(imines)
hyperpolarization
Basically, the benzodiazepines (BZD) and the
Barbiturates (BARB) and those GABA agonists MECHANISMS OF ACTION
agents would affect the receptors of the GABA or ⚫ Benzodiazepines
the sub-units to regulates the influx of chloride ions. - Enhance GABAergic Transmission
↑ frequency of GABAergic channels
PCOL: ↑receptor affinity for GABA
Benzodiazepines – affect the frequency of opening
of the GABA chloride channel or the voltage = inc. influx of Cl-hyperpolarization = relaxation;
channel. Increase the frequency or the number of inactivation of brain = DEPRESSION.
times that the chloride channel would be open for
the influx of the chloride. ACTIONS
Benzodiazepines are more and specifically target
Barbiturates – affect the duration of opening of the the Alpha Receptors (Alpha 1 and 2)
channels. Prolonged the duration of that this GABA
channels are opened. 1. a2 GABA receptors - Reduction of anxiety
through the promotion of GABAenrgic transmission
That will be allowed the influx of the chloride ions. which results in inhibiting neuronal circuits in the
Or they will allow the influx more of Chloride ions limbic system. Alpha 2 receptor acted upon
or GABA agonist they will activate more the GABA, benzodiazepines only reduce anxiety or will
to cause hyperpolarization or invention of manifest an anxiolytic activity.
activation of CNS.
2. a1 GABA receptors - Sedative/hypnotic effects
GABA A MODULATOR occur at doses larger than anxiolytic doses or anti-
⚫ Benzodiazepine anxiety agents.
⚫ Non-Benzodiazepine
⚫ Barbiturates 3. a1 GABA receptors = larger dose cause
Anterograde amnesia
HISTORY
4. a1 GABA receptors = larger dose cause
- 1959 = chlordiazepoxide (Librium®) was
Anticonvulsant properties
introduced Leo Sternbach and Dr Irvin
Cohen
WEEK 14- ANXIOLYTIC AND ANTIPSYCHOTIC AGENTS: ZDI/CJJ

Small doses of Benzodiazepines – causes anxiety (<2 hrs) medication

and anxiolytic affect.
SAR
ACTIONS- BZD
Anticonvulsant- cortex ⚫ 3-OH group are easily
metabolized by phase II
Hypnotic and locus- cortex, ceruleus glucoronidation (short-
acting)
Anxiolytic system- limbic and locus ceruleus ⚫ Lacking amino side chain
is not basic
⚫ Electron withdrawing
group at C7 enhances the
activity
⚫ Electron withdrawing
group at C2 enhances potency
⚫ No substitution must be made at C6,8,9 and a
double band at C4-5 must be present

STRUCTURE
Benzodiazepines Structure

For metabolism Benzodiazepines are actually

prodrug like the prototype (in color green):

Chlordiazepoxide – need undergo demethylation to

be active same with diazepam.
Two benzene rings (A & C) and particular ring
Alprazolam – need to hydroxylated to be active structure (B) from which the structure modification
can be made or render. First the nitrogen in carbon
Oxazepam and Lorazepam - is not a product or not 1 (B) is essential or necessary for activity; replacing
need anymore activation or going to the pass effect the nitrogen or adding in (yellow highlighted) a
to render activity. triazole or imidazole would cause in increasing of
activity among with benzodiazepines.
BENZODIAZEPINES: PLASMA HALF LIFE DETERMINES
USES On carbon 2 or the carbonyl group for the
benzodiazepines (blue highlighted) likewise will be
DRUG HALF-LIFE USES optimal in activity
Diazepam Long (>24 hrs) Anxiety
Withdrawal On the ring on the hydrogen accepting group or
Muscle electron withdrawing group will affect the benzene
Relaxant activity.
Temazepam Intermediate Insomnia
(6-24 hrs) Anxiety In the carbon 3 (purple highlighted) usually in this
Triazolam Short (2-6 hrs) Insomnia position the present of the hydroxyl group or -OH
Midazolam Ultra-short Pre-anesthetic
WEEK 14- ANXIOLYTIC AND ANTIPSYCHOTIC AGENTS: ZDI/CJJ

make benzodiazepine polar and thus readily FINAL STRUCTURE OF BENZODIAZEPINES

excretable. Usually, the benzodiazepine that has a
-OH, group at this position is a short acting or short • 3-OH group are easily
half-life. Because make the benzodiazepine ready metabolized by phase II
for excretion particularly glucuronidation process. glucuronidation (Short-acting)
• Lacking amino side
On the other hand, the absence of the hydroxyl chain is not basic
group -OH, at position 3 make the benzodiazepines • Electron withdrawing
non-polar, thereby more protein bound; there by group at C7 enhances the
more half-life. activity
• Electron withdrawing
On the position 5, the additional of phenyl ring (c) group at C2 enhance potency
increase the activity of the benzodiazepines. • No Substitution must
be made at C6,8,9 and a
On the position 6, 8, 9 (A), of the benzodiazepines double bond at C4-5 must be
have no substitution to secure the pharmacologic present
activity or the benzodiazepines. If there will be a
substitution in that position 6,8,9 again it may CLASSIFICATION OF BENZODIAZEPINES
cause loss of activity in benzodiazepines. 2-Keto Benzos

While in electron withdrawing group position 7,

would increase electron negativity of
benzodiazepines thereby also increase their activity.
Thus, there an X representing the electron negative
group like Halogens

On the other in the phenyl ring itself, having an

electron withdrawing group at position 2 and 4 ⚫ Some administered as prodrug
same it would increase the electronegativity and ⚫ All have active metabolites (commonly
activity of benzodiazepines. desmethyldiazepam)
⚫ Long half-lives (most in excess of 60 hours)
⚫ Do not have polar group in position 3; they
have keto structure or the carbonyl group at
position 2 that makes their activity optimal.

3-hydroxy Benzos No active metabolites

⚫ No active metabolites
⚫ Not metabolized in the liver
⚫ Intermediate half-lives (most ~8-20 hours)
⚫ They have a carboxyl group at position 3 and
usually they don’t have an active metabolize or
not metabolize at the liver so that their activity
is shorter compare to the 2-keto

Triazolo Benzos
⚫ Additional heterocyclic ring attached at the 1
and 2 positions
⚫ Some active metabolites
⚫ Short to intermediate half-lives (anywhere
from 3-14 hours)
WEEK 14- ANXIOLYTIC AND ANTIPSYCHOTIC AGENTS: ZDI/CJJ

2-Keto Benzos CLONAZEPAM (Klonopin)

It’s not keto benzodiazepine in the sense that ⚫ High potency (~20
Cholodiazepoxide thus not have carbonyl group times stronger per
(red circle) at position 2. milligram than
CHLORDIAZEPOXIDE (Librium) diazepam)
⚫ Prototype ⚫ Causes moderate
⚫ First isolated benzo anterograde amnesia
⚫ Oxidized to ⚫ Indicated for
desmethyldiazepam treatment of anxiety,
in the liver also a highly effective
⚫ Indicated for anticonvulsant
treatment of anxiety ⚫ Retain the keto group; has withdrawing groups
and insomnia position 7 even in the position group of phenyl
ring

FLUNITRAZEPAM (Rohypnol)
DIAZEPAM (Valium) ⚫ The original date-rape drug, and the origin
⚫ Most prolific and of the term "roofie"
versatile benzo
⚫ Indicated for ⚫ Pharmacologically very
treatment of similar to clonazepam,
anxiety, seizure, but possesses much
muscle tension, stronger amnesic
insomnia, and properties.
alcohol withdrawal
⚫ Most wildly use ⚫ One of only two drugs
even up to now. in the U.S. for which a first possession charge is
⚫ The difference of the structure is that the a mandatory felony. The other of the two is
position Chloride, phenyl ring and the most crack cocaine.
significance difference of the two is the
carbonyl group at position 2.
Rohypnol Preparations are typically 1mg or 2mg
tablets. The route of administration are as follows:
FLURAZEPAM (Dalmane)
⚫ Longest half-life of ⚫ Oral- the tablet is either swallowed, chewed or
any benzo (~40-250 allowed to dissolve under the tongue. As a
hours) date rape drug, Rohypnol is simply dropped
⚫ Indicated primarily into the victim's drink where it will dissolve
for treatment of undetected. The manufacturer responded to
insomnia, may also this by reformulating the drug and adding a
serve as an blue dye so that it can be detected when used
anxiolytic to spike a drink.
⚫ Because the
modification of the ⚫ Snorting- the tablet is crushed/pounded into
structure powder form for snorting as it takes effect
particularly at carbon 1 (highlighted blue) quicker in this manner,

⚫ Smoking-the crushed powder is sprinkled on

marijuana joints so it can be smoked.
WEEK 14- ANXIOLYTIC AND ANTIPSYCHOTIC AGENTS: ZDI/CJJ

⚫ Injection- the drug is dissolved in liquid and treatment of panic disorder.

injected. ⚫ Also used as an adjunctive treatment for
depression while adjusting to SSRIS.
Rohypnol takes effect within 15-20 minutes after
ingestion and stays in the system for at least 12 TRIAZOLAM (Halcion)
hours. ⚫ Very rapid onset
⚫ Very short half-life
3- Hydroxy Benzos ⚫ Possesses amnesic
properties similar
LORAZEPAM (Ativan) to clonazepam
⚫ Hydroxy group at ⚫ Used almost
position 3 exclusively as a
⚫ Indicated for pre-op anesthetic
treatment of
anxiety, seizure, Imidazolo Benzos
insomnia, panic Midazolam
disorder, and ⚫ IV as short acting
alcohol withdrawal. sedative hypnotic
⚫ Unique among ⚫ induction of
benzos in its use as anesthesia
an adjunctive anti- ⚫ short t1/2
emetic ⚫ Employed for sleep
inducer at the
OXAZEPAM (Seram) elderly patient
⚫ Indicated for suffering from
treatment of anxiety, insomnia
insomnia, and
alcohol withdrawal. BARBITURATES
⚫ Common metabolite - replaced by the benzodiazepines
of many 2-keto
benzos following Advantages:
their oxidation to - Barbiturates are effective and relatively
desmethyldiazepam inexpensive
⚫ One of the benzodiazepines hindi na kailangan - Barbiturates have been extensively studied
ng metabolism para maging active. Itself is and there is a vast amount of information
already active. available related to side effects and toxicity

Triazolo Benzos HISTORY- Adolph Von Baeyer

- Significance: is that they have a triazolo
structure (blue circle) MECHANISM OF ACTION
- Even their carbon 1 forming triazolo Barbiturate’s with affect the duration of the activity
structure for both; 5-member ring structure and opening of GABAergic channel. Thereby Mas
incorporate. matagal nakaopen may more influx of chloride ions
- Difference is that the present of chloride of
triazolam at carbon 2 of phenyl ring. Enhance GABAergic Transmission

ALPRAZOLAM (Xanax) ↑ opening of GABAergic channels.

⚫ First benzo ↑ receptor affinity for GABA.
approved by
FDA for One of the reasons why they replace by
benzodiazepines in popularity because barbiturates
WEEK 14- ANXIOLYTIC AND ANTIPSYCHOTIC AGENTS: ZDI/CJJ

cause: ADR: Physical and psychological BARBITURATES: PLASMA HALF-LIFE

dependence DRUG HALF-LIFE USES
Phenobarbital Long Anticonvulsant
BARBITURATES: STRUCTURE (80-120 hrs)
⚫ Barbiturate Nucleus Pentobarbital Intermediate Preoperative
⚫ 5,5-disubstituted barbituric acid (2,4,6- (15- 50 hrs) Sedation
trioxohexahydropyrimidine) Amobarbital Short (10 hrs) Preoperative
⚫ Metabolism: w and w-1 oxidation, N Sedation
methylation Thiopental Ultra- short Anesthesia
SAR (3-10 hrs) Induction

LONG-ACTING BARBITURATES
⚫ Phenobarbital (Luminal)
⚫ Mephobarbital (Mebaral,
Metharbital)
⚫ Duration of action: > 6
hrs
Position 1: in alkyl group if will added in will ⚫ Low lipid/water partition
increase lipophilicity of barbiturates; when increase = slowly eliminated
lipophilicity shorter duration of action. ⚫ used primarily for
daytime sedation and the
Position 2: the present of carbonyl or -thiono group treatment of seizure
would determine the lipophilicity as well and have disorders.
also short duration of action.
INTERMEDIATE ACTING BARBITURATES
Naging lipophilic kapag thiono group C=S. But when ⚫ Amobarbital (Amytal)
the barbiturate retains the carbonyl group longer ⚫ Butabarbital (Butisol sodium)
duration but slower onset. ⚫ Duration of action: 3-6 hrs

Position 5: Has a two group the R groups, R-groups - Alkyl group at position 5 (yellow)
can be alkyl group (methyl, ethyl, prophyll, butyl) - Matagal ang duration of action since the 2
increase alkyl increase lipophilicity. carbonyls at that position (red)

Increase lipophilicity – fast onset - short duration

Position 5: also rendering the alkyl or aryl group will

determine potency. When the R-group of
barbiturates are still:
- alkyl or aryl group will decrease the
potency
- Phenyl group – it will become anti-
convulsant
- More than 7 carbon – it will become
convulsant

BARBITURATE METABOLISM SHORT- ACTING BARBITURATES

⚫ Liver microsomal drug metabolizing enzymes - ⚫ Pentobarbital (nembutal)
many complex reactions ⚫ Secobarbital (Seconal)
⚫ Most barbiturates are dealkylated ⚫ Duration of action: < 3 hrs
⚫ Conjugation by glucuronidation
⚫ Renal excretion
WEEK 14- ANXIOLYTIC AND ANTIPSYCHOTIC AGENTS: ZDI/CJJ

MISCELLANEOUS DRUGS
They referred to Z drugs and usually employed
in sleep disorder or insomnia
⚫ Azapirone: Buspirone
⚫ Zolpidem (BZ, selective)
⚫ Zaleplon (BZ, selective)

Another agent:
⚫ Meprobamate (Similar to BARBS)
⚫ Glutethimide, Ethchlorvynol, Methyprylon,
Meprobamate (Miltown)

BUSPIRONE
The substitution of position 5 of this two are ⚫ partial agonist at the serotonin 1A receptor
rendered the pentobarbital and Secobarbital with ⚫ serotonin 5HT1A receptor agonist
more rapid metabolism ⚫ produces only anxiolytic effects, no CNS
depression
ULTRA-SHORT ACTING AGENTS ⚫ No physical dependence
⚫ Schedule IV drug- methohexital (Brevital) – ⚫ No additive depression with ethanol
employed at pre-anestric agents ⚫ Onset of action is 1 to 3 weeks; limits it
⚫ Schedule III drugs- thiamylal (Surital) and usefulness.
thiopental (Pentothal)
⚫ With oral administration, the onset is from 15
to 40 minutes
⚫ Pre anesthetic agents

ZOLPIDEM: IMIDAZOPYRIDINE STRUCTURE

⚫ Not a benzodiazepine
⚫ Does act at BZ
receptors
⚫ Minimal muscle relaxing
and anticonvulsant
effect.
⚫ Rapidly metabolized by liver into inactive
enzymes metabolites.
BARBITURATES: PERIPHERAL EFFECTS ⚫ Dosage should be reduced in patients with
hepatic dysfunction, the elderly and patients
⚫ Respiration: depression with increasing doses taking cimetidine
⚫ Cardiovascular: decreased BP and HR at
sedative-hypnotic doses Mechanism of Action:
⚫ Liver: bind cytochrome P450 ⚫ Binds selectively to BZ1 receptors.
- Induce drug metabolizing and other ⚫ Facilitates GABA-mediated neuronal inhibition.
enzymes
- Increases metabolism of steroids,
vitamins K/D, cholesterol and bile salts
WEEK 14- ANXIOLYTIC AND ANTIPSYCHOTIC AGENTS: ZDI/CJJ

ZALEPLON: PYRAZOLOPYRIMIDINE
⚫ SONATA® OLDER SEDATIVE HYPNOTICS
⚫ short acting non-BZD
⚫ hypnotic AMIDES AND IMIDES
⚫ initiate Sleep rather
than keeping sleep
⚫ t1/2-1 hr

ZOPICLONE: CYCLOPYRROLONE • GLUTETHIMIDE (Doriden)

⚫ eszopiclone (Lunesta - Very hydrophobic
Ⓡ) - An enzyme inducer
⚫ moderate acting
⚫ for patient who tend • Alcohols and their carbamate deriv.
to awaken during the
night • ↑ CNS depressant potency when:
• Alkyl groups added is up to 8 carbons
• Branching of the alkyl chain 3° > 2° > 1°
MELATONIN RECEPTOR AGONIST
• Carbamylation of alcohols
Buspirone – Serotonin agonist
• 3° and 2° alcohols
*Not metabolized by oxidation
Ramelteon – Melatonin Agonist
⚫ Rozerem Ⓡ
ETHCHLORVYNOL (Placidyl)
⚫ more effective in initiating sleep rather than
• Rapid onset
circadian rhythm
• Short duration of action
⚫ no addiction liability
⚫ txt of insomia

MEPROBAMATE (Equanil®,MiltownⓇ)
• Anxiolytic
• Sedative - hypnotic
• For absence seizure
• Centrally acting skeletal muscle relaxant
• Schedule 4 drugs
WEEK 14- ANXIOLYTIC AND ANTIPSYCHOTIC AGENTS: ZDI/CJJ

CHLORPHENESIN CARBAMATE imaging procedures

• MaolateⓇ • TCE (trichloroethanol) - resp. for antianxiety
• P-chloro substituted and 1 carbamate property, hypnotic
derivative of the lead compound • With alcohol (Mickey Finn effect),
Mephenesin. "knockout drops
• P-chlorination = lipid/water partition • In alkaline solution = CHC13+ formate ion
coefficient • In hydroalcoholic sol'n =hemiacetal with
• T1/2: 3.5 hrs. EtOH

TRICLOFOS (Triclos®)
• Irritating to GI mucosa
• metabolite: TCE (Trichloro Ethanol
responsible for the effect)
• In use in sedating neonates or infants and
METHOCARBAMOL (Robaxin ®) children particularly in Japan

• Obtained from guiafenesin

PARALDEHYDE
• 2,4,6-Trimethyl-1,3,5-trioxane
• Cyclic trimer of acetaldehyde
• Liquid with strong odor
CARISOPRODOL (Soma®) • Oxidized to glacial acetic acid
• Mono-N- isopropyl substituted relative of • Used in the treatment of delirium tremens
meprobamate
• For acute skeletomuscular conditions
• Side effect: Drowsiness

METHAQUALONE (QUAALUDE)
Mandrax ®
• methaqualone 250 mg combined with
diphenhydramine 5 mg.
ALDEHYDE AND THEIR DERIV. • An aphrodisiac
• Photophobia
Chloral Hydrate (Noctec) – knockout drops • 8-20 grams of Methaqualone and smaller
2,2,2-Trichloroethane-1,1-diol dose of Methaqualone with Alcohol are
BOTH considered deadly.
• CC1, CH(OH)2
• used as sedative
in pediatric
dentistry for
diagnostic
WEEK 14- ANXIOLYTIC AND ANTIPSYCHOTIC AGENTS: ZDI/CJJ

ANTIPSYCHOTICS/ NEUROLEPTICS o Asociality - Decrease on motivation, initiate

HISTORY: and perform self-directed purposeful
Reserpine and chlorpromazine activities
- first drugs found to be useful to reduce o Anhedonia – the lack or the inability of
symptoms of schizophrenia patient to feel pleasure.
- Indole Alkaloids posse’s anti-psychotic NEUROLEPTICS
as well as anti- hypertensive properties. ▪ Rauwolfia alkaloids – prototype (reserpine
in particular)
"Psychosis"
- denotes a variety of mental disorders TYPICAL ANTIPSYCHOTICS
- This is the primary target of agents
- It denotes current delusion or false ⚫ Phenothiazine derivatives
beliefs among patients diagnoses such.
As well hallucination ⚫ Butyrophenones Thioxanthenes

SCHIZOPHRENIA ⚫ Diphenylbutylpiperidine - Pimozide

▪ Characterized by clear sensorium but a
marked thinking disturbance. ATYPICAL ANTIPSYCHOTICS
▪ Excess dopamine in mesolimbic system
(involved in emotions) – the part of brain ⚫ Dibenzoxazepines - Loxapinesuccinate
that necessary involve in controlling are
emotion. ⚫ Dibenzodiazepines - Clozapine
▪ There are positive and negative symptoms
of Schizophrenia: ⚫ THIOBENZODIAZEPINE - Olanzapine
- Positive are the one in an addition to
a normal psychological activity of the ⚫ FLUOROPHENYLINDOLE - Sertindole
patient
- Negative are those that supposedly ⚫ beta-Aminoketone -Molindone
present but are avoided by patients
with Schizophrenia. ⚫ QUETIAPINE

⚫ ZIPRASIDONE

o Flat Effect – lack of any emotions

o Alogia – poverty or lack of speech; they not Note:
communicate well and they do not express TYPICAL NEUROLEPTICS AGENTS
much to what they are thinking; if they ➢ are better in threatening the positive sign
expressing such there will be delusion or than negative sign; since such as the
hallucination delusions and hallucination will be
o Avolition – Lack to accomplish proposals generated by the dopamine 2.
ask
WEEK 14- ANXIOLYTIC AND ANTIPSYCHOTIC AGENTS: ZDI/CJJ

➢ Though typical neuroleptics agents usally - Phenothiazine actually one of the

result to extrapyramidal symptoms. mostly widely use antipsychotic agents.
But some of which been void by
ATYPICAL NEUROLEPTIC AGENTS: antipsychotics agent and had only
➢ The advantage is that they have reduce a retain antiemetic and antihistaminic
occurrent of extra pyramidal symptoms. activity.
➢ They have better activity against negative
symptoms and actually they have weaker SAR
effect blockage towards to dopamine 2 but
more on in serotonin 2a that why they - Position 1 & 4 are left to be
have a reduce pyramidal symptoms. unsubstituted (highlighted by blue).
- Position 2 an electron withdrawing
SIDE EFFECTS group such as example chlorine will
increase the activity of this agent.
▪ Extrapyramidal symptoms (EPS) - Addition of Alkyl group on position 3
- First-generation antipsychotics would improve the activity of the
- dystonia, parkinsonism, and akathisia Phenothiazine as compared to
▪ Weight gain unsubstituted compounds
▪ Drowsiness - Leaving the position 7 unsubstituted
would be necessary for the efficacy of
EPS are cause by the dopamine blockage or the phenothiazine.
depletion of dopamine in the basal ganglia. This - Most important: will be the side chain
lack or deficiency of dopamine is mimics idiopathic on position 10 (yellow line) which will
pathology of the extrapyramidal systems. be the substituent on the ring nitrogen.
This particular side chain will be
The difference of EPS as with Parkinsonism itself is important in anti-psychotic activity of
that one of the drugs induce and mostly it involves to be retain and as well as the potency
only movement disorder such as of anti-psychotic agent as well.
- The 3-carbon chain should be retained
o Dystonia – which will be the manifestation or necessary to retain for the psychotic
of continuous spasm on the muscle activity. If will reduce the three-carbon
contractions. chain it will lose the anti-psychotic
o Akathisia – will be the motor restlessness activities for this agent. And will retain
o Parkinsonism – particular manifestation in the antihistimanic and anti-cholinergic
EPS will be the rigidity, bradykinesia, activity. Like what happen with
tremors, tardive dyskinesia Promethazine and Phenergan.
TYPICAL NEUROLEPTICS AGENTS - It has same structure as well as with
phenothiazine but due to the
PHENOTHIAZINE- SAR shortening of (2C) its only retain
- must have a nitrogen-containing side anthistimanic and antocholinergic
chain substituent on the ring nitrogen activity.
MODIFICATIONS OF ALKYL SIDE CHAINE AT R10:
WEEK 14- ANXIOLYTIC AND ANTIPSYCHOTIC AGENTS: ZDI/CJJ

PHENOTHIAZINE RING SUBSTITUENTS AT R2:

▪ nitrogen of phenothiazine and basic C2- substitution produces greatest antipsychotic
amino group is connected by a three- property
carbon side chain
- Inc. potency
- Increase D2 blocking effect
- Chlorpromazine (Thorazine®)
- First phenothiazine compound
introduced
▪ the ring and side-chain nitrogen’s if
separated by the two-carbon chain
exhibits only antihistaminic and
sedative effect only
▪ fluphenazine and long- chain alcohols
form stable, highly lipophilic esters PHENOTHIAZINE DERIVATIVES

PHENOTHIAZINE PROPYL DIALKYL SIDE CHAIN

MODIFICATIONS OF BASIC AMINO GROUP

a. The activity is retained or increased if the
amino group is replaced with piperidyl or PROMAZINE (Sparine)
Piperazine groups. Example: Mesoridazine - 2 Cl: ↓antipsychotic
- Alkyl Side chain attached to
b. Introduction of hydroxyl, methyl, hydroxy basic amino group.
ethyl groups of piperidine and Piperazine
moieties increase the potency.

Triflupromazine (Vesprin)
WEEK 14- ANXIOLYTIC AND ANTIPSYCHOTIC AGENTS: ZDI/CJJ

- 2 CF3: ↑antipsychotic - High EPS but low sedative and

- The substitution here render autonomic effects
by 3 fluorine attachment

PHENOTHIAZINE- ALKYL PIPERIDYL SIDE CHAIN

Thioridazine (Mellaril) Perphenazine (Trilafon)

- Low EPS - Effective antipsychotic and anti-emetic
- High anticholinergic
- At high doses, pigmentary retinopathy
- Actually, withdrawn worldwide due to PHENOTHIAZINE- PROPHYL PIPERAZINE SIDE CHAIN
ability to cause cardiac arrythmias or
irregular heartbeat.

FLUPHENAZINE (Permitil)
▪ 2-CF3
Mesoridazine (Serentil) - Most potent
- No pigmentary retinopathy ▪ Currently recognize but not approved by
- No longer available since 2004 in the FDA for treatment of behavioral problems
USA since it causes also irregular in older adults with dementia
heartbeat due to prolongation that will
causes cardia arrythmias. Ring Analogue of Phenothiazene: Thioxanthe
⚫ Lacks the ring nitrogen of phenothiazines and
PHENOTHIAZINE- PROPYL PIPERAZINE SIDE CHAIN have side chain attached to the double bond
⚫ Not also approved yet by the FDA for
treatment of behavioral problems in older
adults with dementia

PROCHLORPERAZINE (Compazine)
WEEK 14- ANXIOLYTIC AND ANTIPSYCHOTIC AGENTS: ZDI/CJJ

DIBENZODIAZEPINE: LOXAPINE
DaxolinⓇ
ATYPICAL ANTIPSYCHOTICS
- EWG at pos 2
⚫ Dibenzoxazepines - Loxapine succinate
- Metabolism: Aromatic hydroxylation-
⚫ Dibenzodiazepines - Clozapine
after this will yield phenolic metabolite
⚫ THIOBENZODIAZEPINE - Olanzapine
further undergo N-demethylation to
⚫ FLUOROPHENYLINDOLE - Sertindole
form amoxapine
⚫ beta - Aminoketone -MOLINDONE
- Amoxapine – is an antidepressant
⚫ QUETIAPINE
agent
⚫ ZIPRASIDONE

Weight gain will be the common problem but

Ziprasidone is the least in making weight gain.

DIBENZODIAZEPINE: CLOZAPINE
ClozarilⓇ
⚫ Effective against
both positive and
negative symptoms
⚫ Low EPS
⚫ Agranulocytosis
⚫ This the prototype
among atypical agent
⚫ This significantly
reduce the suicide among the patients with FLUOROBUTYROPHENONES
psychosis, though is required to have a weekly ⚫ Chemically unrelated to phenothiazines
blood test for silver particularly clozapine that ⚫ but have similar activity
may cause seizure and myocarditis.
⚫ Not yet also approve by the FDA for treatment
on behavioral problem in older adults with
dementia.

Para position – fluorine or methoxy group; 3 carbon

chain is important in activity; the tertiary amines for
this group on the 4th carbon it also important in
neuroleptic activity. The shortening or lengthening
of the branching among the agent with decrease
WEEK 14- ANXIOLYTIC AND ANTIPSYCHOTIC AGENTS: ZDI/CJJ

the neuroleptic activity; but higher activity is render

if the substitution is a cyclic form.

FLUOROBUTYROPHENONES

HALOPERIDOL
- Chemically unrelated to
phenothiazines but have similar
activity
- Most widely use despite of high EPS;
this the most widely use classical anti-
psychotic drug

DROPERIDOL
- Short acting, highly sedating
- +Fentanyl = Innovar

Benzimidazolinone

RISPERIDONE (Risperdal)
⚫ Low risk of tardive dyskinesia
⚫ Decrease EPS
⚫ Butyrophenone-like
⚫ Widely use

Benzisoxazole
 ZDI/CJJ

ANTICONVULSANTS MECHANISM OF ACTION

In health neurons are continuously possessing and
transmitting information to one another, so the Modulation of Voltage-Gated ion channel
neuron helps the brain and body to function (Na, K, Ca)
normally, but when the multiple neurons send wrong  VGSC (Phenytoin, CBZ, Lamotrigine, OXC, FBM,
signal or misfire, the sudden electrical discharge was Zonisamide)
changes in sensation and behaviors and may result to  VGCC
occurrence of seizures.  VGPC (Levetiracetam)
 ANTIEPILEPTICS
Acts by altering the sodium neuronal concentrations Enhancement of GABA-mediated inhibitory
by promoting sodium efflux and restoration or transmission
enhancement of GABA inhibitory neuronal function  Drugs that enhances the biosynthesis of GABA
(Gabapentin,Pregabalin, VPA)
Seizure  Drugs that inhibit degradation of GABA
- are characterize by muscle spasm, twitching, (Vigabatrin)
loss of consciousness depends upon severity  Drugs that inhibit reuptake of GABA (tiagabine)
of event.  GABAa modulator (BZD, barbiturates, FBM,
- Anything that’s disturbs brain function TPM)
examples: High fever, lack of oxygen or
trauma to the head can actually result to Attenuation of excitatory neurotransmission
seizure this may be the unsolicited event a
well. MAJOR TYPES OF GENERALIZED SEIZURE
- A sudden uncontrolled electrical disturbance
in the brain and can cause change in Tonic-clonic (grand mal)
behaviors, movement, and feeling and also  most common, most dramatic, loss of
level of unconsciousness. consciousness with tonic-clonic phases
 CBZ, OXC, lamotrigine, VPA, Phenytoin, TPM
Epilepsy  is a convulsive seizure, the person loses
- is define as having multiple unpredictable consciousness and breathing may be irregular,
seizures however you can have seizures even the muscles will stiffen. The person will fall to
the absences of epilepsy. Having a seizure is the floor if they’re standing. They may bite the
not always indicates that you are epileptic tongue which can cause bleeding. Clonic phase
- a neurological disorder where the person the muscle will jerk rhythmically.
experiences recurring unpredictable  What to do:
seizures and however again “NOT SEISUREZ - Stay calm
ARE EPILEPTIC IN NATURE” - Time the length of the seizure if the seizure
- For example, you have 2 or more seizures lasts longer than 5 mis call 911.
tendency you have recurrent seizures again - Do not restrain the person and never put
it will be termed epilepsy. anything in their mouth.
- Protect the person from further injury, place
Convulsion something soft under their head and move
- in a medical condition where the body dangerous object out of the way.
muscle contract relaxes rapidly and - Roll the persons onto their side as the
repeatedly resulting in uncontrolled action seizures subsides.
of the body. - As the seizures is ending, the person may be
bladder or bowel incontinence.
- When the seizures subside, remain with the
person until full awareness returns.
- The person may be extremely tired. Talk
gently to the person after the seizures.
- There are often excess saliva produces
during the seizures
 ZDI/CJJ

partial seizures so the patient is aware to attack

and can be describe it even in detailed
 Example: Jacksonian motor epilepsy
- CBZ / Phenytoin — adults
- Lamotrigine /gabapentin- elderly
- OXC - children

Complex partial
 (Sensory and motor system)
Absence (petit mal)  There is an aura, then a confused or bizarre
 brief, abrupt and self-limiting loss of purposeful behavior for 2 -3 minutes often with
consciousness, patient manifest rapid eye- no memory of the event. In general, there
blinking awareness is altered.
 Lamotrigine, VPA, ethosuximide
SEIZURE CLASSIFICATION
Based on Video: jusme walang sound
 600,000 people in the UK have Epilepsy; These
are the common occurrence of my morning I
experience seizures known as Absences.
Seizures 1: Here I have just taken my anti-
epileptic drug. I am talking to myself because it
helps triggers my absence seizures. Seizures 2:
My triggers are stress, tiredness, miss of
medication and alcohol. Seizures 3,4,5:

Myoclonic
 Consists of short episodes of muscle contraction
which reoccurs after several minutes
 There are sudden jerks of the arms, legs may be
fall, though the side effect of this seizures may Generalized Partial
cause prolonged seizures.  loss of consciousness  no loss of consciousness
 Myoclonic Seizures (Abnormal motor  whole brain at onset  Focal onset
experience; Muscles of limbs and face are
affected more. This maybe bilateral massive
epileptic myoclonus, it presents an involuntary Convulsive Complex Partial
jerking of the facial limbs or trunk muscle in  tonic clonic  change in level of
rhythmic manner.  tonic consciousness
 Clonic Simple Partial
Status epilepticus Nonconvulsive  no change in
 seizures are rapidly recurrent without any  Absence consciousness
recovery of consciousness between them  atypical absence Partial Seizure evolving to
 Based on Video: Ativan then Valium then  Myoclonic secondary generalization
Phenobarbital then Dilantin (binigay sa patient  atonic
na medication based on video)– patient 104-
degree Celsius yung fever

MAJOR TYPE OF FOCAL SEIZURES

Simple partial
 ‘(abnormal electrical activity is confined to a
single focus on the brain)
 For simple partial seizures there are least
complicated as compared to other type of
 ZDI/CJJ

GENERAL SAR FOR CLASSICAL ANTISEIZURE Hydantoins

AGENTS Phenytoin (Dilantin)
5,5-diphenylydantoin
R1= H; R2= R3= PHENYL

 has low water solubility

 weaker acid than barbituric acid
 used for all types of seizure except absence
 produces a low degree of sedation
 Hydantoins is like phenytoin’s would be voltage
gated sodium channels modulator; its similar in
barbiturates in terms activity but lacks depend
liability.
 Adverse effect is gingival hyperplasia, heurism,
among pregnant women FHS/Fetal heart
syndrome) – pregnant categorify D.
There structure is prototypical barbiturates but only
 Narrow spectrum drug.
the difference is at position 3 (R3)
FOSPHENYTOIN (PRODRUG) (CEREBYX®)
4 CLASSES  Cause Vein irritation, tissue damage, muscle
 Barbiturates - An amide at R3 necrosis associated with IV phenytoin
 Hydantoins- An Amines  rapidly cleaved by phosphatases in vivo to form
 Oxazolidinediones- Methoxy Group phenytoin
 Succinimides- Allyl Group  the adverse effect thus not improve even with
administration of benzodiazepines.
SAR
R1 and R2 substituent
 determine the specificity of the compound.
 When these two substituents are both lower
alkyls such as methyl, ethyl, etc., the compounds
tend to be used for absence seizures, but not in
generalized tonic/clonic seizures.
 Aromatic substituents = the compounds are
active against generalized tonic/clonic seizures,
and are inactive against absence seizures

BARBITURATES
 used primarily for their sedative /hypnotic
activity (but some of which is also used as
anticonvulsant)
 have good activity against grand mal and partial
seizures.

Phenobarbital
R1 =H, R2 = ethyl and R3 = phenyl – indicated the Active metabolite – PHT-o-quinone
significance of phenobarbital for GPC/ grand mal type
of seizures) OXAZOLIDINEDIONES
Trimethadione
Mephobarbital  the only oxazolidinedione that is currently
R 1 = methyl, R2 = ethyl and R3 = phenyl metabolized available, and it is seldom used. It is active
by N- demethylation to its active against absence seizures.
constituent, phenobarbital.
 ZDI/CJJ

 One of the voltage gated calcium channel  Epoxide metabolite- will be the suspect for
modulators idiosyncratic reactions such as aplastic anemia
 Adverse effect: Sedation cause by carbamazepine.
 Seldom uses because of the related toxicity and  It also employed in trigeminal anemia; it is a first
a reserved agent for refractory cases. anti-convulsant to treat individual with by polar
disorder. Other side effect will be dipoplia and
ataxia

SUCCINIMIDES
OXCARBAZEPINE (TRILEPTAL)
- Applied in absence seizures
 N,N-diacylurea
- Adverse effect is gastrointestinal effect:
 Major metabolite:
Nausea and vomiting
monohydroxy
Phensuximide
compound
(Milontin)
 For partial seizure
*(R1 = methyl,
 Less potent in
R2 = H, R3 =
carbamazepine
phenyl)
itself for
treatment of
Methsuximide (Celontin)
partial onset of
 (R1 = methyl, R2 = phenyl,
seizures.
R3 =methyl)
 Employed in 2 years older patient.
 N-dealkylated
ethosuximide
PRIMIDONE
 Applied in absence seizures
 is used for all seizures except absence.
 Metabolize by alcohol dehydrogenase to form:
Ethosuximide (Zarontin)
phenobarbital and PEMA (Phenylethylmalona
 “(Rl =H, R2 = ethyl, R3 =
mide) – a ring open that undergoes amine
methyl)
hydrolysis.
 Prototypical
 Patient should be counsel regarding on the risk
anticonvulsant for
of the status epilepticus the proposition of
treating absence
primidone
seizure
 Used for absence
seizures
 More active and less
toxic
 than trimethadione
 Calcium T- channel
blocker

CARBAMAZEPINE (TEGRETOL)
 N,N-diacylurea, a urea derivative
 For generalized tonic clonic and partial seizure
 Na channel blocker
 Undergo oxidation, epoxidation in particular.
Olefinic oxidation
 ZDI/CJJ

VALPROIC ACID  Adverse effect: aplastic anemia and severe

 2-propylPentanoic acid hepatitis.
 like many aliphatic carboxylic acids, is active  It uses in adult with partial seizures with/
against absence seizures, but crosses the blood- without generalization. For children with partial
brain barrier poorly and generalize seizures special once associated
 Hepatotoxic, (2,4-dieneVPA and 4-epoxy-VPA) with lennox gastaut syndrome
teratogenic
 It’s not initially use for seizures; it was only use
as solvent and discovered now as effective to
treat seizures through serendipity
 It also triggering nausea and vomiting dose
dependent; its hepatoxic though and the salt
from is Valproate

GABAPENTIN (NEURONTIN)
 an analogue of gammaaminobutyric acid (GABA)
but has no gabaergic activity,
 acts by modulating Ca influx, stimulating GABA
BENZODIAZEPINES biosynthesis, and competes in the synthesis of L-
Clonazepam glutamic acid
 Absence seizure and myclonic seizure  Pregabalin (Lyrica)
Diazepam (Valium, Diastat)
 Adjunctive for gen. tonic/clonic and status
epilepticus
Clorazepate
- Significant agent cuases drowsiness and
liturgy

AMOTRIGINE (LAMICTAL)
 inhibits the release of excitatory
neurotransmitters, primarily glutamate, by
blocking the voltage dependent sodium
channels, thereby stabilizing the presynaptic
membrane
 Against refractory seizure; its only add on
therapy; also employed in bipolar disorder

FELBAMATE (FELBATOL)
 Carbamates ester of 2-phenyl-1, 3-- propanediol
 act by reducing seizure spread, and by raising
 Adverse effect: steven Johnson syndrome
the seizure threshold.
 The first medication approves after lithium for
 Blockade of NMDA Receptors
the treatment of bipolar disorder
 Its also a broad spectrum; anti- epileptic drug
similar with meprobamate
 ZDI/CJJ

RILUZOLE ( RILUTEK) ZONISAMIDE (ZONEGRAN) AND

TOPIRAMATE (TOPAMAX)
 With acidic sulfonamide or sulfateamino groups,
respectively, which are relatively small, and they
also possess bulky a hydrophobic group at the
other end of their structure.
 Zonisamide also blocks calcium T- zonisamide
 Sodium channel blocker with antiglutamate channels (Zonagran®)
effect  Partial seizure in adults
 Placed in a bottle — stopper shape container
 Benzothiazoles drug for treatment of
amyotrophic lateral sclerosis or lou gehrig's
disease

TOPIRAMATE (TOPAMAX)
 Sulfamate-substituted monosaccharide
 Weak carbonic acid inhibitor SN
 Applied in all type of seizures in both in children
and adult.
 Topiramate increases the effect of GABA while
TIAGABINE (GABITRIL) serving as an aa antagonist at kainic acid/AMPA
 blocks GABA reuptake as the major mode of receptors.
anticonvulsant activity  Topiramate can also be used offlabel in the
 GAT-1 inhibitors treatment of migraine.
 Use as anticonvulsant, in panic disorder  adjunct for partial seizures.
 Against partial seizure
 CHOLINERGIC AGENTS choline will enter the presynapse via
choline transporter ).
BIOSYNTHESIS OF ACETYLCHOLINE
1. Synthesis ⚫ When the choline is already inside, the
2. Storage Acetyl CoA coming from mitochondria will
3. Release be available to produce Acethylcholine by
4. Binding into the cholinergic receptors the action of CHAT (Choline Acetyl
5. Inactivation Transferase)
enzyme: acetylcholinesterase
Metabolites: choline and ethanoic acid ⚫ Next, The Acethlycholine will enter the
vesicle through the VAT (Vesicle
Quick recap: Associated Transporter). It allows the
Autonomic NS- subdivided into three acetylcholine to enter the vesicle. While in
Cholinergic Nervous System (parasymphathetic the vesicle, the acetylcholine is waiting for
NS )- rest and digest, it is activated mostly at its physiologic release (waiting for the
night and would aid in digestion while the body influx of Calcium). Influx of Calcium would
is at rest. trigger the activation of VAMP’s (Vesicle
Major neurotransmitter/ substance that would Associated Membrane Protein) and
activate : acetylcholine SNAP’s (Synaptic Nerve Associated
Adrenergic nervous system (symphathetic NS) Protein)
Enteric NS
⚫ When there’s an influx of Calcium, the
VAMP’S and SNAP’s will contract so that
the vesicle and the synaptic or terminal
membrane will fuse (there will be a fusion).
Fusion will lead to an opening of a pore in
the synapse (synaptic cleft). This is when
the acetylcholine will be release from the
synaptic membrane through the choline
receptors (receptor for the cholinergic
nervous system.

⚫ When the acetylcholine is already attached

to the receptors, it can now activate the
Cholinergic Nervous System
(Parasympathetic Nervous System).

There are times , the natural mechanism of the

body will inactivate first the cholinergic NS.
⚫ When the Cholinergic NS is already
inactivated, the Acetylcholine that is
getting released should be destroyed. It
will be mediated the Acetylcholinesterase
Enzyme. Acetylcholinesterase will destroy
Acethylcholine is biosynthesized in the the Acetylcholine then converted to
cholinergic synapse. This will take place in the Choline by acetation.
cytoplasm.

⚫ It starts with the raw material (choline). To inactivate Cholinergic Nervous System
The Choline needs to enter the (Temporarily):
presynaptic membrane (presynapse). ⚫ Acetylcholine would undergo Reuptake
Mechanism. (reabsorb pabalik kay
⚫ It enters the presynapse via the choline presynapse)
transporter (CHT) ( CHT is sodium ⚫ The inactivation of the Acetylcholine will
dependent . We need sodium so that be mediated by acetylcholinesterase (dito
papasok MOA of other drugs)
⚫ Ex. The Hemicholinium- inhibits the entry EX:
of choline towards the synapse. Inhibits Acetylcholine could fit all Cholinergic Receptors
the Cholinergic Nervous System Activity. (Type 1 and Type 2). But if you have an
⚫ Vesamicol- inhibits/block the VAT. analogue (Drug Derived from the structure of
Nothing can enter the vesicle Acetylcholine. acetylcholine) yes it can fit one receptor but not
No matter how many times it influx the other because of the misfit in the structure
calcium, No matter how many times the of the drug . We have to understand, SAR of this
vesicle and terminal membrane fusion, cholinergic acting agents to the receptors of
there will be no Acetylcholine present to the Acetylcholine.
be release.
⚫ Botox- prevent the activation of VAMP ACETYLCHOLINE—STRUCTURE, SAR, AND
and SNAP. Blocks calcium influx. In RECEPTOR BINDING
Cosmetics, it is used to prevent wrinkles.  The positively charged nitrogen atom is
Prevent muscle contraction. essential to activity. Replacing it with a
neutral carbon atom eliminates activity.
 The distance from the nitrogen to the
ester group is important. (ethylene bridge)
 The ester functional group is important.
 Acetylcholine has a quaternary nitrogen
group which is essential to activity. When
the positive charged is removed, it will
loss activity immediately towards the
cholinergic nervous system. (Kapag
nawala ang charge, tanggal ang activity of
any drug that is suppose to act upon the
Cholinergic Receptors )
⚫ Acetylcholine (main activator of the
cholinergic nervous system)- Drugs that act
upon the Cholinergic Nervousacetylcholine.
System pattern after the structure of
PROPERTIES OF ACETYLCHOLINE
 An ester of acetic acid and choline Ammonium Group
 Can undergo hydrolysis  The replacement of the ammonium
© stomach by acid catalysis- cannot moiety with either a sulfonium or
be given orally phosphonium results in a complete loss of
©Blood (esterases and activity.
acetylcholinesterase)  Increasing one methyl! group to a larger
 There is no selectivity of action- acts upon alkyl (e.g., ethyl) results in 25% activity.
all the receptors of the Cholinergic  Increase two methyl groups in size -> lose
Nervous System all activity.
Receptors:  Replacement of ammonium group with
Nicotinic receptors tert-butyl retains 0.003% of activity.
Muscarinic receptors Implies that the charge distribution and
size are important factors to ACh-R action.
Acetylcholine is able to bind to both receptors
and to all receptors of the Cholinergic
NERVOUS SYSTEM

Me3- three merthyl groups are attached

Ethylene Bridge
 Acts as a "perfect spacer" or ruler
between the carbonyl and the quaternary
ammonium moiety and ensures the
proper distance for receptor binding.
 Rule of Five: Should be no more than four
atoms between the ammonium and the
 terminal methyl group, otherwise a loss of
activity.
 Branching on the ethylene bridge
tolerates methyl only.

Ester Group
 Not very amenable to modification
 A change from a methy! to a phenyl  Increasing one methyl! group to a larger
makes a good antagonist. (kapag nagiging alkyl (e.g., ethyl) results in 25% activity.
piattos, nagiging antagonistic). Increase two methyl groups in size -> lose
 Some activity can be maintained by all activity. Replacement of ammonium
replacement with a ketone/ether and group with tert-butyl retains 0.003% of
carbamate (carbachol). activity.
MOST IMPORTANT ANG CARBACHOL  Ethylene bridge (perfect spacer)
 Ester group- A change from a methy! to a
phenyl makes a good antagonist.- iboblock
yung receptor. Carbonyl is important cause
it will cause a hydrogen bond between
Cyclic Analogs acetylcholine and histidine residue.
 Many have good activity including
muscarine itself.  Hydrogen bonding interaction exists
between the ester group of the
acetylcholine molecule and a histidine
residue.
 a small hydrophobic pocket exists can
accommodate the methyl group of the
Cholinergic Agonist ester, but nothing larger.
 This interaction is thought to be more
important in the muscarinic receptor than
the nicotinic receptor.
 A strong ionic interaction has been
proposed between the charged nitrogen
atom and the anionic side-group of either
a glutamic acid or an aspartic acid residue.

Muscarine:
Have quartenary group (yung may (+)
Isang methane group naretain
Replacing lactone group
 CHOLINERGIC DRUGS  Used in Bronchial Challenge test- how
Direct acting - choline esters. much you can tolerate the bronchial
Activity: Nicotic constriction caused by the metabolite
Indirect acting — AKA anti cholinesterase Electronic effects
(carbamates, organophosphates). Destroy CARBACHOL
Cholinesterase to prolong activity of  long acting
acetylcholine to the receptor. Increase  cholinergic agent which is resistant to
acetylcholine levels, increase cholinergic hydrolysis
activity. Enzyme is their only target. © the acyl methyl group has been replaced by
Target: Acetylcholinesterase enzyme an NH, (comparable size)
© resistance to hydrolysis is due to the
Choline esters electronic effect of the carbamate group
Effect: heart- cardiac depression. Causes
negative inotropic activity. Decrease volume of
distribution of blood. Causes bronchial
constriction
© Acetylcholine  A biostere
© Betanechol  a group which can replace another group
© Methacholine chloride without affecting the pharmacological
© Carbachol chloride activity

DESIGN OF ACETYLCHOLINE DESIGN OF ACETYLCHOLINE

ANALOGUES ANALOGUES
To prepare an compound which is stable.  Combining steric and electronic effects
2 approaches applied:  Bethanechol- urinary retention. W/
 steric hindrance muscarinic effect but no nicotinic effects
 electronic stabilization

Steric hindrance
METHACHOLINE
 quaternary amine
 Cannot pass BBB
 Poor GIT absorption INDIRECT ACTING AGENTS
 resistant to acetylcholinesterases 1. Alcohol — edrophonium
 Used to diagnose bronchial reactivity 2. Carbamates — suffix —tigmine
3. Organophosphates - echothiophate

ANTICHOLINESTERASES AND
ACETYLCHOLINESTERASE
Effect of anticholinesterases
 antagonists of the enzyme cholinesterase-
which hydrolyses acetylcholine.
 Structure of the acetylcholinesterase
enzyme

 Almost the same in the structure of

acetylcholine but the difference is the
ethylene bridge
 Can bind to muscarinic and nicotinic SAR
receptor, longer activity because of being Carbamates (carbamic acid
resistant to acetylcholinesterases ester)
 The trimethylamonium group  Used in the tx of CNS effects of atropine,
© place para to the carbamate group CH, scopolamine and other ar
© But meta position provides better inhibition
(neostigmine)
 Action is reversible
 Presence of dimethyl carbamate
increases stability to hydrolysis
 The pyrrolidine nitrogen (which is ionized
at blood pH) is important. - bind to the
anionic receptor site of the enzyme.
 Acetylcholine binds to the cholinesterase NEOSTIGMINE
enzyme by:  a quaternary nitrogen atom
(a) ionic bonding to an Asp or Glu residue  Since the molecule is permanently
(b) hydrogen bonding to a tyrosine residue. charged, it cannot cross the blood-brain
barrier and cause CNS side-effects.
Eg. physostigmine, neostigmine, pyridostigmine,  Increased stability to hydrolysis is
ambenonium chloride, demecarium bromide, achieved by using a dimethylcarbamate
edrophonium chloride, tacrine hydrochloride group rather than a methylcarbamate
group.
ANTICHOLINESTERASE DRUGS  Antidote for myasthenia gravis- caused by
Physostigmine - used muscle relaxants.
as an antidote in
atropine poisoning
antidote for
anticholinergic toxicity.
 natural product
 also called eserine
 Can cross BBB
 It can both reverse central and peripheral
cholinergical effect

Carbamase- in para position in Physostigmine

Pyrolidine N- responsible for the binding of the
aspaltic glutamic residue of acetylcholinesterase
ORGANOPHOSPHATES
Structure-activity relationships :  Presence of phosphate group that would
 The carbamate group is essential to phosphorylate the amino acid serine in the
activity. active site
© crucial group responsible for physostigmine's  Action is irreversible
antagonistic properties  Activity last for 3-4 months after enzymes
 The benzene ring is important. has regenerated. AchE->RBC (KASI NGA
© involved in some extra hydrophobic bonding DBA 12O DAYS LIFESPAN NG RBC)
with the receptor site  Permits acetylcholine to accumulate at
© important in the mechanism of inhibition nerve endings and produce an
 since it provides a good leaving group. exacerbations of acetylcholine-like
actions
PHYSOSTIGMINE  Includes isofluorophate, echothiophate,
Tertiary amine malathion, parathion
 Hydrophobic
 it can cross the blood-brain barrier
 A is usually O, S or Se SAR
 R1 is alkoxyl, R2 is an  quaternary nitrogen
alkyl, alkoxyl or 3° N -Essential to the structure
 X is a good leaving -reduces passage across the blood-
group brain barrier
 tertiary nitrogen
 Nerve gases -for broader volume of distribution
 The nerve gases dyflos and sarin (they are
intended to act as a biological warfare  Naturally occurring alkaloid: atropine
agents nung world war 2) SIMILARITIES WITH Acetylcholine:
 Dyflos, which has an ID50 of 0.01 mg kg . the basic nitrogen
. ester group with the distance
between each
groups

 Synthetic agents
INSECTICIDES © are bulky analogs of acetylcholine
 parathion and malathion © allowing the molecule to bind with
 non-toxic other receptor without inducing
 The phosphorus/sulfur double bond cholinergic effects
prevents these molecules from
antagonizing the active site on the  Alteration in alpha carbon will decrease
cholinesterase enzyme. the action but the reduction on muscarinic
 Echothiophate- potent long acting effect will be greater
mediator of cholinestrerase. Used for
Ocular hypertension especially glaucoma  Greater reduction in nicotinic activity is
due to betacarbon substitution

MUSCARINIC ANTAGONISTS
The first antagonist was obtained from a
natural product commonly alkaloids (nitrogen
containing compounds derived from plants).
ANTAGONISTS OF THE MUSCARINIC
CHOLINERGIC RECEPTOR
ATROPINE
 Drugs that inhibit the interaction of ACh
 chiral centre
with its receptor are called "cholinergic
 Usually, natural
blocking agents.
products exist
 Affect nerve transmissions to the smooth
exclusively as one
muscle of the gastrointestinal tract, urinary
enantiomer.
tract, and glands
 + Hyoscyamine
ACTION OF ANTAGONIST
HYOSCINE
 Scopolamine
 is also obtained from solanaceous plants ~
 lt has been used as a truth drug.
 With high CNS depressant activity
 SUXAMETHONIUM
 The ester groups are susceptible to
chemical and enzymatic hydrolysis.
 Once hydrolysis occurs, the molecule can
no longer bridge the two receptor sites
and becomes inactive.
 Suxamethonium has a duration of five
minutes, but suffers from other side-
effects.
SYNTHETIC CHOLINERGIC BLOCKING AGENTS HYOSCINE
Amino alcohol esters  Depolarizing
 clinidium Br,  simple analogue of tubocurarine
cyclopentolate  It is a straight-chain molecule
HCl, Dicyclomine  capable of forming a large number of
HCl, Eucatropine conformations.
HCl,
Glycopyrrolate,ox
yphencyclimine
HCl,
propantheline Br
Amino alcohol ethers
 Benztropine
mesylate, NICOTINIC ANTAGONISTS
Orphenadrine Curare
citrate A poison from a plant called Chondrodendron
Amino alcohols tomentosum and caused paralysis as well as
Biperiden, Procyclidine, stopping the heart.
tridihexethy! chloride,
trihexyphenidyl HCl © tubocurarine
Aminoamides © The active principle
 lsopropamide An____ which blocks nerve transmissions from
iodide, tropicamide nerve to muscle.
Miscellaneous Competitive agents are usually bulky rigid
 Diphemanil methylsulfate, papaverine HCl, molecules with an optimum distance of 10 +/-
Ethopropazine HCl 0.1 A.
slow onset (>5 min); long duration of action (30
NEUROMUSCULAR BLOCKING AGENTS mins)
Two classes:
1. Non-depolarizing/Competitive Agents.
 Curare
2. Depolarizing Agents.
 Flexible structures with free bond rotation.
They were devised (not natural products)
through mimicry of the N+ - N+ distance,
but they act by a different mechanism

SUCCINYLCHOLINE
 Depolarizing Agent PANCURONIUM AND VECURONIUM
 substrate for acetylcholinesterase  Pancuronium and vecuronium
 onset — 30 s; duration — 5-10 min  act like tubocurarine, but with a
____acting as the ___, The distance
between the quaternary nitrogens is 1.1
nm as compared to 1.4 nm in tubocurarine.
 Acyl groups were also added to introduce
into the molecule in order to improve
affinity for the receptor sites.
 These compounds have a___and do not
affect blood pressure. However, they are
not as rapid in onset as suxamethonium
and also last too long (45 minutes).

ATRACURIUM
 based on the structures of tubocurarine
and suxamethonium.
 It is superior to both since it____ and is
rapidly broken down in blood.
 administered as an intravenous drip.

OTHER CHOLINERGIC
ANTAGONISTS
 snake toxins
 bind irreversibly to the acetylcholine
receptor, thus blocking cholinergic
transmissions.
 Alpha bungarotoxin - Bungarus
multicinctus
 from the Indian cobra — cardiotoxic
 Adrenergic Agents ADRENERGIC AGONISTS

Biosynthesis of Catecholamines
Derivatives of beta phenylethylamine

Impt features:
⚫ Location of OH substitutions on the
benzene ring
⚫ Nature of substituent on an amino
nitrogen

METABOLITES
CATECHOLAMINES
⚫ Found in the urine Sympathomimetic amine
⚫ Contain 3,4 dihydroxybenzene group
3-Methoxy-4-hydroxy-mandelic Acid (VMA) ⚫ Epinephrine
⚫ NE
⚫ Isoproterenol
⚫ Dopamine

Catechol
⚫ 1,2-
dihydroxybenzene
PROPERTIES OF CATECHOLAMINES
Normetanephrine High Potency
⚫ OH (3.4) show highest potency in
activating alpha or beta receptors

Rapid inactivation
⚫ COMT (POSTSYNAPTICALLY), gut wall
⚫ MAO (intraneurally),liver,gut wall

Poor penetration in the CNS

⚫ Polar
Metanephrine
SUBSTITUTION ON THE BENZENE RING
Dopamine
 Enhance the beta receptor activity
SUBSTITUTION ON THE BENZENE RING ⚫ Addition of isopropyl at the amino
3,5 dihydroxy nitrogen (isoproterenol)
⚫ increase beta 2 activity ⚫ The larger the substituent on the
⚫ Metaproterenol amino group, the lower the activity at
⚫ non cathecolamine alpha receptors; eg, isoproterenol

3 (hydroxymethyl) 4 (hydroxy)
⚫ increase beta 2 selectivity
⚫ albuterol

Absence of one or both -OH groups on the

phenyl ring

⚫ Reduce the potency of the drugs

⚫ Increase the bioavailability after oral
administration SUBSTITUTION ON THE ALPHA GROUP
⚫ Non-catecholamine, prolong the ⚫ block oxidation by monoamine
duration of action oxidase (MAO) and prolong the action
⚫ Increase the distribution of the of such drugs, particularly the
molecule to the central nervous noncatecholamines.
system
⚫ have an enhanced ability to displace
PHENYLEPHRINE catecholamines from storage sites in
noradrenergic nerves

SUBSTITUTION ON THE ALPHA CARBON

⚫ Commonly attached group = CH3
⚫ Alpha-methyl compounds are also
called phenylisopropylamines.
Ephedrine

SUBSTITUTION ON THE AMINO GROUP

Enhance the beta receptor activity

↑ size of alkyl substituents - ↑ beta- Amphetamine

receptor activity

Eg. Norepinephrine epinephrine

SUBSTITUTION ON THE BETA CARBON
⚫ Direct-acting agonists typically have a
beta-hydroxyl group
⚫ This hydroxyl group may be important
for storage of sympathomimetic
amines in neural vesicles.

ALPHA 2 AGONIST
⚫ Clonidine
⚫ Methyldopa
⚫ Guanfacine
⚫ Guanabenz
DIRECT ACTING AGONIST
Phenylephrine CLONIDINE
⚫ Chemical name:
2-(2,6-dichlorophenylamino)-2-imidazoline

Methoxamine
⚫ imidazoline derivative
⚫ exists as a Mesomeric compound.

METHYLDOPA
Alpha-methyl DOPA (Aldomet)

⚫ Metabolically converted to alpha-

NON-CATECHOLAMINES
methyl norepinephrine
⚫ Compounds lacking catechol hydroxyl ⚫ Used for treating essential
groups hypertension.
⚫ Have longer half life (not inactivated by
COMT)
⚫ Phenylephrine
⚫ Ephedrine
⚫ Amphetamine

ALPHA 1 AGONIST
BETA AGONIST
Phenylethanolamines
⚫ Phenylephrine
Nonselective beta agonist
⚫ Metaraminol
⚫ Isoproterenol
⚫ Methoxamine
Dobutamine
2-arylimidazolines
⚫ synthetic
⚫ Xylomethazoline
catecholamine
⚫ Oxymethazoline
⚫ Tetrahydrazoline BETA 1 SELECTIVE AGONIST
⚫ Naphazoline
⚫ (±)-4-[2-[[3-(p-Hydroxyphenyl)-1- ALBUTEROL
methylpropyl)amino]ethy]]pyrocatech Chemical name: a1-[(tert-
ol hydrochloride. Butylamino)methyl]-4-
hydroxy-m-xylene-a,a'-diol sulfate (2:1)
(salt)

Terbutaline sulfate
Two isomers of Dobutamine (±)-a-[(tert- butylamino)methyl]-3,5-
dihydroxybenzy] alcohol sulfate (2:1) (salt).
⚫ (+) isomer The
is a potent beta 1 agonist and an alpha 1 molecular formula is (C12H19NO3)2 *
receptor antagonist. H2SO4

⚫ (-) isomer
is a potent alpha 1 agonist, capable of
causing significant vasoconstriction when
given alone
Dopamine agonists
BETA 2 SELECTIVE AGONIST
1. Fenoldopam
⚫ Albuterol
⚫ D1 receptor agonist
⚫ Metaproterenol
⚫ selectively leads to peripheral
⚫ Pirbuterol
vasodilation in some vascular beds.
⚫ Salmeterol
An IV drug for the treatment of severe
⚫ Formoterol
hypertension
⚫ Terbutaline
⚫ Ritodrine

2. Dopamine
⚫ the immediate metabolic precursor of
norepinephrine
SALMETEROL xinafoate ⚫ activates D1 receptors in several
⚫ Serevent® Diskus® vascular beds, which leads to
⚫ 4-hydroxy-a1-[[[6-(4- vasodilation.
phenylbutoxy)hexyl]amino]methyl]-
1,3-benzenedimethanol, 1-hydroxy-2- Other Sympathomimetics
naphthalenecarboxylate. 1. Ephedrine
⚫ ephedrine is a noncatechol
phenylisopropylamine
⚫ the first orally active sympathomimetic
drug.
⚫ activates B receptors - used in asthma.
⚫ it gains access to the CNS - mild ⚫ Used in some children with attention
stimulant. deficit hyperactivity disorder
⚫ Indirect sympathomimetic also,
promoting norepinephrine release
⚫ benzenemethanol a - [1 -
(methylamino) ethyl] - sulfate

6. Phenylpropanolamine (PPA)

⚫ N-desmethyl analog pf ephedrine

⚫ Component of an OTC agent in
numerous weight reduction and cold
medications.
⚫ Associated with hemorrhagic stroke.

3-amino-1-phenyl-propan-1-ol

7. Tyramine
3. Amphetamine
⚫ normal by-product of tyrosine
⚫ a phenylisopropylamine
metabolism
⚫ a CNS stimulant
⚫ found in high concentrations HO in
⚫ Indirect acting sympathomimetic
fermented foods such as cheese

4. Methamphetamine
⚫ (N-methylamphetamine)
⚫ Desoxyn
⚫ (S)-N,a-dimethylbenzeneethanamine ⚫ readily metabolized by MAO in the
hydrochloride liver
⚫ normally inactive when taken orally
because of a very high first-pass effect,
ie, low bioavailability.
⚫ Patients taking MAO inhibitors must be
very careful to avoid tyramine-
containing foods.
5. Methylphenidate and pemoline 8. Cocaine
⚫ are amphetamine variants
 consist of
a. Quinazoline
b. Dipiperaine
c. Acyl Moiety

ADRENOCEPTOR ANTAGONIST
DRUGS
⚫ ALPHA ADRENERGIC ANTAGONISTS USE/s:
(a- blockers) Antihypertensives
⚫ BETA ADRENERGIC ANTAGONISTS ⚫ used for benign prostatic hyperplasia
(b-blockers) ⚫ side effect: first dose phenomenon

1.1. non-selective alpha blocking agents(a

blockers) Alpha 2 selective blocker
1.1.1 reversible alpha antagonist- Yohimbine
Phentolamine ⚫ indolealkylamine
⚫ dissociate from alkaloid
receptors ⚫ Brand Name:
⚫ an imidazoline Aphrodyne
derivative
⚫ non-selective Corynanthine is alpha1 selective blocker

1.1.2 irreversible alpha antagonist-

Phenoxybenzamine
⚫ related to the B-adrenergic antagonist
nitrogen mustards Aryloxypropanolamines
⚫ beta 1 selective are those with p-
⚫ Beta- substituent no meta substituent rings
halolkyalkylamine
s - forms
irreversible bond by forming an Propranolol
electrophilic compound that will
alkylate the nucleophilic site of the
receptor

3. selective alpha1 -adrenergic blocking

agents
1. Zosin (suffix) SAR
⚫ Terazosin, Prazosin, Doxazosin, essential structures include:
Alfuzosin
2. Tamsulosin ⚫ length of side chain
⚫ Nonquinazoline ⚫ hydroxyl side chain
Quinazolines ⚫ amine nitrogen must be secondary
— selective, competitive alpha1 antagonists,
 (±)-1-(Isopropylamino)-3-[p-(2- Metoprolol
methoxyethyl)phenoxy]-2-propanol L-(+)-
tartrate.

NONSELECTIVE B BLOCKERS

⚫ Propanolol- most lipophilic

⚫ Nadolol
⚫ Pindolol
⚫ Penbutolol
⚫ Carteolol
⚫ Timolol
⚫ Levobunolol
⚫ Sotalol
HORMONES PMOC311
Steroid hormone Steroid biosynthesis
⚫ Comprised of a group of cyclical Classification
organic compounds 1. Sterols
⚫ Characteristic arrangement of 17 C ⚫ R=aliphatic chain
atoms in a four ring structure linked 2. Sex hormones
together from three 6-carbon rings ⚫ R=ketone or hydroxyl; posses 2C
followed by a 5-carbon ring and an side chain
8-C side chain 3. Cardiac glycosides
⚫ used primarily in birth control, ⚫ R=lactone ring
hormone-replacement therapy Bile acids
(HRT), inflammatory conditions, ⚫ R=5C side chain ending with -
and cancer treatment COOH
5. Sapogenins
⚫ R=oxacyclic (etheral ) ring system

STEROL
Zoosterol
⚫ Cholesterol

Phytosterol
⚫ Ergosterol
⚫ Stigmasterol

Mycosterol

Numbering and primary steroid name

Sex hormones
Androgen
⚫ Testosterone

Estrogen
⚫ estrone, estradiol, and estriol

Gestogen
⚫ Progesterone
HORMONES PMOC311
Testosterone Bile acids

Estrogen

Sapogenins
are the aglycone, or non-saccharide, portions of
Progesterone the family of natural products known as
saponins. Sapogenins contain steroid or other
triterpene frameworks as their key organic
feature

Cardiac glycosides

Physicochemical properties
⚫ Crystalline solids
⚫ Water insoluble
◼ Decrease the release rate of the drug
from IM
◼ Dermatological prepn
◼ +OH or dec carbon -> inc water
solubility
◼ lV preparation
⚫ Salts are water soluble
⚫ 4-en-3-one steroids
◼ light sensitive (light-resistant
containers)

Androgen
Testosterone
⚫ Natural androgen
⚫ For normal spermatogenesis,
development of secondary male
characteristics, for growth
Use:
⚫ Breast CA
⚫ Growth and development of male
sex organs
HORMONES PMOC311
⚫ Androstane- Nucleus SAR: Estrogen
Steroidal nucleus — not essential for
activity

Estrogen
Natural estrogen
⚫ Secreted by ovary

Estradiol
⚫ Aka: 17 B estradiol
SAR: ANDROGEN ⚫ Primary female sex hormone
⚫ Principal estrogen in
premenopausal women
⚫ Important in the regulation of
menstrual cycle

Estriol
Estrogen ⚫ 1/3 estrogenic activity of
⚫ Primary female sex hormones estradiol
⚫ Primary circulating after
Functions menopause
⚫ Development of female
reproductive tract and female
secondary sex characters
⚫ Stimulation of proliferative phase of
endometrium
⚫ Vasodilation Estrone
⚫ Cardioprotection ⚫ Less potent than estradiol
⚫ Maintain integrity of skeleton in ⚫ Present in significant amounts
reproductive age during pregnancy
⚫ Principal estrogen produced by
placenta
HORMONES PMOC311
Synthetic estrogen Estrogen Function: Roles and Effects
⚫ Long DOA, slow metabolic rate
⚫ Steroidal : Ethinylestradiol,
Mestranol
⚫ NS : diethylstilbestrol, hexestrol,
dienestrol

Signs and Symptoms of Low

Estrogen

Synthesis of Estrogen

Progesterone
Uses ⚫ Natural progestational hormone
1. Contraception
2. Hormone Replacement Therapy USES
3. Osteoporosis ⚫ Prevent habitual abortion
4. Senile vaginitis ⚫ Txt of functional uterine
bleeding resulting due to lack of
Adverse Effects: estrogen
⚫ Nausea and breast tenderness ⚫ Oral contraceptives
⚫ Headache ⚫ Pregnancy diagnosis
⚫ Edema ⚫ Txt of advance carcinoma in
⚫ Hypertension breast
⚫ Treat premature discomfort in
breast
⚫ Skin elasticity and bone
strength
HORMONES PMOC311
Signs and Symptoms of Low
Progesterone

Progesterone

Progesterone Function: Roles &

Effects

High Progesterone Levels

Low Progesterone Levels

Signs and Symptoms of High

Estrogen Levels