OBAT ANALGETIK, ARIFAH SRI WAHYUNI

ANTIPIRETIK & arifah.wahyuni@ums.ac.id

081329008616

ANTI INFLAMASI
What is pain?

■ An unpleasant sensory (noxious) and emotional

experience associated with actual or potential tissue
damage
■ jaringan yang menerima rangsang --- terluka, ---
terlepas mediator kimia prostaglandin, leukotriene --
impuls diteruskan oleh sumsum tulang belakang ke
otak -- NYERI
Physiology of Pain:
Neurochemical Mediators

• A large number of
neurotransmitters and other
chemical mediators play a role
in pain processing and
modulation
• Mediators act in a complex and
interrelated process

RELIEVING PAIN
• narcotic analgesics : OPIOID
• non-narcotic analgesics : NON-OPIOID : Aspirin, Acetaminophen, NSAID, Selective COX2, SAID
 OPIOID
Daftar OPIOID ada di PMK 44 tahun 2019
 Opioids
■ Opium alkaloids derived from the opium
■ Morphine was isolated by Sertuner in 1813
■ Clasified of opioid :
– Strong opioids used for severe pain : Morphine, Oxycodone, Pethidine, Fentanyl
– Weak Opioids used for moderate pain : Codeine, Tramadol

Natural Fully Synthetic Opioids on the WHO

• Morphine • Pethidine (meperidine)
• Codeine • Tramadol essential drug list
Semi-Synthetic • Nalbuphine • Morphine
• Hydromorphone • Methadone • Codeine
• Oxycodone • Pentazocine
• Fentanyl
• Tramadol
• Diacetylmorphine
(heroin) • Alfentanil
• Naloxone • Sufentanil
(antagonist) • Remifentanil
 Mechanism of Action
■ Opioids act by binding to opioid receptors (complex proteins embedded within the cell
membrane of neurons)
■ Opioid receptors are found in the brain and in the dorsal horn of the spinal cord

There are 3 different opioid

receptors - µ, δ, κ
• m (mu): mediate analgesia
at the supraspinal level
• d (delta): analgesia in the
periphery
• k (kappa): analgesia at the
spinal level
Opioid
SIDE EFFECTS
■ Gastrointestinal : Nausea and
vomiting, Constipation
■ Sedation
■ Respiratory depression in overdose
■ Pruritus
■ Cough suppression (anti-tussive)
■ dizziness, nausea&vomiting
TOLERANCE
■ Used for an extended period
Tolerance is defined as reduction of the
pharmacological effect of an opioid:
■ When the same dose produces a lesser effect
■ Increasing doses of drug is required to produce
the same effect
■ The mechanisms of the development of tolerance
are complex
 Morphine
Routes of
Depressant effects Stimulate effects administration
■ ■ CTZ (nausea, vimiting)  Sc, i.m  analgesic
Analgesia
■ Indifference to surroundings ■ Edinger Wesphal nucleus (III action after 10-15’
■ Mood and subjective effects nerve –producing miosis)  oral  BA : 20-60 %
■ Depression of respiration ■ Vagal centre (bradycardia)  sublingually – quick
■ Cough centre absorption
■ ■ Certain cortical areas and
Temperature regulating centre  i.v. is indicated even
hippocampal
■ Vasomotor centre in emergency
 Epidural or intrathecal
injection produces
DOSE Precaution
Duration : 4-6 hours pain that accompanies chronic
Single dose Max 0,02 g, inflammatory pain
Daily dose Max 0,05 g children before the age of 2 years
Metabolisme
■ Konjugasi dengan glucuronic
acid di hepar dan extra-
hepatic (kidney).
■ Morphine -3 dan morphine -6
glucuronides diekskresikan
melalui ginjal
■ Hati-hati pada pasien dengan
gangguan hati dan ginjal
 morphine
Side effects CONTRAINDICATIONS
 Respiratory depression  acute respiratory depression
 Vomiting  renal failure (due to
 bradycardia accumulation of the
 spasm of sphincters of GI metabolites morphine-3-
glucuronide and morphine-6-
tract accompanied by glucuronide)
constipations
 raised intracranial pressure,
 Decreasing of BP including head injury (risk of
worsening respiratory
depression)
 Biliary colic
Codeine
 Oral tablet 15 mg; 30 mg, analgesic action is not strong, but anticough
effect is considerable
 combination with non opiod analgesics (eg. Paracetamol) is supra-
additive
 Well absorbed & no 1st pass metabolism in the liver
 Codeine adalah prodrug dari morphine; yang menghasilkan efek
analgesic, dosis 60 mg codeine equi-analgesic effect dengan 650 mg
aspirin
 Menyebabkan : sedation, nausea, vomiting and constipation
 TRAMADOL – Weak opioid
■ This is also known as an “atypical
opioid”
■ It has a dual mechanism of action:
– weak opioid receptor binding
properties
– Inhibits the reuptake of serotonin
and noradrenaline at the
descending inhibitory pathway
■ Tersedia
– Oral capsule (50 mg)
– Injection – 50 mg / ml – in 2 ml
ampoules
■ It is well absorbed when given
orally
■ Orally  Onset 30 minutes,
durasi 5-6 jam, iv  onset 5-10
min
■ Sedation is minimal
■ Can cause nausea, vomiting,
dizziness
■ Abuse potential is minimal
■ Maximum daily dose is 400 mg
Dual Mechanism in Tramadol
 Metabolisme TRAMADOL
■ Tramadol dimetabolisme di hati
dan diekskresikan melalui ginjal
60%, 30 % unchanged)
■ Metabolit Tramadol: O-
desmethyltramadol diekskresi di
ginjal
■ The daily dose should be
reduced in the presence of
chronic renal failure
 KETAMINE
■ It is a phencyclidine derivative ■ Intravenous
■ Intramuscular / Subcutaneous (onset – 10 - 15 min)
■ It has been used to provide anaesthesia for many
■ Oral (bioavailability 20%) /
years sublingual (30%) / rectal (30%)
– The side effect of hallucinations has ■ 5mg / kg – IM can be used for painful dressing change in children
limited its use as an anaesthetic agent ■ An anti-sialagogue should be added as it causes salivary
– Ketamine causes an increase in blood secretions that can cause coughing / laryngospasm
■ Low dose ketamine – 0.1 - 0.5 mg / kg / hr can provide excellent
pressure and heart rate, hence it is used
analgesia
as an induction agent when a patient is in
shock
■ It has multiple mechanisms of action
– The main mechanism of action is that of a
non-competitive antagonist at the NMDA
receptors
■ Metabolized by the liver
– Metabolites are about 1/5th as potent as
ketamine
 KETAMINE
Side effects
 Dizziness,
 Hallucinations
 Emergence delirium (larger
doses), benzodiazepines
can reduce these side
effects
 Salivary secretions
 Anti-sialagogues should be
used with ketamine
drug abuse
■ In recent years, ketamine
has been known to be
abused for its “euphoric”
effects
■ Long term use can lead
to cognitive impairment
and memory loss
Promedol (trimeperidine)
• produces similar effects to other opioids, such as analgesia and sedation,
along with side effects such as nausea, itching, vomiting and respiratory
depression which may be harmful or fatal.
• duration of analgesic action - 3-4 hours
• moderate spasmolytic influence on smooth musculature of internal organs
• stimulation of rhythmic contractions of uterus
• can be used for analgesia
• in case of pain syndrome connected with spasms of smooth musculature
Fentanyl
• synthetic opioid analgesic of short action
• analgesic activity is 300 times higher than of morphine
• analgesic effect after intravenous introduction – after 1-3 min, lasts for
15-30 min
• used with neuroleptic droperidol (complex drug – “talamonal”) for
neuroleptanalgesia
fentanyl transdermal system
• should be used for long-term
(chronic) pain requiring continuous
narcotic pain
• Is designed to release the drug into
the skin at a constant rate ranging
from 25 to 100 micrograms/h,
Pentazocin
 agonist-antagonist of opioid receptors
 comparatively with morphine, it is a bit less dangerous in the aspect of
addiction development
 indicated in case of pain of medium intensity in such conditions like other
opioid analgesics. In case of strong pain its administration is limited as in
case of increasing of dose of the drug excitation appears
 it can cause increasing of blood pressure and tachycardia that’s why it’s
not advised to use in case of acute myocardium infarction
 if it is administered for people with narcotic addiction manifestations of
abstinence develop
Buprenorphine
• Partly agonist of mu-opioid receptors
• Acts longer than morphine (approximately 6 hours)
• Analgesic activity is higher than of morphine, that’s why it’s used in doses of
0,3-0,6 mg
• In
case of breathing depression, which it causes, naloxon is less effective since
buprenorphine is slowly released from the connection with mu-receptors
• Indicated for pain decreasing in the same situations as other narcotic analgesics
• May be used for detoxication and supporting treatment of individuals who is
addicted to heroine
NON OPIOID
Mechanism of action of non-opioid analgesics

■ depression of cyclooxygenases activity

■ decreasing of prostaglandins synthesis in peripheral tissues and in
central nervous system
■ decreasing of sensitivity of nervous endings and depression of
transmission of nociceptive impulses on the level of CNS structures
■ pain-relieving action of non-opioid analgesics is partly connected
with their anti-inflammatory activity
Analgetic Vs Antiinflamasi
ANALGESICS
Divided into five main classes based on
mode of action :
– Opioids
– Non-steroidal anti-inflammatory
drugs
– Local anesthetics
– Alpha2-adrenoceptor agonists
– Miscellaneous drugs
ANTI-INFLAMMATORY
■ non-steroid anti-inflammatory drugs
(NSAIDs) (Antipyretic-Analgesic
and Anti-inflammatory Drugs)
■ Steroid anti-inflammatory drugs
glucocorticoids: eg. dexamethasone
■ 5-LOX inhibitors and leukotriene
receptor, Ex : Zafirlukast, zileuton
 Cell wall Releases
Membrane phospholipids
injury

Phospholipase A2

Arachidonic acid

NSAIDs / COX-
2 inhibitors Cyclooxygenase Lipoxygenases
COX-1 & COX-2 that is induced
with injury and inflammation,
cancer

Prostaglandins PMNs

PGF2α PGE2 PGI2

Lymphokines
algesic pyrexia vasodilation
The events of the inflammtory response and mechanisms of anti-flammatory
 Summary of COX-1 vs COX-2 Inhibition

Glucocorticosteroid

ASA, NSAIDs

Coxib
 Cyclooxygenase
(COX)
is found bound to the COX inhibitors
endoplasmatic reticulum. It Nonselective
exists in 3 isoforms: NSAIDs
NSAIDs COX-1/COX-2
inhibitors
• COX-1 (constitutive) acts in
physiological conditions.
• COX-2 (inducible) is induced in COX-2
COX-3
inhibitors
inflammatory cells by inhibitors
• Selective (coxibs)
• Antipyretic
analgesics
pathological stimulus. • Preferential

• COX-3 (in brain).

NON OPIOID Agents
•Salicylates (ASA)
•Acetaminophen (Tylenol)
•Nonsteroidal anti-inflammatory drugs
(NSAIDs)
•Selective COX2
•SAIDs

Copyright 2007 Thomson Delmar Learning, a division of Thomson Learning Inc.

All rights reserved. 10 - 29
ASPIRIN

Aspirin-Mechanism of Action:
Covalent Binding to COX

ASA covalently and irreversibly modifies both COX-1

and COX-2 by acetylating serine-530 in the active site
 Aspirin Metabolism Pathways
acetylsalicylic acid (ASA)

ASA: t1/2 ~20 min

irreversible acetylation of COX

salicylate t1/2 ~3-5 hrs

- Salicylate elimination is 1st order at low and moderate doses;

- When total body salicylate > 600mg (>3.5g/d), elimination is zero order
Side effects of Aspirin therapy in children with rheumatoid arthritis
aspirin has been found to raise serum concentration trans-
aminases, indicating liver damage. Most cases are
• Gastrointestinal symptoms asymptomatic but it is potentially dangerous.
• CNS toxicity
An association between salicylate therapy and
• Allergic reaction (urticaria), angioneurotic edema,
“Reye’s syndrome”, a rare form of hepatic
aspirin asthma, occasionally anaphylactic shock)
encephalopathy seen in children, having viral
• Salicylate reaction (CNS reaction)
infection(varicella, influenza), has been noted.
• Renal damage
• Hematologic effects Aspirin should not be given to children under 15
years unless specifically indicated, e.g. for juvenile
• Metabolic acidosis stimulates medullary arthritis (paracetamol is preferred).
respiratory center  respiratory alkalosis
• Overdose:
Postmyocardial infarction and poststroke patients.
hepatic damage
By inhibiting platelet aggregation in low doses (100
Reye’s syndrome (kids)
severe hepatic damage and
mg daily) Aspirin decreases the incidence of
encephalopathy reinfarction.
Aspirin : Keracunan dan penangannya
• Tanda keracunan pada orang dewasa : ganguan pendengaran,
vertigo

• Pada anak-anak, tanda keracunan : hiperventilasi dan asidosis,

dengan kelesuan yang menyertainya dan hiperventilasi

• Penanganan :
1. Koreksi gangguan asam basa
2. Penggantian cairan elektrolit
3. Pembasaan urin dengan bicarbonate untuk mereduksi
reabsorbsi salicylate
4. Diuresis, hemodialisis
5. Pembersihan lambung/dimuntahkan
Acetaminophen - Analgesia : E.g. Tooth ache / teething pain
in children, backpain, joint and muscle
pain, headache, dysmenorrhoea
- Antipyretic : Relief of fever in adults and
children
- no significant anti-inflammatory effects
- no gastric irritation
- no platelet function interference
- half life 2 –3 h
- weak inhibitor of COX-1, -2;
- not contraindicated for asthma
- not associated with Reye’s Syndrome
- The major concern regarding the use of
acetaminophen is the potential for high
doses to cause liver toxicity
 Paracetamol
Absorption • It is available as tablets (adults),
suspension, or syrup for children Side Effect
• On oral administration it is and suppositories, iv injection Paracetamol is well tolerated and
absorbed from the intestine has no side effects at therapeutic
(70%), stomach and colon • Tmax is 2 - 3 hours with doses
(30%) suppositories
•
CAUTION
(Tmax) is 15 - 30 minutes Since it is metabolized in the liver
Elimination
depends on the preparation it must be used with caution / or
Paracetamol is metabolized in omitted in the presence of liver
• Bioavailability ranges from 60- the liver and only 2 - 5% is impairment
90% excreted unchanged
In patients with renal
Dosage impairment, the dose of
Adults–Up to 1g oral/rectal, every 6 hours (4g should not be exceeded/day paracetamol should be reduced
Children – Oral / rectal 20 mg / kg – every 6 hours
Do not exceed 4g/day in adults
and 125 mg/ kg in children
 Adverse effects
Hepatotoxicity with an overdose of paracetamol
• This can occur when a patient does not get adequate relief with paracetamol and decides to
take more than the prescribed dose of a maximum of 4g/day (8 - 10 g / day)
• Intentional overdose (Paracetamol overdose / poisoning is the leading cause of acute liver
failure in the US, UK and Australia)
• Overdose causes acute liver failure, as the elimination pathways are saturated resulting in
elevated levels of toxic metabolites
• N-acetylcysteine (NAC) is the antidote for paracetamol poisoning and it is most effective when
administered within 8 - 10 hours after ingestion
• Renal toxicity – Overdose can cause severe kidney necrosis
• Allergic reactions are rare
• Long-term use of acetaminophen has been associated with:
• a 3-fold increase in kidney disease
• women taking more than 500 mg/day had a doubling in the incidence of hypertension.
Paracetamol
• It does not affect uric acid levels and lacks platelet-inhibiting properties.
• It is preferable to Aspirin in patients with hemophilia or a history of peptic ulcer and
bronchospasm. It is preferred to Aspirin in children with viral infections.
• Acute paracetamol poisoning occurs especially in small children who have low
hepatic glucuronide conjugating ability. If a large dose (> 150 mg/kg or > 10 g in
adult) is taken, serious toxicity can occur. The letal dose is 250 mg/kg. Daily dose >
7.5 g: hepatotoxicity and nephrotoxicity
• Penanganan keracunan Parasetamol:
• Dimuntahkan (emesis) atau pembersihan lambung
• Pemberian N-acetyl cystine akan menetralkan metabolitnya.
NSAID
 NSAIDs: Classification by half-life
Plasma Elimination Half Lives
Short Half Life (< 6 hours):
more rapid effect and clearance
• Aspirin (0.25-0.33 hrs),
• Diclofenac (1.1 ± 0.2 hrs)
• Ketoprofen (1.8 ± 0.4 hrs),
• Ibuprofen (2.1 ± 0.3 hrs)
• Indomethacin (4.6 ± 0.7 hrs)

Long Half Life (> 10 hours):

slower onset of effect and slower clearance
• Naproxen (14 ± 2 hrs)
• Sulindac (14 ± 8 hrs),
• Piroxicam (57 ± 22 hrs)
3. Pharmacodynamic Effects of NSAIDs
antipyretic : compared with chlorpromazine

NSAIDs Chlorpromazine

Effects Inhibit PGs synthesis Inhibit thermotaxic center in

and enhance hypothalamus. The body
thermolysis temperature change
according to the environment.
Clinical usage Lower the abnormal artificial hibernation,
high temperature to Hypothermic anesthesia,
normal. Used for
various fever.

Side effects GI reactions ， no addiction Extrapyramidal effects

 3. Pharmacodynamic Effects of NSAIDs

Analgesic : compared with Opioids

NSAIDs Opioids

Effects Inhibit PGs and TxA2 Stimulate opioid receptors

synthesis by
inhibiting COX

Clinical usage Headache, toothache ， Various pain including

neuralgia, arthronalgia, severe pain
courbature, menalgia

Side effects GI reactions ， no addiction Addiction

 3. Pharmacodynamic Effects of NSAIDs

Anti-inflammatory: compared with glucocorticoid

NSAIDs Glucocorticoid

Effects Inhibit PGs and TxA2 Various effects including

synthesis by inhibition of
inhibiting COX PLA2(Phospolipase A2)

Clinical usage Rheumatic, rheumatoid, Various inflammation

trauma

Side effects GI reactions Various side effects, such

as metabolism disturbance,
damage of defense etc.
3. Pharmacodynamic Effects of NSAIDs

NSAIDs and Platelets/Endothelial Cells

- Reduces platelet aggregation
- Most of these drugs will potentiate the action of oral anticoagulants such as
coumadin, by their effects on platelet aggregation
- An 80 mg dose will increase bleeding time for 2 folds

Note: Selective inhibition of COX-2 will inhibit the production of PGI 2 but not of
thromboxaneA2, which is produced by COX-1. SO ?
 NSAIDs: Classification by COX selection
Non-specific inhibition of COX-1 results in gastrointestinal and platelet side effects
In vitro assessment of COX-1 – COX-2 activity

Sleisenger & Fordtran's Gastrointestinal and Liver Disease,

8th ed., Copyright © 2006 Saunders, An Imprint of Elsevier
Drug interactions

Drugs Result

Diuretics Decrease diuresis

Beta-blockers Decrease antihypertensive effect

ACE inhibitors Decrease antihypertensive effect

Anticoagulants Increase of GI bleeding

Sulfonylurea Increase hypoglycemic risk

Cyclosporine Increase nephrotoxicity

GCS Increase of GI bleeding

Alcohol Increase of GI bleeding

 Effects of NSAIDs
1. Analgesic and antipyretic action
Aspirin is a weaker analgesic than morphine-type drugs
Aspirin 600 mg < Codeine 60 mg < 6 mg Morphine
No sedation, tolerance, and dependence are produced.

2. Antiinflammatory action is exerted at high daily doses of Aspirin (3 to 6 g).

Clinical symptoms of inflammation are suppressed, but prolongation of the
underlying disease in rheumatoid arthritis, rheumatic fever, and osteoarthritis is not
affect.

3. Inhibition of platelet aggregation in low doses (75–100 mg/24 h

Aspirin).
Lüllmann, Color Atlas of Pharmacology – 2 ndndEd. (2000)
Lüllmann, Color Atlas of Pharmacology – 2 Ed. (2000)
toxicities of NSAIDs
1. Gastric mucosal damage connected with PGE inhibition
2. Bleeding: inhibition of platelet function (TxA2 synthesis)
3. Limitation of renal blood flow Na+ and water retention
4. Asthma and anaphylactoid reactions connected with PGF2α
inhibition
SELEKTIVE COX-2
COX-2 Selective agents
• Penghambatan COX-2 akan
mengurangai respon inflamasi dan COX-2
nyeri tanpa menghambat aksi inhibitors
cytoprotective dari prostaglandins (1) Selective COX-2 inhibitors
• Contoh : Celecoxib [Celebrex], (Coxibs)
• Celecoxib
Rofecoxib [Vioxx], Valdecoxib • Etoricoxib
[Bextra] • Parecoxib
• Rofecoxib and valdecoxib sudah (2) Preferential COX-2 inhibitors
ditarik dari pasaran karena • Meloxicam
• Nimesulide
menyebabkan heart attack and • Nabumetone
stroke
 Etoricoxib Parecoxib

Coxibs are selective COX-2 inhibitors. They exert

antiinflammatory, analgesic, and antipyretic action
with low ulcerogenic potential. Coxibs can cause
infertility. They have prothrombotic cardiovascular
risk. The ulcerogenic potential of preferential
COX-2 inhibitors Meloxicam, Nabumetone, and
Nimesulide (Aulin®) is significant.
Celecoxib is as effective as other NSAIDs in the
treatment of rheumatoid arthritis and osteoarthritis,
and in trials it has caused fewer endoscopic ulcers
than most other NSAIDs. Probably because it is
a sulfonamide, celecoxib may cause rashes.
It does not affect platelet aggregation at usual
doses. It interacts occasionally with warfarin –
would be expected of a drug metabolized
via CYP 2C9.
 .

Etoricoxib
is a second-generation COX-2-selective inhibitor with the highest selectivity ratio of any
coxibs. It is extensively metabolized by hepatic CYP450 enzymes followed by renal excretion
and has an elimination t1/2 of 22 h.
Etoricoxib is approved in the UK for the treatment of the symptoms of osteoarthritis (60 mg
once daily) and rheumatoid arthritis (90 mg once daily), acute gouty arthritis (120 mg once
daily), and for the relief of acute musculoskeletal pain (60 mg once daily).
Ninety mg daily of etoricoxib has superior efficacy compared with 500 mg of naproxen twice
daily in the treatment of rheumatoid arthritis over 12 weeks.
Etoricoxib has similar efficacy to traditional NSAIDs for osteoarthritis, acute gouty arthritis,
and primary dysmenorrhea and has a GI safety profile similar to other coxibs
 Comparative action between COX-1/COX-2 COX-2
COX inhibitors inhibitors inhibitors
1. Analgesic action (+) (+) (+)

2. Antipyretic action (+) (+)

3. Antiinflammatory action (+) (+) (+)

4. Antiplatelet aggregatory (+) (-)

5. Gastric mucosal damage (+) (+) (+) (+)

6. Renal salt / water retention (+) (+)

7. Delay/prolongation of labor (+) (+) (+)

8. Infertility (-) (+) (+)
9. Ductus arteriosus closure (+) ?

10. Aspirin-like asthma (+) ?

11. Cardiotoxicity (-) (+) (+)
NONOPIOID ANALGESICS
(1) Anilides
Paracetamol – tabl. 500 mg
(Acetaminophen – USAN)
Propacetamol (prodrug) COX-3
(2) Pyrazolones inhibitors
Metamizole (antipyretic
(Analgin® – tabl. 500 mg) analgesics)

(3) COX-1/COX-2 inhibitors

Aspirin®, Diclofenac, NSAIDs in
Ibuprofen, Naproxen etc. low doses
(4) COX-2 inhibitors
 SAIDs – steroidal
anti-inflammatory drugs
 Steroidal anti-inflammatory drugs
• 1. Short-acting glucocorticoids • 3. Long-acting
(natural) Betamethasone
Dexamethasone
Hydrocortisone
Cortisone Paramethasone
• 4.Topically acting glucocorticoids
• 2. Intermediate-acting
glucocorticoids Beclomethasone
dipropionate
Prednisone
Budesonide
Prednisolone
Fluocinolone acetonide
Methylprednisolone
Fluocortolone
Triamcinolone
 Preparations of SAIDs

Drugs Anti-inflam. Salt retaining Topical

Cortisol 1 1.0 1

Cortisone 0.8 0.8 0

Prednisone 4 0.8 0

Prednisolone 5 0.3 4

Methylpredni- solone 5 0 5

Intermediate acting

Triamcinolone 5 0 5

Paramethasone 10 0 -

Fluoprednisolone 15 0 7
 Preparations of SAIDs

Drugs Anti-inflam. Salt retaining Topical

Long acting

Betamethasone 25-40 0 10

Dexamethasone 30 0 10

Mineralocorticoids

Fludrocortisone 10 250 10

DOCA 0 20 0
TERIMA KASIH
BAROKALLAHU FII KUM