Phytochemicals are chemical compounds such as beta-carotene that occur naturally in plants.

The term is
generally used to refer to those chemicals that may affect health, but are not yet established as essential
nutrients.While there is abundant scientific and government support for recommending diets rich in fruits
and vegetables, there is only limited evidence that health benefits are due to specific phytochemicals.

Phthalide Synonyms: 4,5,6,7-Tetrachloro-1(3H)-isobenzofuranone,

4,5,6,7-Tetrachloro-2-benzofuran-1(3H)-one, 4,5,6,7-
TETRACHLOROPHTHALIDE, 4,5,6,7-Tetrachlorophthalidefthalide,
4,5,6,7-tetrachloro-;Rabcide;TCP

Chemical Name: Phthalide, 4,5,6,7-tetrachloro-

Formula: C8H2Cl4O2
Molecular Weight:271.911 g/mol

3-n-Butylphthalide:
Synonyms:1(3H)-Isobenzofuranone, 3-butyl-, 3-Butyl-1(3H)-
isobenzofuranone, 3-BUTYLPHTHALIDE, 3-n-Butylphthalide,
Butylphthalide, Phthalide, 3-butyl-,

Chemical Name:1(3H)-Isobenzofuranone, 3-butyl- 3-Butyl-1(3H)-

isobenzofuranone
Formula: C12 H14O2
Molecular Weight:190.238 g/mol

3nB is a compound that is unique to celery and is responsible for the characteristic flavor and odor of celery.
3nB was discovered as the active component of celery in response to investigations by researchers seeking to
explain some of the medicinal effects of celery including the lowering of blood pressure and the relief of
arthritis. 3nB first drew significant scientific attention when researchers at the University of Chicago Medical
Center identified it as the factor in celery responsible for the blood pressure lowering effect of celery.1 The
research was prompted by one of the researcher's father, who after eating a quarter-pound of celery every day
for one week observed his blood pressure dropped from 158 over 96 to a normal reading of 118 over 82.

Subsequent animal studies found that a very small amount of 3nB lowered blood pressure by 12 to 14% and
also lowered cholesterol by about 7%.
3nB appears to help lower blood pressure by both acting as a diuretic and vasodilator through impacting the
production of prostaglandins (discussed below) as well as acting in a similar manner to drugs known as
calcium-channel blockers. 3nB has also been shown to lower blood cholesterol levels and reduce the
formation of arterial plaque in experimental studies (animal and test tube studies). This effect may increase
the elasticity of the blood vessels and also lead to lower blood pressure readings. 3nB also appears to
promote some effects on areas and systems of the brain that control vascular resistance.
Celery extract on the other hand has actually been shown to not only help prevent stroke in animal studies,
but also improve blood flow as well and act to protect the brain and enhance energy production with the
brain in a similar manner to Ginkgo biloba extract. It has produced dramatic recovery in neurological and
brain function in animals in studies that simulate a stroke. It has also been shown to significantly increase
lifespan in animal studies.

A celery extract standardized to contain 85% 3nB and other celery phthalides has been evaluated in the
treatment of "rheumatism" the general term used for arthritic and muscular aches and pain. In these studies
efficacy was evaluated by well-established clinical protocols used to measure the effectiveness of
conventional drugs used in arthritis and muscular pain. This protocol allows objective measures of clinical
pain that can be assessed statistically and for individual comparisons. Due to the chronic, fluctuating nature
of rheumatism, the design of the study was a longitudinal study. This sort of study compares the results
achieved when using the active substance to a time when it is not used.

Based upon al of the existing research it is clear that 3nB exerts a profound effect on many of the body's
control systems. Chief among them the prostaglandin system. Prostaglandins are chemicals that mediate or
control many important body processes including regulating inflammation, pain, and swelling; blood
pressure; and heart, digestive, and kidney function as well. Some of the effects noted for 3nB on the
prostaglandin system are quite unique and novel. Rather than simply inhibiting the production of
prostaglandins by blocking enzymes that produce them like aspirin or even the more expensive and selective
Cox-2 inhibitors, 3nB appears to help restore balance in the prostaglandin system.Exactly how it
accomplishes this effect is still a mystery. Drug companies are researching the unique effects of 3nB in order
to develop drugs that can be patented and sold for a huge profit. It does not look like that line of research is
necessary, however

Flavonoid
Flavonoid merupakan golongan terbesar senyawa fenolik di samping fenol sederhana, fenilpropanoid,
dan kuinonfenolik (Harborne 1986). Sebanyak 2% dari seluruh karbon yang difotosintesis oleh tanaman
diubah menjadi flavonoid atau senyawa yang berhubungan erat dengannya (Markham 1988). Dalam
tumbuhan, aglikon flavonoid terdapat dalam berbagai bentuk struktur. Semuanya mengandung 15 atom
C dalam inti dasarnya yang tersusun dalam konfigurasi C6-C3-C6, yaitu dua cincin aromatik
dihubungkan oleh 3 karbon yang dapat atau tidak dapat membentuk cincin ketiga. Cincin diberi nama A,
B, dan C, atom karbon dinomori menurut sistem penomoran yang menggunakan angka untuk cincin A
dan C serta angka beraksen untuk cincin B. Struktur umum flavonoid dapat dilihat pada Gambar 1.

Apigenin
Apigenin merupakan komponen flavonoid utama dari seledri yang termasuk ke dalam golongan flavon
(Harborne 1986). Gambar 2 menunjukkan struktur kimia apigenin. Rumus molekulnya adalah C15H10O5
dengan bobot molekul 270,23 g/mol. Nama Intenational Union of Pure and Applied Chemistry dari
apigenin adalah 5,7-dihidroksi-2-(4-hidroksifenil)-4H-1-benzopiran-4-on. Titik leleh apigenin 345–350
C. Apigenin memiliki banyak kegunaan, salah satunya dalam bidang farmasi. Senyawa ini dapat
digunakan sebagai obat asam urat (Duke 1999).
Sedation and Analgesia for Diagnostic or Therapeutic Procedures
Definitions:
The Sedation Continuum:
Sedation is a continuum, it is not always possible to predict how an individual will respond.

Conscious Sedation describes a state of sedation, tranquilization and amnesia, that allows a patient to
tolerate a painful diagnostic or therapeutic procedure while maintaining adequate cardiorespiratory function
and the ability to respond purposefully to verbal command and/or tactile stimulation.
Deep Sedation is a state of unconsciousness from which the patient is not easily aroused, which may be
accompanied by impairment of airway protective reflexes and ventilatory drive.
General Anesthesia refers to a state of unconsciousness plus partial or complete loss of protective reflexes
including the inability to independently maintain an airway.

As the dose increases and the level of drug in the central nervous system rises, consciousness decreases and
the risk of cardiorespiratory depression increases. As the dose increases further, the patient continues to
advance along the sedation continuum until protective airway reflexes are lost and general anesthesia is
reached. This continuum is not drug-specific, since various states, from mild sedation to general anesthesia,
can be achieved with essentially all sedative agents.

Diazemam ftalid
rheumatism" – the general term used for arthritic and muscular aches and pain.13,14 In these studies efficacy
was evaluated by well-established clinical protocols used to measure the effectiveness of conventional drugs
used in arthritis and muscular pain. This protocol allows objective measures of clinical pain that can be
assessed statistically and for individual comparisons. Due to the chronic, fluctuating nature of rheumatism,
the design of the study was a longitudinal study. This sort of study compares the results achieved when using
the active substance to a time when it is not used.
Based upon al of the existing research it is clear that 3nB exerts a profound effect on many of the body’s
control systems. Chief among them the prostaglandin system. Prostaglandins are chemicals that mediate or
control many important body processes including regulating inflammation, pain, and swelling; blood
pressure; and heart, digestive, and kidney function as well. Some of the effects noted for 3nB on the
prostaglandin system are quite unique and novel. Rather than simply inhibiting the production of
prostaglandins by blocking enzymes that produce them like aspirin or even the more expensive and selective
Cox-2 inhibitors, 3nB appears to help restore balance in the prostaglandin system.16 Exactly how it
accomplishes this effect is still a mystery.
Drug Discovery and Evaluation
Pharmacological Assays
Efek pada motilitas
(Aktivitas sedative atau stimulasi)

Pertimbangan-pertimbangan umum
Sifat sedative obat diuji sebagian besar pada tikus atau mencit. aktivitas motorik spontan mereka tergantung
pada berbagai faktor, seperti situasi sosial (satu atau lebih hewan), keakraban dengan cahaya uji lingkungan,
dan suhu. Aktivitas motorik spontan Istilah mencakup berbagai jenis gerakan, seperti daya, pemeliharaan,
mengendus, grooming, makan dan minum. Fenomena ini bisa dikenal dengan baik oleh pengamat terampil,
tetapi sulit untuk merekam selama jangka waktu yang lama dan menduga jumlah. Sebuah fenomena khusus,
yang disebut "thigmotaxis" yang berarti bahwa tikus memiliki kecenderungan untuk tetap dekat ke dinding
kandang, telah dijelaskan oleh Barnett (1963). Selain itu, metode untuk mengukur rasa ingin tahu telah
direkomendasikan.

Metode pengamatan intermiten

TUJUAN DAN DASAR PEMIKIRAN
Metode ini dijelaskan oleh Ada (1953) dirancang untuk mengetahui aktivitas sedative atau stimulasi.
Penggunaan 3 tikus per kelompok tersirat situasi sosial khusus binatang. Untuk uji aktivitas obat penenang,
tikus yang diperlakukan dengan tambahan stimulan, dan untuk pengujian aktivitas stimulan dengan obat
penenang. Setiap kelompok mencit diamati berulang kali hanya untuk waktu singkat selama satu jam dan
dibandingkan dengan kelompok kontrol oleh pengamat "buta".

PROSEDUR
Tikus baik berbagai jenis kelamin dengan berat rata-rata 25 g dipuasakan dari makanan dan air selama 24
jam sebelum ujian. Untuk menghindari pengaruh dari ritme sirkadian percobaan dilakukan hanya 8:00-12:00
dua belas hewan dibagi menjadi 3 kelompok tikus. Satu kelompok 3 mencit berfungsi sebagai kelompok
kontrol; kelompok lain menerima dosis yang berbeda dari obat uji secara intraperitoneal. Untuk uji aktivitas
obat penenang, tikus yang disuntikkan setelah 10 menit subkutan dengan 0,5 mg / kg methamphetamine.
Untuk uji aktivitas stimulan, tikus yang diperlakukan dengan 800 mg / kg paraldehyde. Sepuluh menit
setelah itu, tiap kelompok ditempatkan dalam botol gelas diameter 12 cm dan 20 cm yang pada gilirannya
ditempatkan dalam kotak kayu 130 × 50 × 30 cm. Botol kaca yang menyala dari atas. Sepuluh menit setelah
pemberian methamphetamine atau paraldehyde pengamatan dimulai.

EVALUASI
Selama 1 jam pengamat terlihat setiap menit selama 1 s untuk setiap tabung dan register jika tidak, satu, dua
atau tiga tikus menunjukkan perubahan karakteristik dalam tenaga, pemeliharaan, perawatan atau sniffing.
Jumlah maksimum dalam 1 jam akan menjadi 180. Secara umum menurun aktivitas, dalam 1 h. Namun
demikian, metamfetamin hewan yang dirawat memiliki jumlah total antara 120 dan 150. Kelompok
perlakuan dengan obat penenang yang efektif menunjukkan penurunan dosis tergantung dari jumlah total.
Jumlah yang penting dalam kelompok perlakuan dihitung sebagai persentase dari kontrol. Dari kurva dosis-
respons ED50-nilai dapat dihitung.

PENILAIAN KRITIS ATAS METODE

Metode ini memberikan hasil yang dapat diandalkan untuk obat penenang dan untuk senyawa dengan
aktivitas penekan pusat, seperti antihistaminics, neuroleptik dan hipnotik. Kerugian dari metode ini terletak
pada fakta bahwa seorang pengamat terampil dan terlatih yang diperlukan untuk mendapatkan hasil diulang.
Oleh karena itu, beberapa usaha telah dilakukan untuk automatize metode observasi intermiten.

MODIFIKASI METODE YANG

Schaumann dan Stoepel (1961) mengikuti prinsip pengamatan intermiten menggunakan kamera yang
dipasang di atas kandang kawat kecil (10 × 10 cm). Tikus di kandang difoto dengan waktu bukaan 3 s setiap
menit 7,5 selama 2,5 h. Tikus tanpa gerakan memberikan gambar yang jelas, dihitung sebagai nol. Sedikit
gerakan mendorong kabur kontur, dihitung sebagai 1 point, dan gerakan utama memberikan sepenuhnya
kabur gambar, dihitung sebagai 2 poin. Normal tikus menunjukkan 20 atau kurang poin selama 20
pengamatan. Tikus dengan lebih dari 20 poin dianggap stimu-terisolasi, tikus dengan kurang dari 5 poin
untuk dibius. Dengan cara ini ED50-nilai dapat dihitung.
Vogel dan Ada (1963) menerbitkan sebuah alat dengan pendaftaran otomatis pengamatan intermiten. 18
kandang yang digunakan yang mempunyai dasar bebas bergerak dengan berat badan minimal yang didukung
oleh mata air. Sebuah magnet permanen kecil yang menempel di bawah lantai menginduksi arus listrik
dalam kumparan jika bagian bawah dipindahkan. Dua tikus dibawa ke kandang masing-masing. Register
perangkat kontrol selama periode variabel antara 0,5 dan 3 s jika bagian bawah satu kandang dipindahkan
atau tidak. Dalam satu menit, semua 18 kandang yang terdaftar berturut-turut. Jumlah gerakan dalam satu
jam dicatat untuk setiap kandang. Sensitivitas sistem induksi listrik adalah variabel. kalibrasi adalah mungkin
yang menangkap setiap gerakan dari binatang, bagaimanapun, tidak mendaftarkan gerakan karena bernapas.
Kurva dosis-respons dapat dibentuk untuk obat stimulan dan obat penenang.
Meyer (1962) diukur waktu sampai motilitas eksplorasi menurun sepertiga dari nilai awal. Koek et al. (1987)
menggunakan prinsip pengamatan berselang sebentar-tenda untuk berbagai kegiatan seperti tikus daya,
pemeliharaan, mengendus, menjilat, menggigit, grooming, kehilangan meluruskan, ekor Straub, dll. untuk
membandingkan efek perilaku obat.

Aktivitas Hypnotic
Pertimbangan-pertimbangan umum
Istilah "hipnotis" harus didefinisikan. Dalam manusia, tujuan mengambil hipnotik adalah untuk mendapatkan
"normal" tidur malam dari mana pasien dapat dibangunkan tanpa mabuk berikutnya. Dalam percobaan
binatang, istilah "hipnotis" telah diterapkan ke tahap yang lebih dalam depresi pusat ketidaksadaran
diinduksi obat berhubungan dengan hilangnya otot dan refleks meluruskan. Oleh karena itu, sebagian besar
model farmakologis yang dipertanyakan dalam kaitannya dengan predictivity mereka untuk menemukan
hipnotis yang ideal untuk terapi manusia. Banyak tes farmakologis didasarkan pada potensiasi tidur waktu
diinduksi oleh barbiturat atau agen obat penenang lainnya. Sejak peristiwa biokimia selama tidur agak tidak
diketahui ada dalam metode in vitro ada untuk pengujian senyawa dengan aktivitas hipnotis potensial.

THE SOCIETY FOR PEDIATRIC

SEDATION SEDATION PROVIDER COURSE
SEDATIVE DRUGS
Sedative drugs are medications that result in central nervous system depression. Use of these drugs may
result in loss of protective reflexes, with subsequent respiratory and/or cardiac dysfunction.

Many of the clinical effects of medications administered to achieve sedation are dose related and must be
assessed individually for each child. Sedative drugs may be administered orally, intranasally, rectally,
parenterally or by inhalation. Specific types of sedatives can be further defined by their characteristic or
predominant clinical effect. Some of the more common definitions of drugs used for sedation include:
o Sedative: A sedative decreases activity, moderates excitement and calms the patient.
o Hypnotic: A hypnotic produces drowsiness and facilitates the onset and maintenance of sleep.
o Analgesic: An analgesic relieves pain by altering perception of nociceptive stimuli.
o Anxiolytic: An anxiolytic relieves apprehension and fear due to an anticipated act or illness.
o Amnesic (antegrade): An amnestic agent affects memory incorporation such that the patient is unable
to recall events following delivery of the drug.

B. LEVELS OF SEDATION
The transition from minimal to moderate sedation and from moderate to deep sedation can be difficult to
predict and must be anticipated whenever sedation is administered. The definitions of minimal sedation,
moderate sedation, deep sedation and general anesthesia are defined below.

Professional organizations have defined sedation in different ways. Across the board all these organizations
have defined different “levels” of sedation ranging from minimally impaired consciousness to complete
unconsciousness or general anesthesia. Any provider who delivers sedation should recognize that different
levels of sedation are possible and they are not specific to a given drug. Any drug (given a large enough
dose) will produce obtundation, and likewise even the most powerful anesthetic can produce minimal
sedation when given in a very small dose.

Sedation providers should recognize that these definitions are arbitrary and there is no clear demarcation
between the different levels. The current recommendations from JCAHO state that a provider of sedation
should be able to manage or “rescue” a patient from one level of sedation “deeper” than that which is
intended. This is a recognition of the fact that it is impossible to always know the effect that a given dose of
a sedation medication will have on an individual patient. It is also a recognition of the fact that different
levels of sedation require different levels of expertise in management of the airway and physiological
function for a patient. Below are the levels of sedation as defined by the AAP and ASA.

o MINIMAL SEDATION (ANXIOLYSIS)

A drug induced state in which patients respond normally to verbal commands. Cognitive function and
coordination may be impaired. Protective reflexes are maintained and ventilatory and cardiovascular
functions are unaffected.

o MODERATE SEDATION
A drug-induced depression of consciousness during which patients respond purposefully to verbal
commands, either alone or accompanied by light tactile stimulation. No interventions are required to
maintain a patent airway and the patient is able to handle secretions without aspiration. Spontaneous
ventilation is adequate, although there may be minimal to mild alterations in ventilatory responsiveness.
Cardiovascular function is usually maintained. There is significant loss of orientation to environment,
with moderate impairment of gross motor function.

o DEEP SEDATION
Deep sedation is a medically controlled state of depressed consciousness or unconsciousness from which
the patient is not easily aroused. Patients respond purposefully to painful stimulation. It may be
accompanied by a partial or complete loss of protective reflexes, which may include the inability to
maintain a patent airway independently and respond purposefully to physical stimulation or verbal
command. Patients may require assistance in maintaining a patent airway and spontaneous ventilation
 may be inadequate. Moderate loss of ventilatory responsiveness may occur. Cardiovascular function is
usually maintained.

o GENERAL ANESTHESIA
General anesthesia is a drug-induced loss of consciousness during which patients are not arousable, even
by painful stimulation. The ability to independently maintain ventilatory function is often impaired.
Patients often require assistance in maintaining a patent airway, and positive pressure ventilation may be
required because of depressed spontaneous ventilation or drug-induced depression of neuromuscular
function. Cardiovascular function may be impaired as well. Only anesthesiologists are credentialed to
administer and/or supervise planned general anesthesia care. Supervised residents and supervised clinical
anesthetists are authorized to administer general anesthesia under the medical direction of an
anesthesiologist.

Summary of Levels of Sedation and Clinical Response

OVERVIEW OF DRUGS USED FOR SEDATION - GENERAL APPROACH TO

PROCEDURAL SEDATION

The four primary goals of pediatric procedural sedation include maintaining patient safety, providing
effective pain control, reducing anxiety and psychological stress, and promoting conditions conducive to
successful performance of the procedure. To achieve these goals the sedation practitioner must have a clear
idea of the desired clinical effects (i.e., the therapeutic window).
1. THE THERAPEUTIC WINDOW
The therapeutic window refers to the drug concentration associated with the desired clinical effects. It
describes the relationship between the drug concentration and its therapeutic and adverse effects.
 o Concentrations of drug within the therapeutic window are associated with the desired clinical
effect.
o Drug concentrations above and below the “therapeutic window” result in inadequate and
adverse clinical effects (e.g., hypoventilation), respectively.
o Large interpatient variability exists between drug concentration and clinical response.
o The goal is to administer the sedative drug that achieves the desired clinical effect (“right”
drug) (pharmacodynamics) at the “right” time (pharmacokinetics).

2. PHARMACOKINETIC (PK) AND PHARMACODYNAMIC (PD) PRINCIPLES

A thorough understanding of the drug’s pharmacokinetic and pharmacodynamic profile will promote
safe and effective patient sedation. This next section will discuss the intimate relationship between
the pharmacokinetics and pharmacodynamics of a sedative drug in achieving the desired effects.

PHARMACODYNAMIC FACTORS deal with “what the drug does to the body” (including both
desired and adverse clinical effects). These effects are similar within a given class of drugs (e.g.,
opioids) and are dependent on the target organ and sedative receptor system. Common drug-receptor
systems include the following:

o Opioid (µ1,µ2) receptors - G-protein-coupled receptors: fentanyl, morphine (agonists),

naloxone (antagonist)
o Gamma-aminobutyric acid (GABAA) receptors – Ligand gated ion channels, the primary
inhibitory neurotransmitter system in the central nervous system: barbiturates, etomidate,
propofol (augment GABAergic neurotransission)
o Benzodiazepine receptors – Part of the GABAA receptor system: midazolam, diazepam
(agonists), flumazenil (antagonist)
o N-methyl-D-aspartate (NMDA) receptors – Glutamate (excitatory) neurotransmitter system:
ketamine blocks NMDA receptor and decreases excitatory neurotransmission
o Central 2- receptors – G-protein-coupled receptors: clonidine, dexmedetomidine (agonists)

PHARMACOKINETIC FACTORS deal with “what the body does to the drug.”
Pharmacokinetic properties typically distinguish drugs within a given class (e.g. fentanyl vs
morphine).

This section is divided into 3 parts based on the predominant characteristic feature of the sedative drug:
Sedative-Anxiolytics – Drugs that reduce anxiety
Sedative-Hypnotics – Drugs that result in sleep
Sedative-Analgesics – Drugs that have analgesic properties
Sedative-Hypnotic Drugs
Michael H. Nelson, Ph.D., R.Ph.
Pharmacy 725: Principles of Drug Mechanisms
Wingate University School of Pharmacy