Pharmacology for Anesthetist

By
Tamiru.T(Asistant Professor)

3/14/2024 by Tamiru,T 1
 Outline

Principles of pharmacology
Pharmacokinetics
pharmacodynamics of IVAA

3/14/2024 by Tamiru,T 2
 WHAT IS DRUGS
• A substance used as a medicine for the
treatment of disease.
• A substance taken because of its biologically
active properties . Caffeine, nicotine, alcohol,
cannabis, heroin and cocaine.

3/14/2024 by Tamiru,T 3
 Definitions
• Pharmacokinetics
The process by which a drug is absorbed, distributed,
metabolized and eliminated by the body
• Pharmacodynamics
The interactions of a drug and the receptors
responsible for its action in the body

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Pharmacokinetics and pharmacodynamics

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 Why we Study PK and PD?
• Individualize patient drug therapy

• Monitor medications with a narrow therapeutic

index
• Decrease the risk of adverse effects

• Maximizing pharmacologic response of medications

• Evaluate PK/PD as a diagnostic tool for underlying

disease states
3/14/2024 by Tamiru,T 6
 The Life Cycle of a Drug (pharmacokinetics)

• Absorption
• Distribution
• Degradation
• Excretion

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 Absorption

• Is the processes by which a drug moves from the site of

administration to the bloodstream.

• Routes of drug administration:

 Oral, sublingual

 Rectal

 Inhalational

 Transdermal

 Transmucosal

 Subcutaneous

 intramuscular
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 intravenous
 Absorption

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 Drug absorption is influenced by…
 By the physical characteristics of the drug
o Solubility
o pKa, Ph
o Diluents
o Binders
o Formulation)

 Dose
 Site of absorption gut, lung, skin, muscle)

3/14/2024 by Tamiru,T 10
 Slow Absorption

• Orally (swallowed)

• through Mucus Membranes

– Oral Mucosa (e.g. sublingual)
– Nasal Mucosa (e.g. insufflated)

• Topical/Transdermal
(through skin)
• Rectally (suppository)

3/14/2024 by Tamiru,T 11
 Faster Absorption

• Parenterally (injection)
o Intravenous (IV)
o Intramuscular (IM)
o Subcutaneous (SC)
o Intraperitoneal (IP)

• Inhaled (through lungs)

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 Oral drug administration

 convenient

 inexpensive

 relatively tolerant of dosing errors.

 but it requires cooperation of the patient

 Exposes the drug to first-pass hepatic metabolism

 permits gastric pH, enzymes, motility, food, and other drugs to

potentially reduce the predictability of systemic drug delivery

3/14/2024 by Tamiru,T 13
 Cont..
• Non-ionized (uncharged) drugs are more readily absorbed than
ionized (charged) forms.
• Acidic environment (stomach) favors the absorption of acidic drugs
(A – + H+ → AH).
• A more alkaline environment (intestine) favors basic drugs (BH+ →
H+ + B).
• Most drugs are largely absorbed from the intestine rather than the
stomach

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 General Principle
.The faster the absorption, the quicker the
Onset and the shorter the duration

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 Drug solubility

• Water-soluble
 Ionized (have electrical charge)
 Crosses through pores in capillaries, but not cell membranes

• Lipid(fat)-soluble
 Non-ionized (no electrical charge)
 Crosses pores, cell membranes, blood-brain-barrier

3/14/2024 by Tamiru,T 16
 Dissociation constant or pKa

• Indicates the pH where 50% of the drug is ionized

(water soluble) and 50% non-ionized (lipid soluble)

• This affects a drug's solubility, permeability, binding,

and other characteristics.

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 Bioavailability
 Is the fraction of administered dose reaching the systemic
circulation.
 Nitroglycerin is well absorbed by the gastrointestinal tract
but has low bioavailability when administered orally.
 The reason is nitroglycerin undergoes extensive first-pass
hepatic metabolism

3/14/2024 by Tamiru,T 18
 Cont.…
• All venous drainage from the stomach and small intestine flows to
the liver.
• Bioavailability of highly metabolized drugs may be significantly
reduced by first-pass hepatic metabolism.
• Sublingual or buccal drug absorption bypasses the liver and first-
pass metabolism due to venous drainage in to superior vena cava
• Rectal administration partly bypasses the portal system
• It is an alternative route in small children or patients who are
unable to tolerate oral ingestion.

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 Parenteral routes of drug administration

• It includes Subcutaneous , Intramuscular Intravenous injection.

• Subcutaneous and intramuscular absorption depend on drug

diffusion from the site of injection to the bloodstream.
• The rate at which a drug enters the bloodstream depends on both
blood flow to the injected tissue and the injectate formulation.
• Drugs dissolved in solution are absorbed faster than those
present in suspensions.
• Intravenous injections completely bypass the process of
absorption
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 Distribution

• A drug is distributed by the blood stream throughout the body.

• Highly perfused organs ( vessel-rich group) receive a
disproportionate fraction of the cardiac output .
• These tissues receive a disproportionate amount of drug in the
first minutes following drug administration.
• These tissues approach equilibration with the plasma
concentration more quickly than less well perfused tissues due to
the differences in blood flow

3/14/2024 by Tamiru,T 21
3/14/2024 by Tamiru,T 22
 Distribution
• Membrane permeability
– cross membranes to site of action
• Plasma protein binding
– bound drugs do not cross membranes
– malnutrition = albumin =  free drug
• Lipophilicity of drug
– lipophilic drugs accumulate in adipose tissue

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 Cont.…

• less well perfused tissues such as fat and skin may have
enormous capacity to absorb lipophilic drugs, resulting in a large
reservoir of drug following long infusions.
• Drug molecules obey the law of mass action.
• When the plasma concentration exceeds the concentration in
tissue, the drug moves from the plasma into tissue.
• When the plasma concentration is less than the concentration in
tissue, the drug moves from the tissue back to plasm

3/14/2024 by Tamiru,T 24
 Cont.…
• Distribution is a major determinant of endorgan drug
concentration.
• The rate of rise in drug concentration in an organ is determined by
that organ’s perfusion and the relative drug solubility in the organ
compared with blood.
• The equilibrium concentration in an organ relative to blood
depends only on the relative solubility of the drug in the organ
relative to blood, unless the organ is capable of metabolizing the
drug.

3/14/2024 by Tamiru,T 25
 Cont..

• Molecules in blood are either free or bound to plasma proteins

and lipids.

• The free concentration equilibrates between organs and tissues.

• However, the equilibration between bound and unbound

molecules is instantaneous.

• As unbound molecules of drug diffuse into tissue, they are

instantly replaced by previously bound molecules.

• Plasma protein binding does not affect the rate of transfer

directly, but it does affect relative solubility of the drug in blood
and tissue.
3/14/2024 by Tamiru,T 26
 Cont.…
• If the drug is highly bound in tissues, and unbound in
plasma, then the relative solubility favors drug transfer
into tissue.
• A drug that is highly bound in tissue, but not in blood,
will have a very large free drug concentration gradient
driving drug into the tissue.

3/14/2024 by Tamiru,T 27
 Cont.…
• If the drug is highly bound in plasma and has few binding
sites in the tissue, then transfer of a small amount of drug
may be enough to bring the free drug concentration into
equilibrium between blood and tissue.

• Thus, high levels of binding in blood relative to tissues

increase the rate of onset of drug effect, because fewer
molecules need to transfer into the tissue to produce an
effective free drug concentration.
3/14/2024 by Tamiru,T 28
 Cont..

• Albumin binds acidic drugs (eg, barbiturates

• α1-acid glycoprotein (AAG) binds basic drugs (local anesthetics).

• If the concentrations of these proteins are diminished , then the

relative solubility of the drugs in blood is decreased, increasing

tissue uptake.

3/14/2024 by Tamiru,T 29
 Cont.…
• Kidney disease, liver disease, chronic congestive heart
failure, and malignancies decrease albumin production.
• Trauma , infection, myocardial infarction, and chronic
pain increase AAG levels.
• Pregnancy is associated with reduced AAG
concentrations.

3/14/2024 by Tamiru,T 30
 Cont..

• Lipophilic molecules can readily transfer between the blood and

organs.
• Charged molecules are able to pass in small quantities into most
organs.
• However, the blood–brain barrier is a special case.
• Permeation of the central nervous system by ionized drugs is
limited by pericapillary glial cells and endothelial cell tight
junctions.
• Most drugs that readily cross the blood–brain barrier (eg, lipophilic
drugs like hypnotics and opioids) are avidly taken up in body fat.
3/14/2024 by Tamiru,T 31
 Cont..

• The time course of distribution of drugs into peripheral tissues is

complex
• Following intravenous bolus administration, rapid distribution of
drug from the plasma into peripheral tissues accounts for the
profound decrease in plasma concentration observed in the first
few minutes.
• For each tissue, there is a point in time at which the apparent
concentration in the tissue is the same as the concentration in
the plasma.

3/14/2024 by Tamiru,T 32
 Cont.….
• The redistribution phase (for each tissue) follows this moment of

equilibration.

• During redistribution, drug returns from peripheral tissues back

into the plasma.

• This return of drug back to the plasma slows the rate of decline

in plasma drug concentration.

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 Cont.…

• Distribution generally contributes to rapid emergence by

removing drug from the plasma for many minutes

following administration of a bolus infusion.

• Following prolonged infusions, redistribution generally

delays emergence as drug returns from tissue reservoirs

to the plasma for many hours.

3/14/2024 by Tamiru,T 34
 Cont.…
• All intravenous anesthetic drugs are better modeled with at least
two compartments: a central compartment and a peripheral
compartment.
• The behavior of many of these drugs is best described using three
compartments: a central compartment, a rapidly equilibrating
peripheral compartment, and a slowly equilibrating peripheral
compartment.

3/14/2024 by Tamiru,T 35
 Cont…
• The central compartment may be thought of as including the
blood and any ultra-rapidly equilibrating tissues such as the
lungs.
• The peripheral compartment is composed of the other body
tissues.
• For drugs with two peripheral compartments, the rapidly
equilibrating compartment comprises the organs and muscles,
while the slowly equilibrating compartment roughly represents
distribution of the drug into fat and skin.
3/14/2024 by Tamiru,T 36
 Cont.…
• Vessel-rich organ 10 % of body mass but take 75% of CO
o Brain and heart

o Liver and kidney

o Endocrine gland

• Muscle Muscle, skin are 50 % body mass but get only 19 % CO

• Fat Fat 20 % of body mas and take 6 % CO

• Vessel-poor tissue 20 % body mass but take <1 % CO

o Bone

o Ligament

o cartilage
3/14/2024 by Tamiru,T 37
 Biotransformation
• Is the chemical process by which the drug molecule is altered
in the body.

• The liver is the primary organ of metabolism for drugs.

• The exception is esters, which undergo hydrolysis in the plasma

or tissues.

• The end products of biotransformation are often (but not

necessarily) inactive and water soluble.

• Water solubility allows excretion by the kidneys

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 Drug Metabolism

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 Metabolism
• Drugs and toxins are seen as foreign to patients bodies
• Drugs can undergo metabolism in the lungs, blood, and
liver
• Body works to convert drugs to less active forms and
increase water solubility to enhance elimination

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 Metabolism
• Liver - primary route of drug metabolism
• Liver may be used to convert pro-drugs
(inactive) to an active state
• Types of reactions
– Phase I (Cytochrome P450 system)
– Phase II

3/14/2024 by Tamiru,T 41
 Phase I reactions
• Cytochrome P450 system
• Located within the endoplasmic reticulum of
hepatocytes
• Through electron transport chain, a drug bound to the
CYP450 system undergoes oxidation or reduction
• Enzyme induction
• Drug interactions

3/14/2024 by Tamiru,T 42
Phase I reactions types
• Hydrolysis
• Oxidation
• Reduction
• Demethylation
• Methylation
• Alcohol dehydrogenase metabolism

3/14/2024 by Tamiru,T 43
 Phase II reactions

• Polar group is conjugated to the drug

• Results in increased polarity of the drug
• Types of reactions
– Glycine conjugation
– Glucuronide conjugation
– Sulfate conjugation

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 Excretion

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 Excretion

• Some drugs and many drug metabolites are excreted

by the kidneys.
• Renal clearance is the rate of elimination of a drug
from the body by kidney excretion.
• This concept is analogous to hepatic clearance
• renal clearance can be expressed as the renal blood
flow times the renal extraction ratio

3/14/2024 by Tamiru,T 46
 Cont..
• Small unbound drugs freely pass from plasma into the glomerular

filtrate.

• The nonionized (uncharged) fraction of drug is reabsorbed in the

renal tubules, whereas the ionized (charged) portion is excreted in

urine.

• The fraction of drug ionized depends on the pH; thus renal

elimination of drugs that exist in ionized and nonionized forms

depends in part on urinary pH.

• 3/14/2024
The kidney actively secretes some
by Tamiru,T drugs into the renal tubules.47
 Cont..

• Many drugs and drug metabolites pass from the liver into the intestine

via the biliary system.

• Some drugs excreted into the bile are then reabsorbed in the intestine

• a process called enterohepatic recirculation.

• Occasionally metabolites excreted in bile are subsequently converted

back to the parent drug.

• For example, lorazepam is converted by the liver to lorazepam

glucuronide.

• In the intestine, β-glucuronidase breaks the ester linkage, converting

3/14/2024 by Tamiru,T 48
lorazepam glucuronide back to lorazepam.
 Excretion
• Liver
– Enzymes(cytochrome P-450)
transform drugs into more water-
soluble metabolites
– Repeated drug exposure increases
efficiency  tolerance

• Kidneys
– Traps water-soluble (ionized)
compounds for elimination via urine
(primarily), feces, air, sweat

3/14/2024 by Tamiru,T 49
 Excretion
• Pulmonary = expired in the air
• Bile = excreted in feces
– enterohepatic circulation
• Renal
– glomerular filtration
– tubular reabsorption
– tubular secretion

3/14/2024 by Tamiru,T 50
 Excretion: Other routes
• Lungs
alcohol breath
• Breast milk
acidic ---> ion traps alkaloids
alcohol: same concentration as blood
antibiotics
• Also bile, skin, saliva

3/14/2024 by Tamiru,T 51
 cont.
• Half-life:
Plasma half-life: Time it takes for plasma concentration of a
drug to drop to 50% of initial level.
Whole body half-life: Time it takes to eliminate half of the
body content of a drug.
– Factors affecting half-life
o age
o renal excretion
o liver metabolism
o protein binding
3/14/2024 by Tamiru,T 52
 Cont.…
• If every molecule of drug that enters the liver is metabolized,
then hepatic clearance will equal liver blood flow

• This is true for very few drugs - propofol.

• For most drugs, only a fraction of the drug that enters the
liver is removed.

• The fraction removed is called the extraction ratio.

• The hepatic clearance can therefore be expressed as the liver

blood flow times the extraction ratio.

3/14/2024 by Tamiru,T 53
 Cont.…
• If the extraction ratio is 50%, then hepatic clearance is 50% of liver
blood flow.
• The clearance of drugs efficiently removed by the liver (ie, having a
high hepatic extraction ratio) is proportional to hepatic blood flow.
• For example, because the liver removes almost all of the propofol
that goes through it, if the hepatic blood flow doubles, then the
clearance of propofol doubles. .
• Even severe loss of liver tissue, as occurs in cirrhosis, has little
effect on propofol clearance.
• Drugs such as propofol have flow-dependent clearance.
3/14/2024 by Tamiru,T 54
 Cont.…
• Many drugs have low hepatic extraction ratios and are
slowly cleared by the liver.
• For these drugs, the rate-limiting step is not the flow of
blood to the liver, but rather the metabolic capacity of
the liver itself.
• Changes in liver blood flow have little effect on the
clearance of such drugs

3/14/2024 by Tamiru,T 55
 Cont..

• If liver enzymes are induced, then clearance will increase

because the liver has more capacity to metabolize the drug.

• Conversely, if the liver is damaged, then less capacity is

available for metabolism and clearance is reduced.

• Drugs with low hepatic extraction ratios thus have capacity-

dependent clearance.
3/14/2024 by Tamiru,T 56
 Linear Pharmacokinetics
• Linear = rate of elimination
120
is proportional to amount 100

of drug present

concentration
80

60
• Dosage increases result in 40

proportional increase in 20
0
plasma drug levels
dose

3/14/2024 by Tamiru,T 57
Loading Doses
• Loading doses allow
rapid achievement of 40
therapeutic serum 35
levels 30
• Same loading dose 25 w/ bolus
used regardless of 20
w/o
metabolism/eliminatio 15 bolus
n dysfunction 10
5
0

3/14/2024 by Tamiru,T 58
 Nonlinear Pharmacokinetics
• Nonlinear = rate of elimination
is constant regardless of 50
45
amount of drug present 40
35

concentration
• Dosage increases saturate 30
25
binding sites and result in non- 20
15
proportional 10
5
increase/decrease in drug 0

levels dose

3/14/2024 by Tamiru,T 59
 Special Patient Populations
• Renal Disease: same hepatic metabolism, same/increased
volume of distribution and prolonged elimination  
dosing interval
• Hepatic Disease: same renal elimination, same/increased
volume of distribution, slower rate of enzyme metabolism
  dosage,  dosing interval
• Cystic Fibrosis Patients: increased metabolism/
elimination, and larger volume of distribution   dosage,
 dosage interval
3/14/2024 by Tamiru,T 60
 Compartment Models
• Reading assignment??

3/14/2024 by Tamiru,T 61
 PHARMACODYNAMICS

• Is the study of how drugs affect the body, involves the concepts of

– Potency ,Efficacy and therapeutic window.

• Pharmacokinetic models can range from entirely empirical dose

versus response relationships to mechanistic models of ligand–

receptor binding.

• The fundamental pharmacodynamics concepts are captured in the

relationship between exposure to a drug and physiological

response to the drug called the dose–response or concentration–

response relationship
3/14/2024 by Tamiru,T 62
 Exposure–Response Relationships

• As the body is exposed to an increasing amount

of a drug, the response to the drug similarly
increases, typically up to a maximal value.

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 Exposure–Response Relationships

3/14/2024 by Tamiru,T 64
 What Are The Common Drug Targets?
• Most common targets are body proteins:
• Receptors: Can alter transmitter signaling
• Example: Using risperidone to block dopamine
receptors in schizophrenic patients
• Enzymes: Can alter transmitter synthesis
• Example: Using L-DOPA, a substrate for DOPA
decarboxylase, to increase dopamine synthesis in the
brains of patients with Parkinson’s
3/14/2024 by Tamiru,T
Disease 65
3/14/2024 by Tamiru,T 66
 Drug Targets (con’t)
• Transporters: Can alter transmitter inactivation
• Example: Using fluoxetine (Prozac) to inhibit
serotonin reuptake in depressed patients
• Ion Channels: Can alter neuronal excitability
• Example: Using phenytoin to block sodium
channels in epileptic patients

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 Modes of Action
• Agonism • Antagonism
– A compound that does the – A compound inhibits an
job of a natural substance. enzyme from doing its job.
– Does not effect the rate of – Slows down an
an enzyme catalyzed enzymatically catalyzed
reaction. reaction.
• Up/down regulation
– Tolerance/sensitivity at the
cellular level may be due to
a change in # of receptors
(without the appropriate
subunit) due to changes in
stimulation

3/14/2024 by Tamiru,T 68
 Drug Effectiveness
• Dose-response (DR) curve

– Represents the relation between

drug dose and magnitude of drug
effect
• Drugs can have more than one effect

• Drugs vary in effectiveness

– Different sites of action

– Different affinities for receptors

• The effectiveness of a drug is considered

relative to its safety (therapeutic index)
3/14/2024 by Tamiru,T 69
ED50 = effective dose in 50% of population

100

% subjects 50
ED50

0
0 X
DRUG DOSE

3/14/2024 by Tamiru,T 70
 Therapeutic Index

• Effective dose (ED50) = dose at which 50% population shows response

• Lethal dose (LD50) =dose at which 50% population dies
• TI = LD50/ED50, an indication of safety of a drug (higher is better)

ED50 LD50

3/14/2024 by Tamiru,T 71
 Potency
• Relative strength of response for a given dose
– Effective concentration (EC50) is the concentration of an agonist needed to
elicit half of the maximum biological response of the agonist
– The potency of an agonist is inversely related to its EC50 value
• D-R curve shifts left with greater potency

3/14/2024 by Tamiru,T 72
 Efficacy

• Maximum possible effect relative

to other agents
• Indicated by peak of D-R curve
• Full agonist = 100% efficacy
• Partial agonist = 50% efficacy
• Antagonist = 0% efficacy

3/14/2024 by Tamiru,T 73
 Tolerance
(desensitization)

• Decreased response to same

dose with repeated (constant)
exposure
• or more drug needed to achieve
same effect
• Right-ward shift of D-R curve
• Sometimes occurs in an acute
dose (e.g. alcohol)
• Can develop across drugs (cross-
tolerance)
• Caused by compensatory
mechanisms that oppose the
effects of the drug
3/14/2024 by Tamiru,T 74
 Sensitization

• Increased response to same dose

with repeated (binge-like)
exposure
• or less drug needed to achieve
same effect
• Left-ward shift in D-R curve
• Sometimes occurs in an acute do

It is possible to develop tolerance to some side effects AND sensitization

3/14/2024 to other side effects of the same drug
by Tamiru,T 75
 Drug-drug Interactions
• Pharmacokinetic and pharmacodynamics
 With pharmacokinetic drug interactions, one drug affects the
absorption, distribution, metabolism, or excretion of another.
 With pharmacodynamics drug interactions, two drugs have
interactive effects in the brain.
 Either type of drug interaction can result in adverse effects in
some individuals.
 In terms of efficacy, there can be several types of interactions
between medications: cumulative, additive, synergistic, and
antagonistic.
3/14/2024 by Tamiru,T 76
Cumulative Effects

Hi

Drug B
Response

Drug A
Lo
Time
The condition in which repeated administration of a drug may produce effects
that are more pronounced than those produced by the first dose.
3/14/2024 by Tamiru,T 77
Additive Effects

Hi

A+ B
Response
A B

Lo
Time
The effect of two chemicals is equal to the sum of the effect of the two
chemicals taken separately, eg., aspirin and motrin.
3/14/2024 by Tamiru,T 78
Synergistic Effects

A+ B
Hi

Response
A B

Lo
Time

The effect of two chemicals taken together is greater than the sum of their
separate effect at the same doses, e.g., alcohol and other drugs
3/14/2024 by Tamiru,T 79
Antagonistic Effects

Hi

A+ B

Response
A B

Lo
Time

The effect of two chemicals taken together is less than the sum of their separate
effect at the same doses
3/14/2024 by Tamiru,T 80
 cont
• Affinity
– propensity of a drug to bind with a receptor

• Selectivity
– specific affinity for certain receptors

3/14/2024 by Tamiru,T 81
 Effect of Disease on Drug Disposition
• Absorption
– PO/NG administered drugs may have altered absorption due
to:
• Alterations in pH
• Edema of GI mucosa
• Delayed or enhanced gastric emptying
• Alterations in blood flow
• Presence of an ileus

3/14/2024 by Tamiru,T 82
 Effect of Disease on Drug Disposition
• Drug distribution may be affected:
– Altered organ perfusion due to hemodynamic changes
• May effect delivery to site of action, site of metabolism and
site of elimination
• Inflammation and changes in capillary permeability may
enhance delivery of drug to a site
– Hypoxemia affecting organ function
• Altered hepatic function and drug metabolism

3/14/2024 by Tamiru,T 83
 Effect of Disease on Drug Disposition
– Alterations in protein synthesis
• If serum albumin and other protein levels are low, there
is altered Vd of free fraction of drugs that typically are
highly protein bound therefore a higher free
concentration of drug

– Substrate deficiencies
• Exhaustion of stores
• Metabolic stress

3/14/2024 by Tamiru,T 84
 Effect of Disease on PD
• Up regulation of receptors
• Down regulation of receptors
– Decreased number of drug receptors
• Altered endogenous production of a substance may
affect the receptors

3/14/2024 by Tamiru,T 85
 REMEMBER

No drug produces a single effect!!!

3/14/2024 by Tamiru,T 86
 Any question ?

3/14/2024 by Tamiru,T 87