Assignment

On
Biopharmaceutics & Pharmacokinetics I
PHA-3112

Submitted From:
Md. Nazmus Sakib
ID:201811232002 Submitted To:
Department of Pharmacy Nilima Karmaker
Bangladesh University Lecturer
Department of Pharmacy
Bangladesh University
 1) What are the factors considered for gastric emptying ?
Ans:
Gastric emptying: Gastric emptying is the process by which the contents of the
stomach are moved into the duodenum.Metabolic load, neural regulatory
mechanisms and hormonal influence achieve a balanced emptying of contents from
the stomach into the duodenum for absorption in the small intestine.
Factors considered for gastric emptying :
Promote:
Gastric volume:
Increased food volume in stomach promotes increased emptying
Antral distension stimulates vasovagal excitatory reflexes leading to increased
antral pump activity
Liquid vs solid food
Clear fluids are empty rapidly ( 30 minutes). Solids stay in stomach longer (1-2
hours)
Pylorus is open enough for H2O/fluids to empty with ease. Constriction of the pyloric
sphincter to solids until chyme is broken down into small particles and mixed to
almost fluid consistency
Types of food
The rate of gastric emptying is Carbohydrates>Fats>Protien
Hormonal factors
Gastrin has mild to moderate stimulatory effects on motor functions in the body
of the stomach. Enhances activity of pyloric pump
Motilin released by epithelium of the small intestine enhances the strength of the
migrating motor complex which is a peristaltic wave that begins within the
oesophagus and travels thru the whole GIT every 60-90 min during the interdigestive
period. Help empty remaining food in stomach
Neural
Parasympathetic innervation (via vagus) stimulates motility
Local myenteric reflex
Drugs
Prokinetics eg cisapride, erythromycin metoclopramide
Inhibit
 Duodenal distension
Results in inhibitory enterogastic reflexes
Slow or even stop stomach emptying if the volume of chyme in the duodenum
becomes too much
Osmolarity of chyme
Iso-osmotic gastric contents empty faster than hyper or hypo-osmotic contents
due to feedback inhibition produced by duodenal chemoreceptors (hyper more
inhibitory than hypo)
Acid
pH of chyme in the small intestine of < 3.5-4 will activate reflexes to inhibit
stomach emptying until duodenal chyme can be neutralized by pancreatic and other
secretions
Temperature
Cold liquid (40C) empty more slowly
Hormones
Cholecystokinin released from duodenum in response to breakdown products of
fat and protein digestion. Blocks the stimulatory effects of gastrin on the antral
smooth muscle
Secretin released from the duodenum in response to acid, has a direct inhibitory
effect on the gastric smooth muscles
Others eg somatostatin, vasoactive intestinal peptide (VIP), gastic inhibitory
peptide (GIP)
Neural
Sympathetic nerves (via the celiac plexus) inhibits motility
Patient factors
Pregnancy delays gastric emptying (progesterone)
Anxiety delays gastric emptying
Pain
Elderly
Disease states eg diabetes mellitus (autonomic neuropathy), post-operative
bowel surgery with resultant ileus, high intra-abdominal pressure
Drugs eg. opioids
Mechanical eg pyloric stenosis
2. ‘Dosage form factors play an important role in drug absorption’- Justify
the statement.
Ans:
Bioavailability: Drug bioavailability is the fraction of the administered dose that
reaches the systemic circulation. We can also define bioavailability as rate and
extent of unchanged drug form it’s dosage form and become available at the site of
action. Dosage form factors also play an important role in drug absorption which is
given in below. It is a sub part of Drug absorption .
Dosage form: Dosage forms (also called unit doses) are pharmaceutical drug
products in the form in which they are marketed for use, with a specific mixture of
active ingredients and inactive components (excipients), in a particular configuration
(such as a capsule shell, for example), and apportioned into a particular dose .
Dosage Form Route of Bioavailability (%) Characteristics
administration
Solid Oral 5 to 100 Most Oral route drugs
convenient have to face first
pass effect that
reduce its
bioavailability
Semi Solid Rectal 30 to <100 Here is less fast
pass effect than
Oral
drugadministration
Liquid Intravenous 100(by definition) Drugs are sent
directly into your
vein using a
needle or tube. It
has most rapid
onset.
Intramuscular 75 to 100 Large An intramuscular
volume often injection is a
feasible technique used to
deliver a
medication deep
into the muscles.
This allows the
medication to be
absorbed into the
bloodstream
quickly. It may be
painful.
Subcutaneous 75 to 100 Smaller Subcutaneous
volume than IM means under the
skin. Here a short
needle is used to
inject a drug into
the tissue layer
 between the skin
and the muscle. It
may be also
painful.
Gaseous Inhalation 5 to 100 Often very rapid
onset
3. What are the patient related factors considered in drug absorption?
Ans:
Patient related factors: There are some patient related factors that effecting drug
absorption
1. Age: This cause drug absorption due to
Infants have
 High Gastric pH
 Low Intestinal surface
 Low blood flow to GIR
And elderly persons
 Altered gastric emptying
 Decreased intestinal surface area and GI blood flow
 Higher incidents of achlorhydria Bacteria overgrowth.

2. Gastric emptying:
 Apart from dissolution of a drug & its permeation through the bio membrane,
the passage from stomach to the small intestine, called as gastric emptying.
 Rate limiting step, because the major site of drug absorption is intestine.
 It increases bioavailability of a drug.
 It is first order process.

3. Intestinal transit
 Small intestine- major site for drug absorption,long intestinal transit is
desirable for complete drug absorption.
 The residence time depends on the intestine that occurs due to peristaltic
contractions..
 It promotes drug absorption by,
I) Increasing drug intestinal membrane contact,
II) Enhancing dissolution especially poorly soluble drugs, through induced
agitation.

4. Gastrointestinal pH:
107 fold difference in the H+ Ion concentration is observed between the gastric &
colon fluids.
 5. Blood Flow To the GIT
 The GIT is extensively supplied by blood capillary network & the lymphatic
system.
 The blood flow rate to the GIT is 500 to 1000 times (28% of cardiac output)
more than the lymph flow.
 GI perfusion rate could be a rate limiting step in the absorption of lipid soluble
drugs.
 The perfusion rate increases after meals but absorption is not influenced
significantly.

6. Disease States:
Classes of diseases states, can affect on Bioavailability of drug:
 Gastrointestinal diseases:
 Altered GI motility
 GI diseases & infections
o Achlorhydria – decreased gastric acid secretion & increased stomach pH
o Malabsorption syndrome
o Celiac disease
o Crohn’s disease
o Infections like gastroenteritis, cholera, colitis, amoeviasis& constipation
o GI surgery
 Cardiovascular diseases:
 CHF influence bioavailability of drug viz. oedema of intestine,
 Decreased blood flow to the GIT & gastric emptying rate,
 Altered GI pH, secretion & microbial flora
 Hepatic diseases:
 Such as hepatic cirrhosis.

7. Presynaptic metabolism (First-pass effects):

 Before a drug reaches blood circulation, it has to pass for the first time
through organs of elimination namely the GIT & liver.
 The loss of drug through biotransformation by such eliminating organs during
its passage to systemic circulation is called as FIRST-PASS METABOLISM
 Following system affect on FIRST-PASS METABOLISM
 Luminal enzymes
 Digestive enzymes
 Bacterial enzymes
 Mucosal / Gut wall enzymes
 Hepatic enzymes
4. Give the schematic chart of drug metabolizing organ.
Ans:
Drug metabolism:
Drug metabolism is defined as the chemical transformation of a drug within biological
system with the help of enzyme to give active or inactive metabolite which is more
polar than the parent compound so that it is eliminated from the body easily.
Drug metabolising organs:
Most drugs must pass through the liver, which is the primary site for drug
metabolism. Once in the liver, enzymes convert prodrugs to active metabolites or
convert active drugs to inactive forms. The liver’s primary mechanism for
metabolizing drugs is via a specific group of cytochrome P-450 enzymes. The level
of these cytochrome P-450 enzymes controls the rate at which many drugs are
metabolized. So liver is the heart of metabolism.
Schematic chart of metabolising organs (decreasing order) are:
Liver>Lungs>Kidney>Intestine>Placenta>Skin>Brain>Muscle>Spleen
5. Give a short note on Drug Metabolizing Enzymes.
Ans:
They are broadly classified in to two:
i. Microsomal and
ii. Non microsomal.
 Microsomal enzymes: Microsomal enzymes catalysed majority of drug
biotransformation reaction. The large variety of microsomal enzyme catalyse
oxidative, reductive & hydrolytic and glucouronidation reactions. They are
located on smooth endoplasmic reticulum, mainly in liver then kidney, lungs,
intestinal mucosa.they are inducible by drugs, diet. Ex- CYPs, FMOs, EHs,
UGTs etc.

 Non microsomal enzymes: Non microsomal enzymes are non specific

enzymes that catalyse few oxidative, a no. of reductive & hydrolytic rections
and also conjugation reaction other than glucouronidation. They are presence
in cytoplasm and mitochondria of hepatic cells as well as in other tissues
including plasma. Not inducible but having polymorphism. Ex- protein
oxidases, esterases, amidases, conjugated gases.
These types of enzymes are less or not present in the neonatal. So the
drug may cause toxic effect due to less metabolism of drug. Some syrups containing
alcohol in very less extent, still it is harmful to children. Other containing codeine may
cause lethal effect.
6. Why Biotransformation is required?
Ans: Biotransformation means chemical alteration of chemicals such as nutrients,
amino acids, toxins, and drugs in the body. It is also needed to render non-polar
compounds polar so that they are not reabsorbed in renal tubules and are excreted.
Biotransformation of xenobiotics can dominate toxicokinetic and the metabolites may
reach higher concentrations in organisms than their parent compounds.
Importance of biotransformation:
1. Drug metabolism: The metabolism of a drug or toxin in a body is an example of a
biotransformation. The body typically deals with a foreign compound by making it
more water-soluble, to increase the rate of its excretion through the urine. So,
biotransformation is important
2.it is important Factor in multidrug resistance.
3.it is important to convert non polar lipophilic compounds which the body can not
excrete into more polar hydrophilic compounds which the body can excrete in short
period of time
Because if the lipid soluble non polar compounds are not metabolized to the
water soluble compounds, they will remain in the blood and tissues and maintain
their pharmacological effects for an indefinite time.
4. Complex drug: Most drugs are complex and do not have smaller molecular mass;
naturally polar and not fully ionised at body PH. For these reason drug have to
broken down into smaller part.
5. It is important to terminate drug action by inactivating it by changing its
physiochemical properties from:
Lipophilic to hydrophilic
Unionised to ionised
Nonpolar to polar
Plasma protein bound to free.
7. Write down the Enzymes Involved in Phase I Reactions.
Ans:
Enzymes Involved in Phase I Reactions

Oxidation

 Cytochrome P450 monooxygenase system

 Flavin-containing monooxygenase system

 Alcohol dehydrogenase and aldehyde dehydrogenase

 Monoamine oxidase

 Co-oxidation by peroxidases

Reduction

 NADPH-cytochrome P450 reductase

 Reduced (ferrous) cytochrome P450

Hydrolysis

 Esterases and Amidase

 Epoxide hydrolase
 8. Write down the Enzymes Involved in Phase I Reactions.
Ans: The enzyme-catalysed reactions of Phase I metabolism bind oxygen,
hydrogen, water, or amino acids to the lipophilic drug molecule to expose or
introduce a hydroxyl (-OH), amino (-NH2), sulfhydryl (-SH), or carboxyl (-COOH)
polar functional group, and thus, result in a modest increase in the parent drug's
water solubility. These reactions include hydrolysis, reduction, and oxidation.
Oxidation:
Reactions resulting in the addition of oxygen and/or the removal of hydrogen.
 Cytochrome P450 monooxygenase system
 Flavin-containing monooxygenase system
 Alcohol dehydrogenase and aldehyde dehydrogenase
 Monoamine oxidase
 Co-oxidation by peroxidases
Reduction:
Reactions resulting in the addition of hydrogen and/or the removal of oxygen.
 NADPH-cytochrome P450 reductase:
Cytochrome P450 reductase, also known as NADPH: ferrihemoprotein
oxidoreductase, NADPH: hemoprotein oxidoreductase, NADPH:P450
oxidoreductase, P450 reductase, POR, CPR, CYPOR, is a membrane-bound
enzyme required for electron transfer to cytochrome P450 in the microsome of the
eukaryotic cell from a FAD- and FMN-containing enzyme NADPH: cytochrome P450
reductase The general scheme of electron flow in the POR/P450 system is: NADPH
→ FAD → FMN → P450 → O2
 Reduced (ferrous) cytochrome P450:
During reduction reactions, a chemical can enter futile cycling, in which it gains a
free-radical electron, then promptly loses it to oxygen (to form a superoxide anion).
Hydrolysis:
In a reaction with water, a bond in the compound is broken, resulting in two
compounds. At the same time the water molecule splits in two, with a hydrogen
transferring to one of the compounds and a hydroxide to the other compound.
 Esterases and amidase
 Epoxide hydrolase
Ques: How will you estimate Liver Extraction Ratio (ER)?
Ans:
The liver extraction ratio (ER) provides a direct measurement of drug removal from
the liver after oral administration of a drug.
 ER= (Ca- Cv)/ Ca
 Here Ca is drug concentration in renal artery
 Cv is drug concentration in renal vein
 9. Give a brief description on Restrictive & Non-Restrictive Clearance.
Ans:
Restrictive Clearance: The drugs cleared by restrictive elimination have
• Limited first pass effect after oral administration
• Low hepatic extraction ration < 0.3
• Clearance is low and unaffected by liver blood flow
• Clearance is profoundly influenced by changes in hepatic enzyme activity (caused
by drugs, malnutrition, age, liver disease)
Most drugs are restrictively cleared—for example, diazepam, quinidine, tolbutamide,
and warfarin. The clearance of these drugs is proportional to the fraction of unbound
drug (fu)
Non-Restrictive Clearance: Clearance of few drugs doesn’t depend on whether the
drug is bound to protein or not and this is known as Non-restrictive Clearance.
Ex: Propranolol, Morphine, etc.
some drugs, such as propranolol, morphine, and verapamil, are nonrestrictively
extracted by the liver regardless of drug bound to protein or free.
Drug elimination of these drugs is exclusively hepatic
Kinetically, a drug is nonrestrictively cleared if its hepatic extraction ratio (ER) is
greater than the fraction of free drug (f u), and the rate of drug clearance is
unchanged when the drug is displaced from binding.
 10.Describe salivary and dermal excretion of drugs.
Ans:
Drug excretion is the process of eliminating a drug from the body. The majority of
drugs are eliminated by pathways that involve the kidneys (see the record on Renal
Drug Excretion) or the liver. Renal excretion plays an important role in eliminating
unchanged drugs or their metabolites into urine.
Salivary excretion: Salivary excretion is not really a method of drug excretion as the
drug will usually be swallowed and reabsorbed, thus, it is a form of 'salivary
recycling'. Drug excretion into saliva is dependent on pH partition and protein
binding. In most of the cases salivary concentrationrepresents the free drug
concentration in plasma. This mechanism plays a main role in terms of drug
monitoring, which determines drug concentration to assist in drug dosage
Adjustment. The action of drugs generally ends with their metabolism and/or
elimination in urine or to a lesser extent inbile, expired air or directly through the
intestinal wall. A minor role is played by sweat, tears, breast milk and saliva. Saliva is
not truly an excretory route however as it is usually swallowed, thus allowing some
drugs to be reabsorbed from the gastrointestinal tract. Gingival fluid is different from
glandular saliva particularly regarding albumin, globulin and fibrinogen
concentrations which are similar to those in plasma.7 The pH of saliva varies from
5.8 to 8.4. Unionized fat-soluble drugs are excreted passively from saliva. The bitter
after taste in the mouth of a patient is main indication of drug excreted. Few basic
drugs inhibit saliva secretion andare responsible for mouth dryness. Compounds
usually excreted in saliva are Caffeine, Phenytoin, and Theophylline. The salivary
elimination of various compounds, like mercury derivatives, has been known for a
long era and it is admitted that the salivary concentration of liposoluble drugs is the
reflection of their plasma concentration in free form. But compounds such as iodide
and spiramycin, are higher in saliva than in plasma.
Dermal excretion: Drugs excreted through derma or skin via sweat follows pH
partition hypothesis. Excretion of drugs through skin may lead to urticaria and
dermatitis.
Compounds like benzoic acid; salicylic acid; alcohol and heavy metals like lead;
mercury and arsenic are excreted in sweat.