Name: Shaikh Rumana Inushahmad

Group: MA 333

Date: 7/7/2022
Card: 99

1. Pharmacokinetics. Distribution, binding with proteins and metabolism of drugs.

Pharmacokinetics basically refers to the activity of drugs in the body over a period of time, including the processes by
which drugs are absorbed, distributed in the body, localized in the tissues, and excreted.

Sites of drug distribution

Plasma: 3 liters

Extracellular water: 9 liters

Intracellular water: 29 liters

Volume of distribution (Vd)

Definition: The apparent volume into which the drug is distributed uniformly to produce the observed blood
concentration.

Clinical significance:

 Determination of the site of drug distribution e.g.:

A total Vd < 5 L: means that the drug is confined to the vascular compartment and can be removed by dialysis.

A total Vd 5-15 L: means that the drug is restricted to the ECF.

A total Vd > 41 L: means that the drug is highly bound to tissue proteins and cannot be removed by dialysis.

 Calculation of the total amount of drug in the body by single measurement of plasma concentration (from the
equation).
 Calculation of the loading dose (LD) needed to attain a desired plasma

concentration(Cp): LD = Vd x Cp.

 Calculation of drug clearance.

Binding of drugs to plasma proteins

-Most drugs when introduced into the body are bound to plasma proteins.

-Albumin: the most important plasma protein and it can bind -ve or +ve charged drugs.

Clinical significance:

 The pharmacological effect of the drug is related only to its free part not to its bound part (the bound part acts
only as a reservoir from which the drug is slowly released).
 Binding of drugs to plasma proteins prolongs their effects.
 When the drug has high plasma protein binding (e.g., 99% for warfarin), the free part that exerts the
pharmacologic effect is 1%. Any small displacement of the bound part by another drug (say for example
another1% is displaced) can lead to dramatic toxicity (doubles the amount of the free part in plasma).
 Many disease states (e.g. chronic liver disease, pregnancy, renal failure) can affect the level of albumin and the
nature of plasma proteins, thus causing serious problems with some drugs.

Metabolism of drugs (Biotransformation)

Biotransformation is the metabolism of drugs in the body. The main organ for drugs metabolism is the liver.
Biotransformation is realized in two stages
 Stage I reactions are non-synthetic and include oxidation, reduction, hydrolysis.
-Microsomal oxidation/reduction with participation of enzymes of cytochrome P-450 system is an important
way of biotransformation of many drugs. The result of stage I is the formation of active or inactive products
which enter the stage II reactions.
-Enzymes catalyzing phase l reactions include cytochrome P450, aldehyde and alcohol dehydrogenase,
deaminases, esterases. amidases, and epoxide hydratases.
-The majority of phase I reactions is done by the cytochrome P450 (CYP450) enzyme system located primarily
inside membranous vesicles (microsomes) on the surface of the smooth endoplasmic reticulum of
parenchymal liver cells. CYP450 activity is also present in other tissue e.g., kidney, testis, ovaries and GIT.
 Stage II reactions are synthetic (conjugation with glucuronic and sulfuric acids, methylation, acethylation).
They lead to the formation of inactve metabolits excreted from the body.
-It involve coupling of a drug or its metabolite to water-soluble substrate (usually glucuronic acid) to form
water-soluble conjugate.
-Glucuronyl transferase is a set of enzymes that is responsible for the majority of stage Il reactions. This set of
enzymes is also located inside liver microsomes and is the only stage Il reaction that is inducible by drugs and
is a possible site of drug interactions e.g., phenobarbital induces glucuronidation of thyroid hormone and
reduces their plasma levels.
-Some glucuronide conjugates secreted in bile can be hydrolyzed by intestinal bacteria and the free drug can
be reabsorbed again (enterohepatic circulation), this can extend the action of some drugs.
-Other examples of non-glucurounide conjugation reactions include sulphate conjugation (steroids), glycine
conjugation (salicylic acid), and glutathione conjugation (ethacrynic acid).

Drugs which increase the activity of microsomal enzymes in the liver are named the inductors of microsomal
oxidation (e.g., phenobarbital, chlorpromazine).
Drugs which decrease the activity of microsomal enzymes in the liver are named the inhibitors of microsomal
oxidation eg.metronidazole.
-Many lipid soluble drugs must be converted into a water-soluble form (polar) to be excreted.

-Some drugs are not metabolized at all and excreted unchanged (hard drugs).

Metabolism of drugs may lead to:

 Conversion of active drug into inactive metabolites - termination of drug effect.

 Conversion of active drug into active metabolites - prolongation of drug effect e.g., codeine (active drug) is
metabolized to morphine (active product).
 Conversion of inactive drug into active metabolites (prodrugs) e.g. enalapril (inactive drug) is metabolized to
enalaprilat (active metabolite).
 Conversion of non-toxic drug into toxic metabolites (.g. paracetamol is converted into the toxic product
Nacetylbenzoquinone).

Biochemical reactions involved in drug metabolism

The drug must enter phase I of chemical reactions be excreted as water-soluble compound. If the drug is not liable to
conversion into water-soluble compound by phase l, it must enter phase Il to increase solubility and enhance
elimination.

First-pass metabolism (pre-systemic elimination)

Definition: metabolism of drugs at the site of administration before reaching systemic circulation .g. the liver after oral
administration, the lung after inhalation, the skin after topical administration, etc.

Hepatic first-pass metabolism:

• Complete: lidocaine.
• Partial: propranolol, morphine,nitroglycerine
• None: atenolol and mononitrates
How to avoid?

• By increasing the dose of the drug.

• By giving the drug through other routes e.g sublingual, inhalation, or i.V.
Bioavailability: it is the fraction of the drug become available for systemic effect afteradministration. The bioavailability
of drugs given i.v. is 100%.

Factors affecting bioavailability:

• Factors affecting absorption.

• Factors affecting metabolism.
• First-pass metabolism.

2. Tranquilizers. Benzodiazepines. Mechanism of action. Examples of medicines. Indications. Side effects.

Mechanism of action:

Binding to benzodiazepine receptors → increase of GABA activity

Inhibition of the excitability of brain subcortical regions (thalamus, hypothalamus, limbic system) and their
connections with the brain cortex

• BDZ have special receptors in the CNS and peripheral tissue.

• By acting on these receptors, BDZ cause allosteric modulation of GABA action on GABA, receptors resulting in 1
Cl- conductance and hyperpolarization.
• Six BDZ receptor subtypes have been discovered; subtype 1 is the most widely expressed.

Examples of medicines:

 Alprazolam (Xanax)
 Chlordiazepoxide (Librium)
 Clorazepate (Tranxene)
 Diazepam (Valium)
 Halazepam (Paxipam)
 Lorzepam (Ativan), Oxazepam (Serax), Prazepam

Indications:

Anxiety disorders: Acute anxiety, Generalized anxiety disorders (GAD), Social phobia (social anxiety disorder).

BDZ are effective for the short-term management (<6 weeks) of these anxiety disorders (selective serotonin-reuptake
inhibitors [SSRIs; see later] are now considered the first-line choices for the long-term management of anxiety disorders.

Insomnia: BDZ that have a rapid onset and sufficient duration are widely used (e.g., temazepam).
Anticonvulsants: Lorazepam (and diazepam), given by i.v. may be used for initial treatment of status epilepticus and
drug-induced seizures. The development of tolerance precludes their long-term use.

Short surgical procedures, Preanesthetic medication : Shorter acting benzodiazepines (e.g., midazolam) are preferred
before during surgery or endoscopy.

Adverse effects:

• Sedation, memory disturbance, dull attention (interfere with learning ability).

• Tolerance and physical dependence (treated by gradual withdrawal).
• Rebound insomnia after discontinuation.
• Hangover: a state of psychomotor depression occurs in the following day after the use of long acting drugs
(residual effect).
• Apnea after rapid i. v. injection (flumazenil is the antidote)

3. Drugs for treatment of gout, uricosuric agents.

NSAIDS

Uricodepressive (inhibits the synthesis of uric acid)/ UA synthesis inhibitor : Allopurinol, Thiopurinol

Uricosuric agents (increase the uric acid excretion, decrease urate reabsorption) : Probenecid,
Sulpinpyrazone, Colchinine, Benzobromarone

1) Decrease reabsorption of uric acid: Anturan, Probenecid, Aerhamidum

2) Increase soluble urates: Urodanum, Soluran
3) Increase excretion of uric acid: Urolesan, Fitolysin, Extractum Rubia tinctoria siccum

Mixed acting (alters uric acid synthesis, inhibits its reabsorption, promotes ex of uric acid) : Allomarone

4.Pharmacology of Tetracycline.

Tetracycline is a broad spectrum polyketide antibiotic produced by the Streptomyces genus of Actinobacteria.
It exerts a bacteriostatic effect on bacteria by binding reversible to the bacterial 30S ribosomal subunit and
blocking incoming aminoacyl tRNA from binding to the ribosome acceptor site. It also binds to some extent to
the bacterial 50S ribosomal subunit and may alter the cytoplasmic membrane causing intracellular components
to leak from bacterial cells.
Indication
Used to treat bacterial infections such as Rocky Mountain spotted fever, typhus fever, tick fevers, Q fever,
rickettsialpox and Brill-Zinsser disease. May be used to treat infections caused by Chlamydiae spp., B.
burgdorferi, upper resp infections caused by typical (S. pneumoniae, H. influenzae, and M. catarrhalis) &
atypical organisms (C. pneumoniae, M. pneumoniae, L. pneumophila). May also be used to treat acne.
Tetracycline may be an alternative drug for people who are allergic to penicillin

Pharmacodynamics
Tetracycline is a short-acting antibiotic that inhibits bacterial growth by inhibiting translation. It binds to the
30S ribosomal subunit and prevents the amino-acyl tRNA from binding to the A site of the ribosome. It also
binds to some extent to the 50S ribosomal subunit. This binding is reversible in nature. Additionally
tetracycline may alter the cytoplasmic membrane of bacteria causing leakage of intracellular contents, such as
nucleotides, from the cell.

Mechanism of action
Tetracycline passively diffuses through porin channels in the bacterial membrane and reversibly binds to the
30S ribosomal subunit, preventing binding of tRNA to the mRNA-ribosome complex, and thus interfering with
protein synthesis.

Absorption
Bioavailability is less than 40% when administered via intramuscular injection, 100% intravenously, and 60-
80% orally (fasting adults). Food and/or milk reduce GI absorption of oral preparations of tetracycline by 50%
or more.

Route of elimination
They are concentrated by the liver in the bile and excreted in the urine and feces at high concentrations in a
biologically active form.

5.WRITE PRESCRIPTIONS:

 Neostigmine methylsulfate in amp.,

Rp.: Sol. Neostigmini methyl sulfas 0.05% -1ml

D.t.d. N.10 in ampull.

S. Inject intramuscularly 1 injection 2 times per day

 Drotaverine in amp.,

Rp.: Sol. Drotaverini 2% - 2ml.

D.t. d. No.10 in amp.

S. Inject intramuscularly 2 times a day.

 Cinnarizine in tablets,

Rp.: Cinnarizum 0.025

D.t.d. N.50 in Tabulettis

S. Orally by 1 tablet 2 times per day

 Dimedrol in amp.,

Rp.: Sol. Dimedrolum 1%-1ml

D.t.d. N. 10 in amp.

S. Inject intramuscularly 1 injection 2 times per day

 Diazolin in dragee.

Rp.: Dragee Diazolinum 0.1 N.20

D.S. Take orally by 1 Dragee 3 times a day

TASK: How much substance is contained in 1 ml of a solution with a concentration of 1:

1000?

1:1000 therefore 1g of substance in 1000ml of solution.

1g=1000mg

So, 1000mg in 1000ml

Hence, there will be 1mg OR 0.001g of substance in 1ml of the solution.