Paracetamol

Analgesics
Paracetamol
Pharmacodynamics
Paracetamol has analgesic and antipyretic properties but it has no useful anti-inflammatory properties.
Paracetamol's effects are thought to be related to inhibition of prostaglandin synthesis.
To date, the mechanism of action of paracetamol is not completely understood. The main mechanism proposed is the inhibition
of cyclooxygenase (COX), and recent findings suggest that it is highly selective for COX-2. Because of its selectivity for
COX-2 it does not significantly inhibit the production of the pro-clotting thromboxanes. While it has analgesic and antipyretic
properties comparable to those of aspirin or other NSAIDs, its peripheral anti-inflammatory activity is usually limited by
several factors, one of which is the high level of peroxides present in inflammatory lesions. However, in some circumstances,
even peripheral anti-inflammatory activity comparable to NSAIDs can be observed.
Pharmacokinetic properties
Absorption: paracetamol is readily absorbed from the gastrointestinal tract.
Distrubution: peak plasma concentrations occur about 10 to 60 minutes after oral doses. Paracetamol is distributed into most
body tissues. It crosses the placenta and is present in breast milk. Plasma-protein binding is negligible at usual therapeutic
concentrations but increases with increasing concentrations.
Metabolism: It is metabolised in the liver. A minor hydroxylated metabolite which is usually produced in very small amounts
by mixed-function oxidases in the liver and which is usually detoxified by conjugation with liver glutathione may accumulate
following paracetamol overdosage and cause tissue damage.
Elimination: It is excreted in the urine, mainly as the glucuronide and sulphate conjugates. The elimination half-life varies
from about 1 to 4 hours.
Dose
Adults including elderly and children over 12 years: One to two tablets every 4-6 hours as required, to a maximum of 8 tablets
daily in divided doses.
Children 6-12 years: Half to one tablet every 4-6 hours as necessary, to a maximum of 4 tablets daily in divided doses.
Children under 6 years: Not recommended for children under 6 years of age. Alternative presentations of paracetamol are
recommended for paediatric usage in order to obtain suitable doses of less than 250mg.
Side effects
Side effects from paracetamol are rare. However, side effects can include:
-a rash or swelling this could be a sign of an allergic reaction
-hypotension (low blood pressure) when given in hospital by infusion (a continuous drip of medicine into a vein in your arm)
-liver and kidney damage, when taken at higher-than-recommended doses (overdose)
- In extreme cases the liver damage that can result from a paracetamol overdose can be fatal.
Ibuprofen
Pharmacodynamics
For symptomatic treatment of rheumatoid arthritis, juvenile rheumatoid arthritis and osteoarthritis. May be used to treat mild to
moderate pain and for the management of dysmenorrhea. May be used to reduce fever. Has been used with some success for
treating ankylosing spondylitis, gout and psoriatic arthritis. May reduce pain, fever and inflammation of pericarditis. May be
used IV with opiates to relieve moderate to severe pain. Ibuprofen lysine may be used IV to treat patent ductus arteriosus
(PDA) in premature neonates.
Ibuprofen is a nonsteroidal anti-inflammatory agent (NSAIA) or nonsteroidal anti-inflammatory drug (NSAID), with analgesic
and antipyretic properties. Ibuprofen has pharmacologic actions similar to those of other prototypical NSAIAs, which are
thought to act through inhibition of prostaglandin synthesis.
Mechanism of action
The exact mechanism of action of ibuprofen is unknown. Ibuprofen is a non-selective inhibitor of cyclooxygenase, an enzyme
invovled in prostaglandin synthesis via the arachidonic acid pathway. Its pharmacological effects are believed to be due to
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inhibition cylooxygenase-2 (COX-2) which decreases the synthesis of prostaglandins involved in mediating inflammation,
pain, fever and swelling. Antipyretic effects may be due to action on the hypothalamus, resulting in an increased peripheral
blood flow, vasodilation, and subsequent heat dissipation. Inhibition of COX-1 is thought to cause some of the side effects of
ibuprofen including GI ulceration. Ibuprofen is administered as a racemic mixture. The R-enantiomer undergoes extensive
interconversion to the S-enantiomer in vivo. The S-enantiomer is believed to be the more pharmacologically active enantiomer.
Absorption
~ 80% absorbed from GI tract
Time to reach peak plasma concentration = 47 minutes (suspension), 62 minutes (chewable tablets), 120 minutes (conventional
tablets)
Protein binding
90-99% to whole human plasma and site II of purified albumin, binding appears to be saturable and becomes non-linear at
concentrations exceeding 20 mcg/ml.
Metabolism
R-enanatiomer undergoes extensive enantiomeric conversion (53-65%) to the more active S-enantiomer in vivo. Metablized by
oxidation to 2 inactive metabolites: (+)-2[4-(2-hydroxy-2-methylpropyl)phenyl]propionic acid and (+)-2-[4-(2-
carboxypropyl)phenyl]propionic acid. Very small amounts of 1-hydroxyibuprofen and 3-hydroxyibuprofen have been
recovered from urine. Cytochrome P450 2C9 is the major catalyst in the formation of oxidative metabolites. Oxidative
metabolites may be conjugated to glucuronide prior to excretion.
Half life
2-4 hours
Dose
ADULT and CHILD over 12 years, initially 300400 mg 34 times daily; increased if necessary to max. 2.4 g daily;
maintenance dose of 0.61.2 g daily may be adequate
Pain and fever in children, CHILD 13 months, see BNF for Children; CHILD 36 months (body-weight over 5 kg), 50 mg 3
times daily (max. 30 mg/kg daily in 34 divided doses); CHILD 6 months1 year, 50 mg 34 times daily (max. 30 mg/kg daily
in 34 divided doses); CHILD 14 years, 100 mg 3 times daily (max. 30 mg/kg daily in 34 divided doses); CHILD 47 years,
150 mg 3 times daily (max. 30 mg/kg daily in 34 divided doses); CHILD 710 years, 200 mg 3 times daily (up to 30 mg/kg
daily (max. 2.4 g) in 34 divided doses); CHILD 1012 years, 300 mg 3 times daily (up to 30 mg/kg daily (max. 2.4 g) in 34
divided doses)
Rheumatic disease in children (including juvenile idiopathic arthritis), CHILD 3 months18 years (body-weight over 5 kg),
3040 mg/kg (max. 2.4 g) daily in 34 divided doses; in systemic juvenile idiopathic arthritis up to 60 mg/kg (max. 2.4 g)
daily [unlicensed] in 46 divided doses
Side Effects
Feeling sick (nausea), Ulcers of the stomach, worsening of existing bowel conditions (ulcerative colitis, Crohn's disease),
Blood problems (associated with unexplained bruising or bleeding, fever, sore throat, mouth ulcers, extreme paleness of the
skin or weakness), skin problems (including hives, itching, rash, irritation), small increased risk of heart attack or stroke,
headache, dizziness, tingling of the hands or feet, ringing in the ears, diarrhoea, unusual sensitivity of the skin to the sun,
tiredness, mood swings and confusion.
Diclofenac
Pharmacodynamics
For the acute and chronic treatment of signs and symptoms of osteoarthritis and rheumatoid arthritis.
Diclofenac is an acetic acid nonsteroidal antiinflammatory drug (NSAID) with analgesic and antipyretic properties. Diclofenac
is used to treat pain, dysmenorrhea, ocular inflammation, osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, and
actinic keratosis
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Mechanism of action
The antiinflammatory effects of diclofenac are believed to be due to inhibition of both leukocyte migration and the enzyme
cylooxygenase (COX-1 and COX-2), leading to the peripheral inhibition of prostaglandin synthesis. As prostaglandins
sensitize pain receptors, inhibition of their synthesis is responsible for the analgesic effects of diclofenac. Antipyretic effects
may be due to action on the hypothalamus, resulting in peripheral dilation, increased cutaneous blood flow, and subsequent
heat dissipation.
Absorption
Completely absorbed from the gastrointestinal tract.
Volume of distribution
1.3 L/kg
Protein binding
More than 99%
Route of elimination
Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate
conjugates of the metabolites. Little or no free unchanged diclofenac is excreted in the urine. Approximately 65% of the dose
is excreted in the urine and approximately 35% in the bile as conjugates of unchanged diclofenac plus metabolites.
Half life
2 hours
Clearance
oral cl=622 mL/min [healthy]
renal cl <1 mL/min [healthy]
Toxicity
Symptoms of overdose include loss of consciousness, increased intracranial pressure, and aspiration pneumonitis.
LD50=390mg/kg (orally in mice)
Food Interactions
Avoid alcohol.
Take with food to reduce irritation.
Dose
Usual Adult Dose for Osteoarthritis
Diclofenac free acid capsules: 35 mg orally 3 times a day

Diclofenac potassium immediate-release tablets: 50 mg orally 2 or 3 times a day
Diclofenac sodium enteric-coated tablets: 50 mg orally 2 or 3 times a day or 75 mg orally 2 times a day
Maximum dose: 150 mg daily
Diclofenac sodium extended-release tablets: 100 mg orally once a day
Use: For the relief of signs and symptoms of osteoarthritis.
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Usual Adult Dose for Ankylosing Spondylitis
Diclofenac sodium enteric-coated and delayed-release tablets: 25 mg orally 4 times a day. An additional 25 mg dose may be
administered at bedtime, if necessary
Maximum dose: 125 mg per day
Use: For acute or long-term use in the relief of signs and symptoms of ankylosing spondylitis.
Usual Adult Dose for Dysmenorrhea
Diclofenac potassium immediate-release tablets: 50 mg orally 3 times a day
Comments: An initial dose of 100 mg orally followed by 50 mg oral doses may provide better relief for some patients; initiate
treatment upon appearance of the first symptoms and continue for a few days.
Use: For the relief of signs and symptoms of primary dysmenorrhea.
Usual Adult Dose for Rheumatoid Arthritis
Diclofenac potassium immediate-release tablets: 50 mg orally 3 or 4 times a day

Diclofenac sodium enteric-coated and delayed-release tablets: 50 mg orally 3 to 4 times a day or 75 mg orally twice a day
Diclofenac sodium extended-release tablets: 100 mg orally once a day

Maximum dose: 100 mg orally 2 times a day; this would be for the rare patient in whom the benefits outweigh the clinical
risks.
For the relief of signs and symptoms of rheumatoid arthritis
Usual Adult Dose for Migraine
Diclofenac potassium for oral solution packets: 50 mg (1 packet) orally once
Comments: This drug is not indicated for the prophylactic therapy of migraine or for use in cluster headaches; the safety and
efficacy of a second dose has not been established.
Use: For acute treatment of migraine with or without aura.
Usual Adult Dose for Pain
Oral:
Diclofenac potassium liquid-filled capsules: 25 mg orally 4 times a day
Diclofenac free acid capsules: 18 mg or 35 mg orally 3 times a day
Diclofenac potassium immediate-release tablets: 50 mg orally 3 times a day; an initial dose of 100 mg orally followed by 50
mg oral doses may provide better relief in some patients.
Comment: Neither the diclofenac potassium liquid filled capsules nor the diclofenac free acid capsules are interchangeable
with each other or with other diclofenac products containing the sodium or potassium salt.
Parenteral:
37.5 mg IV bolus over 15 seconds every 6 hours as needed for pain
Maximum Dose: 150 mg per day
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Side effects
More frequently reported side effects include: fluid retention, diarrhea, constipation, dyspepsia, nausea, abdominal pain, and
headache
Tramadol
Pharmacodynamics
Indicated in the treatment of moderate to severe pain. Consider for those prone to constipation or respiratory depression.
Tramadol is used to treat postoperative, dental, cancer, and acute musculosketetal pain and as an adjuvant to NSAID therapy in
patients with osteoarthritis.
Tramadol, a centrally-acting analgesic, exists as a racemic mixture of the trans isomer, with important differences in binding,
activity, and metabolism associated with the two enantiomers. Although its mode of action is not completely understood, from
animal tests, at least two complementary mechanisms appear applicable: binding of parent and M1 metabolite to -opioid
receptors and weak inhibition of reuptake of norepinephrine and serotonin. Opioid activity is due to both low affinity binding
of the parent compound and higher affinity binding of the O-demethylated metabolite M1 to -opioid receptors. In animal
models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in -opioid binding.
Opiate antagonist naloxone only partially antagonized tramadol-induced analgesia.
Mechanism of action
Tramadol and its O-desmethyl metabolite (M1) are selective, weak OP3-receptor agonists. Opiate receptors are coupled with
G-protein receptors and function as both positive and negative regulators of synaptic transmission via G-proteins that activate
effector proteins. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane,
opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive
neurotransmitters such as substance P, GABA, dopamine, acetylcholine and noradrenaline is inhibited. The analgesic
properties of Tramadol can be attributed to norepinephrine and serotonin reuptake blockade in the CNS, which inhibits pain
transmission in the spinal cord. The (+) enantiomer has higher affinity for the OP3 receptor and preferentially inhibits
serotonin uptake and enhances serotonin release. The (-) enantiomer preferentially inhibits norepinephrine reuptake by
stimulating alpha(2)-adrenergic receptors.
Absorption
Racemic tramadol is rapidly and almost completely absorbed after oral administration. The mean absolute bioavailability of a
100 mg oral dose is approximately 75%. The mean peak plasma concentration of racemic tramadol and M1 occurs at two and
three hours, respectively, after administration in healthy adults.
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Racemic tramadol is rapidly and almost completely absorbed after oral administration. The mean absolute bioavailability of a
100 mg oral dose is approximately 75%. The mean peak plasma concentration of racemic tramadol and M1 occurs at two and
three hours, respectively, after administration in healthy adults.
Protein binding
20% bound to plasma proteins.
Metabolism
Hepatic. The major metabolic pathways appear to be N- and O- demethylation and glucuronidation or sulfation in the liver.
One metabolite (O-desmethyltramadol, denoted M1) is pharmacologically active in animal models. CYP3A4 and CYP2B6
facilitates the biotransformation of tramadol to N-desmethyl-tramadol. CYP2D6 facilitates the biotransformation of tramadol
to O-desmethyl-tramadol.
Tramadol is eliminated primarily through metabolism by the liver and the metabolites are excreted primarily by the kidneys.
Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as
metabolites.
Half life
Tramadol and its metabolites are excreted primarily in the urine with observed plasma half-lives of 6.3 and 7.4 hours for
tramadol and M1, respectively.
Clearance
5.9 mL/min/Kg [Healthy Adults, 100 mg qid, MD p.o]
8.5 mL/min/Kg [Healthy Adults, 100 mg SD p.o]
6.89 mL/min/Kg [Geriatric, (<75 yr), 50 mg SD p.o.]
4.23 mL/min/Kg [Hepatic Impaired, 50 mg SD p.o.]
4.23 mL/min/Kg [Renal Impaired, Clcr10-3mL/min, 100 mg SD i.v.]
3.73 mL/min/Kg [Renal Impaired, CLcr<5 mL/min, 100 mg SD i.v.]
6.4 mL/min/Kg [Male following a 100 mg IV dose]
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5.7 mL/min/Kg [Female following a 100 mg IV dose]
Toxicity
Dose
ADULT and CHILD over 12 years, by mouth, acute pain, usual initial dose 100 mg then 50100 mg every 46 hours; chronic
pain, initially 50 mg then adjust according to response; total of more than 400 mg daily not usually required
ADULT and CHILD over 12 years, by intramuscular injection or by intravenous injection (over 23 minutes) or by
intravenous infusion, 50100 mg every 46 hours
Postoperative pain, 100 mg initially then 50 mg every 1020 minutes if necessary during first hour to total max. 250 mg
(including initial dose) in first hour, then 50100 mg every 46 hours; max. 600 mg daily
Side effects
Feeling sick (nausea), being sick (vomiting), sweating, flushing, dry mouth, feeling drowsy or tired, feeling dizzy (especially
after standing up suddenly from a sitting position), headache, constipation, shortness of breath, weakness, lack of energy.
Morphine
Pharmacodynamics
For the relief and treatment of severe pain.
Morphine is a narcotic pain management agent indicated for the relief of pain in patients who require opioid analgesics for
more than a few days. Morphine interacts predominantly with the opioid mu-receptor. These mu-binding sites are discretely
distributed in the human brain, with high densities in the posterior amygdala, hypothalamus, thalamus, nucleus caudatus,
putamen, and certain cortical areas. They are also found on the terminal axons of primary afferents within laminae I and II
(substantia gelatinosa) of the spinal cord and in the spinal nucleus of the trigeminal nerve. In clinical settings, morphine exerts
its principal pharmacological effect on the central nervous system and gastrointestinal tract. Its primary actions of therapeutic
value are analgesia and sedation. Morphine appears to increase the patient's tolerance for pain and to decrease discomfort,
although the presence of the pain itself may still be recognized. In addition to analgesia, alterations in mood, euphoria and
dysphoria, and drowsiness commonly occur. Opioids also produce respiratory depression by direct action on brain stem
respiratory centers.
Mechanism of action
The precise mechanism of the analgesic action of morphine is unknown. However, specific CNS opiate receptors have been
identified and likely play a role in the expression of analgesic effects. Morphine first acts on the mu-opioid receptors. The
mechanism of respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to
increases in carbon dioxide tension and to electrical stimulation. It has been shown that morphine binds to and inhibits GABA
inhibitory interneurons. These interneurons normally inhibit the descending pain inhibition pathway. So, without the inhibitory
signals, pain modulation can proceed downstream.
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Absorption
Bioavailability is approximately 30%.
1 to 6 L/kg
Protein binding
30-40%
Metabolism
Primarily hepatic (90%), converted to dihydromorphinone and normorphine. Also converted to morphine-3-glucuronide
(M3G) and morphine-6-glucuronide. Virtually all morphine is converted to glucuronide metabolites; only a small fraction (less
than 5%) of absorbed morphine is demethylated.
A small amount of glucuronide conjugates are excreted in bile, with minor enterohepatic recycling. Seven to 10% of
administered morphine sulfate is excreted in the feces.
Half life
2-4 hours
Clearance
20 30 mL/min/kg [Adult]
1852 +/- 116 mL/min [Chinese]
1495 +/- 80 mL/min [Caucasian]
Toxicity
LD50 = 461 mg/kg (rat, oral), 600 mg/kg (mouse, oral). Human lethal dose by ingestion is 120-250 mg of morphine sulfate.
Symptoms of overdose include cold, clammy skin, flaccid muscles, fluid in the lungs, lowered blood pressure, "pinpoint" or
dilated pupils, sleepiness leading to stupor and coma, slowed breathing, and slow pulse rate.
Dose
The following dosing recommendations can only be considered suggested approaches to what is actually a series of clinical
decisions over time in the management of the pain of each individual patient.
Immediate release tablets:

Opioid naive: Initial dose: 15 to 30 mg orally every 4 hours as needed
Oral solution:
Opioid naive: Initial dose: 10 to 20 mg orally every 4 hours as needed
-Oral solution: Opioid naive patients should be initiated on 10 mg per 5 mL or 20 mg per 5 mL strengths. Opioid-tolerant
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patients that have already been titrated to a stable analgesic regimen using lower strengths of morphine may be initiated on the
100 mg per 5 mL (20 mg/mL).
Extended-release oral:
Different extended-release products are not bioequivalent. Conversion from one extended-release product to the same total
daily dose of another extended-release product may lead to either excessive sedation at peak or inadequate analgesia at trough.
Individual product information should be consulted before prescribing and the dosage should be adjusted to the individual
patient.
Opioid naive:
Initial dose: 30 mg orally every 24 hours
Opioid tolerant:
Dose should be taken 1 to 2 times daily depending upon the product prescribed.
Suppository:
10 to 20 mg rectally every 4 hours needed
Subcutaneous/IM:
Initial dose: 10 mg every 4 hours as needed
Dose range: 5 to 20 mg every 4 hours as needed
IV:-For relief of pain and as preanesthetic:

Initial dose: 4 to 10 mg every 4 hours administered slowly over 4 to 5 minutes
Dose range: 5 to 15 mg
Daily dose range: 12 to 120 mg
Alternate dose: 2 to 10 mg/70 kg of body weight
-Acute myocardial infarction:
Initial dose: 4 to 8 mg
Maintenance dose: 2 to 8 mg every 4 to 15 minutes as needed
-Open heart surgery: 0.5 to 3 mg/kg IV as the sole anesthetic or with an anesthetic agent
-Severe chronic pain associated with terminal cancer:
Continuous IV Infusion: Prior to initiation of the infusion (in concentrations between 0.2 to 1 mg/mL), a loading dose of 15
mg or higher of morphine sulfate may be administered by IV push to alleviate pain.
-IV patient controlled analgesia or subcutaneous patient controlled analgesia:
1 to 2 mg injected 30 minutes after a standard IV dose of 5 to 20 mg. The lockout period is 6 to 15 minutes.
Epidural:
Initial dose: 5 mg in the lumbar region may provide satisfactory pain relief for up to 24 hours. If adequate pain relief is not
achieved within one hour, careful administration of incremental doses of 1 to 2 mg at intervals sufficient to assess effectiveness
may be given.
Maximum dose: 10 mg per 24 hr
Intrathecal:
-Dosage is usually one-tenth that of epidural dosage
-Initial dose: 0.2 to 1 mg may provide satisfactory pain relief for up to 24 hours. Repeated intrathecal injections are not
recommended.
Side effects
Abdominal or stomach pain, blurred vision, bulging soft spot on the head of an infant, burning, crawling, itching, numbness,
prickling, "pins and needles", or tingling feelings, change in the ability to see colors, especially blue or yellow, chest pain or
discomfort, confusion, cough, decreased urination, dizziness, faintness, or lightheadedness when getting up suddenly from a
lying or sitting position, fainting, fast, pounding, or irregular heartbeat or pulse, headache, hives, itching, or skin rash,
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increased sweating, loss of appetite, nausea or vomiting, nervousness, pounding in the ears, puffiness or swelling of the eyelids
or around the eyes, face, lips, or tongue, severe constipation, severe vomiting, shakiness in the legs, arms, hands, or feet,
shortness of breath, slow heartbeat, sweating or chills, wheezing
Cardiac Drugs
Aspirin
Pharmacodynamics
For use in the temporary relief of various forms of pain, inflammation associated with various conditions (including
rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, osteoarthritis, and ankylosing spondylitis),
and is also used to reduce the risk of death and/or nonfatal myocardial infarction in patients with a previous infarction or
unstable angina pectoris.
Acetylsalicylic acid is an analgesic, antipyretic, antirheumatic, and anti-inflammatory agent. Acetylsalicylic acid's mode of
action as an antiinflammatory and antirheumatic agent may be due to inhibition of synthesis and release of prostaglandins.
Acetylsalicylic acid appears to produce analgesia by virtue of both a peripheral and CNS effect. Peripherally, acetylsalicylic
acid acts by inhibiting the synthesis and release of prostaglandins. Acting centrally, it would appear to produce analgesia at a
hypothalamic site in the brain, although the mode of action is not known. Acetylsalicylic acid also acts on the hypothalamus to
produce antipyresis; heat dissipation is increased as a result of vasodilation and increased peripheral blood flow.
Acetylsalicylic acid's antipyretic activity may also be related to inhibition of synthesis and release of prostaglandins.
Mechanism of action
The analgesic, antipyretic, and anti-inflammatory effects of acetylsalicylic acid are due to actions by both the acetyl and the
salicylate portions of the intact molecule as well as by the active salicylate metabolite. Acetylsalicylic acid directly and
irreversibly inhibits the activity of both types of cyclooxygenase (COX-1 and COX-2) to decrease the formation of precursors
of prostaglandins and thromboxanes from arachidonic acid. This makes acetylsalicylic acid different from other NSAIDS
(such as diclofenac and ibuprofen) which are reversible inhibitors. Salicylate may competitively inhibit prostaglandin
formation. Acetylsalicylic acid's antirheumatic (nonsteroidal anti-inflammatory) actions are a result of its analgesic and anti-
inflammatory mechanisms; the therapeutic effects are not due to pituitary-adrenal stimulation. The platelet aggregation-
inhibiting effect of acetylsalicylic acid specifically involves the compound's ability to act as an acetyl donor to
cyclooxygenase; the nonacetylated salicylates have no clinically significant effect on platelet aggregation. Irreversible
acetylation renders cyclooxygenase inactive, thereby preventing the formation of the aggregating agent thromboxane A2 in
platelets. Since platelets lack the ability to synthesize new proteins, the effects persist for the life of the exposed platelets (7-10
days). Acetylsalicylic acid may also inhibit production of the platelet aggregation inhibitor, prostacyclin (prostaglandin I2), by
blood vessel endothelial cells; however, inhibition prostacyclin production is not permanent as endothelial cells can produce
more cyclooxygenase to replace the non-functional enzyme
Absorption
Absorption is generally rapid and complete following oral administration but may vary according to specific salicylate used,
dosage form, and other factors such as tablet dissolution rate and gastric or intraluminal pH
N/A
Protein binding
High (99.5%) to albumin. Decreases as plasma salicylate concentration increases, with reduced plasma albumin concentration
or renal dysfunction, and during pregnancy.
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Metabolism
Acetylsalicylic acid is rapidly hydrolyzed primarily in the liver to salicylic acid, which is conjugated with glycine (forming
salicyluric acid) and glucuronic acid and excreted largely in the urine.
N/A
Half life
The plasma half-life is approximately 15 minutes; that for salicylate lengthens as the dose increases: doses of 300 to 650 mg
have a half-life of 3.1 to 3.2 hours; with doses of 1 gram, the half-life is increased to 5 hours and with 2 grams it is increased to
about 9 hours.
Clearance
N/A
Toxicity
Oral, mouse: LD50 = 250 mg/kg; Oral, rabbit: LD50 = 1010 mg/kg; Oral, rat: LD50 = 200 mg/kg. Effects of overdose include:
tinnitus, abdominal pain, hypokalemia, hypoglycemia, pyrexia, hyperventilation, dysrhythmia, hypotension, hallucination,
renal failure, confusion, seizure, coma, and death.
Dose
Usual Adult Dose for Ankylosing Spondylitis
For treatment of inflammatory diseases such as ankylosing spondylitis, osteoarthritis, rheumatoid arthritis, and SLE-associated
arthritis and pleurisy:
3 grams per day in divided doses (spondyloarthropathies may require up to 4 grams per day in divided doses).
Serum salicylate levels may be useful in guiding therapeutic decisions regarding dosage titration. Serum salicylate levels of
150 to 300 mcg/mL are associated with anti-inflammatory response. However, the incidence of toxicity increases with
salicylate levels greater than 200 mcg/mL.
Usual Adult Dose for Osteoarthritis
Usual Adult Dose for Rheumatoid Arthritis
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Usual Adult Dose for Systemic Lupus Erythematosus
Usual Adult Dose for Fever
325 to 650 mg orally or rectally every 4 hours as needed, not to exceed 4 g/day.
325 to 650 mg orally or rectally every 4 hours as needed, not to exceed 4 g/day.
Usual Adult Dose for Rheumatic Fever
80 mg/kg/day orally in 4 equally divided doses, up to 6.5 g/day.
Dosage may be adjusted according to patient response, tolerance, and serum salicylate levels (therapeutic range is 250 to 400
mcg/mL for rheumatic fever). Generally after 1 to 2 weeks, the dosage is decreased to approximately 60 to 70 mg/kg/day and
given for an additional 1 to 6 weeks or longer if necessary, then gradually withdrawn over 1 to 2 weeks. An appropriate course
of antibiotic therapy should be initiated at the time of diagnosis of rheumatic fever.
Usual Adult Dose for Myocardial Infarction
160 to 162.5 mg orally once a day beginning as soon as an acute myocardial infarction is suspected and continuing for 30
days. If a solid dose formulation is used, the first dose should be chewed, crushed, or sucked. Long-term aspirin therapy for
secondary prevention is recommended after 30 days.
Usual Adult Dose for Ischemic Stroke
50 to 325 mg orally once a day. Therapy should be continued indefinitely.
Usual Adult Dose for Angina Pectoris
75 mg to 325 mg orally once a day beginning as soon as unstable angina is diagnosed and continuing indefinitely.
Usual Adult Dose for Angina Pectoris Prophylaxis
75 mg to 325 mg orally once a day, continued indefinitely.
Usual Adult Dose for Thromboembolic Stroke Prophylaxis
Usual Adult Dose for Myocardial Infarction - Prophylaxis
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Usual Adult Dose for Ischemic Stroke - Prophylaxis
Usual Adult Dose for Revascularization Procedures - Prophylaxis
For coronary artery bypass graft (CABG):

325 mg orally once a day beginning 6 hours after the procedure and continuing for 1 year or indefinitely as needed.
For percutaneous transluminal coronary angiography (PTCA):

325 mg orally once 2 hours prior to procedure, then 160 to 325 mg orally once a day indefinitely.
For carotid endarterectomy:

80 mg orally once a day up to 650 mg orally twice a day beginning prior to surgery and continuing indefinitely.
Side effects
Commonly: Dyspepsia (indigestion), feeling sick (nausea), vomiting.
Less commonly: Irritation of the gut may lead to ulcers and bleeding into stools, difficulty breathing or an asthma attack (in
those with a history of these and allergic reactions).
Rarely: toxic effect on the liver, leading to jaundice (yellowing of the eyes and skin).
Clopidogrel
Pharmacodynamics
For the reduction of atherosclerotic events (myocardial infarction, stroke, and vascular death) in patients with
atherosclerosis documented by recent stroke, recent myocardial infarction, or established peripheral arterial
disease.
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Since clopidogrel is a prodrug, it must be metabolized by CYP450 enzymes to produce the active
metabolite that inhibits platelet aggregation. This active metabolite selectively inhibits adenosine
diphosphate (ADP) binding to its platelet P2Y12 receptor and subsequently the ADP-mediated
activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation.
Mechanism of action
The active metabolite of clopidogrel prevents binding of adenosine diphosphate (ADP) to its platelet
receptor, impairing the ADP-mediated activation of the glycoprotein GPIIb/IIIa complex. It is proposed
that the inhibition involves a defect in the mobilization from the storage sites of the platelet granules
to the outer membrane. he drug specifically and irreversibly inhibits the P2Y12 subtype of ADP
receptor, which is important in aggregation of platelets and cross-linking by the protein fibrin. No
direct interference occurs with the GPIIb/IIIa receptor. As the glycoprotein GPIIb/IIIa complex is the
major receptor for fibrinogen, its impaired activation prevents fibrinogen binding to platelets and
inhibits platelet aggregation. By blocking the amplification of platelet activation by released ADP,
platelet aggregation induced by agonists other than ADP is also inhibited by the active metabolite of
clopidogrel.
Absorption
Absorption is at least 50% based on urinary excretion of clopidogrel-related metabolites.
Bioavailability has not been found to be affected by food
N/A
Protein binding
98%
Metabolism
Hepatic, extensive and rapid, by hydrolysis to the main circulating metabolite, a carboxylic acid
derivative, which accounts for approximately 85% of the circulating drug-related compounds. A
glucuronic acid derivative of the carboxylic acid derivative has also been found in plasma and urine.
Neither the parent compound nor the carboxylic acid derivative has a platelet inhibiting effect.
Following an oral dose of 14C-labeled clopidogrel in humans, approximately 50% of total radioactivity
was excreted in urine and approximately 46% in feces over the 5 days post-dosing.
Half life
Carboxylic acid derivative: 8 hours (after single and multiple doses). Covalent binding to platelets has
accounted for 2% of radiolabeled clopidogrel with a half-life of 11 days.
Clearance
N/A
14
Toxicity
A single dose of clopidogrel at 1500 or 2000 mg/kg was lethal to mice and rats, with 3000 mg/kg lethal
to baboons. Symptoms included vomiting, breathing difficulty, hemorrhage, and prostration.
Dose
Usual Adult Dose for Acute Coronary Syndrome

Unstable Angina (UA)/Non-ST-Elevation Myocardial Infarction (NSTEMI):
-Loading dose: 300 mg orally once
-Maintenance dose: 75 mg orally once a day
-Duration of therapy: Optimal duration unknown.
ST-Elevation Myocardial Infarction (STEMI):

-Loading dose: 300 mg orally once (OPTIONAL)
-Maintenance dose: 75 mg orally once a day, with or without thrombolytics
-Duration of therapy: Optimal duration unknown.
Comments:
-Administer this drug in combination with aspirin 75 mg to 325 mg orally once a day.
-The benefit of this drug for patients who undergo primary percutaneous coronary intervention is
unknown.
Uses: Prevention of atherothrombotic events in patients with non-ST-segment elevation acute

coronary syndrome (UA, NSTEMI, those who are to be managed medically, those who are to be
managed with coronary revascularization) and STEMI.
Usual Adult Dose for Ischemic Stroke

75 mg orally once a day
Uses: Prevention of atherothrombotic events in patients with a history of recent myocardial

infarction, recent stroke, or established peripheral arterial disease.


Usual Adult Dose for Peripheral Arterial Disease

15
Side effects
Bleeding such as bruising
Haematoma (unusual bleeding or bruising under the skin)
Nose bleed
Blood in the urine
Bleeding in the stomach or gut
Diarrhoea
Abdominal pain
Constipation
Feeling sick
Vomiting
Indigestion or heartburn
Inflammation of the mouth (stomatitis)
Vertigo
Headache
Decrease in blood pressure
Confusion
Hallucinations;
Skin disorders such as rashes and itching, swelling in the mouth, blisters of the skin, generalised allergic reactions
Joint pain
Muscular pain
Fever
Taste disorders
Breathing difficulties, sometimes associated with cough.
Glyceryl trinitrate (GTN)

Pharmacodynamics
For the prevention of angina
16
Nitroglycerin, an organic nitrate, is available in many forms as a vasodilator. Nitroglycerin is used in
the treatement of angina pectoris and perioperative hypertension, to produce controlled hypotension
during surgical procedures, to treat hypertensive emergencies, and to treat congestive heart failure
associated with myocardial infarction.
Mechanism of action
Similar to other nitrites and organic nitrates, nitroglycerin is converted to nitric oxide (NO), an active
intermediate compound which activates the enzyme guanylate cyclase. This stimulates the synthesis
of cyclic guanosine 3',5'-monophosphate (cGMP) which then activates a series of protein kinase-
dependent phosphorylations in the smooth muscle cells, eventually resulting in the
dephosphorylation of the myosin light chain of the smooth muscle fiber. The subsequent release of
calcium ions results in the relaxation of the smooth muscle cells and vasodilation.
Absorption
N/A
3 L/kg
Protein binding
N/A
Metabolism
Hepatic, cytochrome P450 (P450) is a key enzyme of organic nitrate biotransformation
N/A
Half life
3 minutes
Clearance
1 L/kg/min
Toxicity
Increased intracranial pressure, with any or all of persistent throbbing headache, confusion, and
moderate fever; Vertigo; Palpitations; Visual disturbances; Nausea and vomiting (possibly with colic
and even bloody diarrhea); Syncope (especially in the upright posture); Air hunger and dyspnea, later
followed by reduced ventilatory effort; Diaphoresis, with the skin either flushed or cold and clammy;
Heart block and bradycardia; Paralysis; Coma; Seizures; Death.
Dose

INTRAVENOUS SOLUTION:
5 mcg/min continuous IV infusion via non-absorptive tubing; increase by 5 mcg/min every 3 to 5
minutes as needed up to 20 mcg/min, then by 10 or 20 mcg/min if needed
17
Comments:
-Starting doses of 25 mcg/min or higher have been used with polyvinyl chloride (PVC) tubing.
-Lower concentrations increase potential dosing precision and volume to be delivered; consider
patient fluid requirements and expected infusion duration when selecting an appropriate dilution.
Use: Treatment of angina pectoris in patients who have not responded to sublingual
nitroglycerin and beta-blockers.
LINGUAL SPRAY:
1 to 2 sprays (0.4 to 0.8 mg) on or under tongue every 5 minutes as needed, up to 3 sprays in
15 minutes; if pain persists after maximum dose, prompt medical attention is recommended
Comments:
-Administer while sitting due to rapid onset.
-Advise patient not to inhale or swallow this medication.
Use: Acute relief of an anginal attack.
SUBLINGUAL TABLET:
0.3 to 0.6 mg sublingually or in the buccal pouch every 5 minutes as needed, up to 3 doses in
15 minutes; if pain persists after maximum dose, prompt medical attention is recommended
Comments:
-Administer while sitting down due to rapid onset.
-Advise patient not to chew or swallow this medication.
Use: Acute relief of an anginal attack.

LINGUAL SPRAY:
1 to 2 sprays (0.4 to 0.8 mg) on or under tongue 5 to 10 minutes prior to activity that might
precipitate an acute attack
Comments:
-Advise patient not to inhale or swallow this medication.
18
SUBLINGUAL TABLET:
0.3 to 0.6 mg sublingually or in the buccal pouch 5 to 10 minutes prior to engaging in activities
that might precipitate an acute attack
Comments:
-Advise patient not to chew or swallow this medication.
TOPICAL OINTMENT:
1/2 inch (7.5 mg) topically upon rising and 1/2 inch (7.5 mg) 6 hours later; titrate as needed and
tolerated
Comments:
-Clinical trial doses have ranged from 1/2 to 2 inches (7.5 to 30 mg) applied to 36 square inches
of truncal skin.
-Ointment should be applied to a dry and hairless area of the trunk.
TRANSDERMAL PATCH:
0.2 to 0.4 mg/hr patch applied topically once a day for 12 to 14 hours per day; titrate as needed
and tolerated up to 0.8 mg/hr
Comments:
-Patch should be applied to a dry and hairless area of the upper arm or body; rotate application
sites to avoid skin irritation.
-Doses between 0.4 and 0.8 mg/hr have shown continued effectiveness for 10 to 12 hours daily
for at least 1 month of intermittent administration.
EXTENDED RELEASE CAPSULE:

2.5 to 6 mg orally 3 to 4 times a day; titrate as needed and tolerated
Comments:
-Subjects were titrated up to 26 mg four times a day in one clinical trial.
19
Comments:
Use: Control of congestive heart failure in the setting of acute myocardial infarction.
Usual Adult Dose for Hypertension

Comments:
Uses:
-Treatment of perioperative hypertension.
-Induction of intraoperative hypotension.
Usual Adult Dose for Anal Fissure and Fistula

RECTAL OINTMENT:
1 inch of ointment (375 mg of ointment equivalent to 1.5 mg of nitroglycerin) intra-anally every
12 hours for up to 3 weeks
Comments:
-A finger covering such as plastic wrap, a disposable surgical glove, or a finger cot should be
placed on the finger to apply ointment.
-Insert finger no further than first finger joint and apply around side of anal canal; if unable to
insert finger due to pain, apply directly to outside of anus.
Use: Treatment of moderate to severe pain associated with chronic anal fissure.
20
Side effects
Headaches
Dizziness
Feeling light-headed
Low blood pressure
Nausea
Diarrhoea
Vomiting
Anal discomfort, itching, soreness (rectal ointment only)
Rectal bleeding (rectal ointment only)
Temporary loss of consciousness
Rapid heart beat
Application site reactions including itching, swelling, rash, burning (transdermal patch)
Chest pain
Flushing
Slowing of the heart rate
Stomach pain
Restlessness
Sweating
Anxiety
Serious allergic reaction (see below)
Red blood cell problems with a condition known as methaemoglobinaemia (when red blood cells stop working properly
leading to a decrease in blood oxygen content).
Ramipril
Pharmacodynamics
For the management of mild to severe hypertension. May be used to reduce cardiovascular mortality following
myocardial infarction in hemodynamically stable individuals who develop clinical signs of congestive heart
failure within a few days following myocardial infarction. To reduce the rate of death, myocardial infarction and
stroke in individuals at high risk of cardiovascular events. May be used to slow the progression of renal
disease in individuals with hypertension, diabetes mellitus and microalubinuria or overt nephropathy.
Ramipril is an ACE inhibitor similar to benazepril, fosinopril and quinapril. It is an inactive prodrug that is
converted to ramiprilat in the liver, the main site of activation, and kidneys. Ramiprilat confers blood pressure
lowing effects by antagonizing the effect of the RAAS. The RAAS is a homeostatic mechanism for regulating
hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure
or blood flow is reduced, renin is released from the granular cells of the juxtaglomerular apparatus in the
kidneys. In the blood stream, renin cleaves circulating angiotensinogen to ATI, which is subsequently cleaved
to ATII by ACE. ATII increases blood pressure using a number of mechanisms. First, it stimulates the
secretion of aldosterone from the adrenal cortex. Aldosterone travels to the distal convoluted tubule (DCT)
and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number
of sodium channels and sodium-potassium ATPases on cell membranes. Second, ATII stimulates the
21
secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland. ADH
stimulates further water reabsorption from the kidneys via insertion of aquaporin-2 channels on the apical
surface of cells of the DCT and collecting tubules. Third, ATII increases blood pressure through direct arterial
vasoconstriction. Stimulation of the Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade
of events resulting in myocyte contraction and vasoconstriction. In addition to these major effects, ATII
induces the thirst response via stimulation of hypothalamic neurons. ACE inhibitors inhibit the rapid
conversion of ATI to ATII and antagonize RAAS-induced increases in blood pressure. ACE (also known as
kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator. Inhibiting the
deactivation of bradykinin increases bradykinin levels and may sustain the effects of ramiprilat by causing
increased vasodilation and decreased blood pressure.
Mechanism of action
There are two isoforms of ACE: the somatic isoform, which exists as a glycoprotein comprised of a single
polypeptide chain of 1277; and the testicular isoform, which has a lower molecular mass and is thought to
play a role in sperm maturation and binding of sperm to the oviduct epithelium. Somatic ACE has two
functionally active domains, N and C, which arise from tandem gene duplication. Although the two domains
have high sequence similarity, they play distinct physiological roles. The C-domain is predominantly involved
in blood pressure regulation while the N-domain plays a role in hematopoietic stem cell differentiation and
proliferation. ACE inhibitors bind to and inhibit the activity of both domains, but have much greater affinity for
and inhibitory activity against the C-domain. Ramiprilat, the principle active metabolite of ramipril, competes
with ATI for binding to ACE and inhibits and enzymatic proteolysis of ATI to ATII. Decreasing ATII levels in the
body decreases blood pressure by inhibiting the pressor effects of ATII as described in the Pharmacology
section above. Ramipril also causes an increase in plasma renin activity likely due to a loss of feedback
inhibition mediated by ATII on the release of renin and/or stimulation of reflex mechanisms via baroreceptors.
Absorption
The extent of absorption is at least 50-60%. Food decreases the rate of absorption from the GI tract without
affecting the extent of absorption. The absolute bioavailabilities of ramipril and ramiprilat were 28% and 44%,
respectively, when oral administration was compared to intravenous administration.
Not Available
Protein binding
Protein binding of ramipril is about 73% and that of ramiprilat about 56%.
Metabolism
Hepatic metabolism accounts for 75% of total ramipril metabolism. 25% of hepatic metabolism
produces the active metabolite ramiprilat via liver esterase enzymes. 100% of renal metabolism
converts ramipril to ramiprilat. Other metabolites, diketopiperazine ester, the diketopiperazine acid,
and the glucuronides of ramipril and ramiprilat, are inactive.
N/A
22
Half life
Plasma concentrations of ramiprilat decline in a triphasic manner. Initial rapid decline represents
distribution into tissues and has a half life of 2-4 hours. The half life of the apparent elimination phase
is 9-18 hours and that of the terminal elimination phase is > 50 hours. Two elimination phases occur
as a result of ramiprilat's potent binding to ACE and slow dissociation from the enzyme. The half life
of ramiprilat after multiple daily doses (MDDs) is dose-dependent, ranging from 13-17 hours with 5-10
mg MDDs to 27-36 hours for 2.5 mg MDDs.
Clearance
N/A
Toxicity
Symptoms of overdose may include excessive peripheral vasodilation (with marked hypotension and
shock), bradycardia, electrolyte disturbances, and renal failure. The most likely adverse reactions are
symptoms attributable to its blood-pressure lowing effect. May cause headache, dizziness, asthenia,
chest pain, nausea, peripheral edema, somnolence, impotence, rash, arthritis, and dyspnea. LD 50 =
10933 mg/kg (orally in mice).
Dose

Initial dose: 2.5 mg orally once a day for patients not taking a diuretic
Maintenance dose: 2.5 to 20 mg/day in one or two equally divided doses
Comments:
-Adjust dose according to blood pressure response.
-The antihypertensive effect may diminish toward the end of a once daily dosing interval;
consider increasing dose or twice daily administration.
-If blood pressure is not controlled with this drug alone, a diuretic may be added.
Use: Treatment of hypertension, to lower blood pressure, alone or in combination with a thiazide
diuretic.
Usual Adult Dose for Congestive Heart Failure

Initial dose: 2.5 mg orally twice a day
Maintenance dose: 5 mg orally twice a day
Comments:
-If possible, decrease concomitant diuretic dose to reduce likelihood of hypotension.
-After first initial dose, observe at least two hours and until blood pressure has stabilized at least
23
an additional hour.
-If patient becomes hypotensive on initial dose, reduce to 1.25 mg twice a day.
-After one week on initial dose, increase toward maintenance dose as tolerated; may increase
about every 3 weeks.
-Initial hypotension does not preclude subsequent titration with this drug, following effective
hypotension management.
Use: Treatment of stable patients who have demonstrated clinical signs of congestive heart
failure within the first few days after sustaining acute myocardial infarction.
Usual Adult Dose for Cardiovascular Risk Reduction

Initial dose: 2.5 mg orally once a day for one week; 5 mg orally once a day for next three weeks,
then increase as tolerated
Maintenance dose: 10 mg orally once a day
Comments:
-If patient is hypertensive or recently post myocardial infarction, may administer in divided
doses.
Use: Reduce the risk of myocardial infarction, stroke, or death from cardiovascular causes in
patients 55 years or older at high risk of developing a major cardiovascular event because of a
history of coronary artery disease, stroke, peripheral vascular disease, or diabetes that is
accompanied by at least one other cardiovascular risk factor (hypertension, elevated total
cholesterol levels, low high-density lipoprotein (HDL) levels, cigarette smoking, or documented
microalbuminuria); can be used in addition to other needed treatment such as antihypertensive,
antiplatelet, or lipid lowering therapy.
Side effects
Feeling sick (nausea)
Dizziness
Headache
Sleepiness
Slowed reactions
Tiredness
Excessive sweating
24
Fainting
Irregular heart beat (arrhythmia)
Angina (pain in the chest owing to the poor blood supply to the heart)
Dry cough
Dry mouth
Constipation
Diarrhoea
Indigestion
Bronchitis (infection of the lungs)
Sinusitis (sinus infection)
Shortness of breath
Hair loss
Itchy skin rash
Itching
Reddening and/or warming of patches of skin
Muscle pain
Joint pain
Difficulty sleeping (insomnia)
Nervousness
Restlessness
Depressed mood
Anxiety
Loss of appetite
Tingling, numbness or 'pins and needle' sensations (paraesthesia)
Muscle cramps
Muscle pain
Low blood pressure
Visual disturbances
Pancreatitis (inflammation of the pancreas)
Bronchospasm (tightening of the windpipe causing difficulty in breathing)
Loss of appetite
25
Reduced sex drive in men
Red, sore, itching or watery eyes (conjunctivitis)
Causing or worsening of Raynaud's syndrome (poor blood circulation to fingers and/or toes,
causing pain, numbness and coldness in these areas).
Propranolol
For the prophylaxis of migraine.
Pharmacodynamics
Propranolol, the prototype of the beta-adrenergic receptor antagonists, is a competitive, nonselective beta-
blocker similar to nadolol without intrinsic sympathomimetic activity. Propanolol is a racemic compound; the l-
isomer is responsible for adrenergic blocking activity.
Mechanism of action
Propranolol competes with sympathomimetic neurotransmitters such as catecholamines for binding
at beta(1)-adrenergic receptors in the heart, inhibiting sympathetic stimulation. This results in a
reduction in resting heart rate, cardiac output, systolic and diastolic blood pressure, and reflex
orthostatic hypotension.
Absorption
Propranolol is almost completely absorbed from the GI tract; however, plasma concentrations
attained are quite variable among individuals.
4L
Protein binding
More than 90%
Metabolism
Hepatic
Propranolol is extensively metabolized with most metabolites appearing in the urine
Half life
4 hours
Clearance
n/a
Toxicity
Symptoms of overdose include bradycardia, cardiac failure, hypotension, and brochospasm. LD 50=565
mg/kg (orally in mice).
Dose

Initial dose:
Immediate-release: 40 mg orally 2 times a day
Sustained-release: 80 mg orally once a day
26
XL sustained-release: 80 mg orally once a day at bedtime
Maintenance dose:
Immediate-release: 120 to 240 mg orally per day
Sustained-release: 120 to 160 mg orally per day
XL sustained-release: 80 to 120 mg orally once a day at bedtime
Maximum dose:
IR/SR: 640 mg orally per day
XR: 120 mg orally per day
Comments:
-The XL sustained-release formulation should be administered once daily at bedtime
(approximately 10 PM) and should be taken consistently either on an empty stomach or with
food.
-Dose titration should be done gradually until adequate blood pressure control is achieved.
-The recommended dosing is the same whether used alone or added to a diuretic.
-The time needed for full hypertensive response to a given dosage is variable and may range
from a few days to several weeks.
-While twice daily dosing of the immediate release formulation is effective and can maintain a
reduction in blood pressure throughout the day, some patients, especially when lower doses are
used, may experience a modest rise in blood pressure toward the end of the 12 hour dosing
interval. This can be evaluated by measuring blood pressure near the end of the dosing interval
to determine whether satisfactory control is being maintained throughout the day. If control is not
adequate, a larger dose, or 3 times daily therapy may achieve better control.

Immediate-release: Total daily doses of 80 to 320 mg orally 2 to 4 times a day have been shown
to increase exercise tolerance and to reduce ischemic changes in the ECG.
Sustained-release: Initial dose: 80 mg orally once a day. Dosage should be gradually increased
at 3 to 7 day intervals. The average optimal dosage appears to be 160 mg once a day.
Comments:
-If treatment is to be discontinued, dosage should be reduced gradually over a period of a few
weeks.
Usual Adult Dose for Arrhythmias

Immediate-release: 10 to 30 mg orally 3 to 4 times a day, before meals and at bedtime
IV: 1 to 3 mg at a rate not exceeding 1 mg/min. Sufficient time should be allowed for the drug to
27
reach the site of action even when a slow circulation is present. A second dose may be given
after 2 minutes. Thereafter, additional drug should not be given in less than 4 hours.
Comments:
-IV administration is usually reserved for life-threatening arrhythmias or those occurring under
anesthesia.
-IV doses should be administered under careful monitoring, such as electrocardiography, and
central venous pressure.
-The rate of IV administration should not exceed 1 mg (1 mL) per minute to decrease the
possibility of lowering blood pressure and causing cardiac standstill.
-Transfer from IV to oral therapy should be considered as soon as possible.

Immediate-release:
Initial dose: 40 mg orally 3 times a day for 1 month, then increase to 60 to 80 mg orally 3 times
a day as tolerated.
Maintenance dose: 180 mg to 240 mg orally per day in divided doses (2 to 4 times daily)
Maximum dose: 240 mg orally per day
Usual Adult Dose for Migraine Prophylaxis

Immediate-release:
Initial dose: 80 mg orally per day in divided doses
Maintenance dose: 160 to 240 mg orally per day in divided doses
Sustained-release:
Initial dose: 80 mg orally once a day
Maintenance dose: 160 to 240 mg once a day
Comments:
-The dosage should be increased gradually to achieve optimum migraine prophylaxis. If a
satisfactory response is not obtained within 4 to 6 weeks after reaching the maximum dose,
therapy should be discontinued.
-Withdrawal of therapy should be accomplished over a period of several weeks.
Usual Adult Dose for Benign Essential Tremor

Immediate-release:
Initial dose: 40 mg orally 2 times a day
Maintenance dose: 120 to 320 mg orally per day
Comments:
28
-Optimum reduction of essential tremor is usually achieved with a dose of 120 mg orally per day.
-Occasionally, it may be necessary to administer 240 to 320 mg orally per day.
Usual Adult Dose for Aortic Stenosis

Immediate-release: 20 to 40 mg orally 3 to 4 times a day, before meals and at bedtime
Sustained-release: 80 to 160 mg orally once a day
Use: Hypertrophic Subaortic Stenosis
Usual Adult Dose for Pheochromocytoma

Immediate-release:
Preoperatively: 60 mg orally daily in divided doses for 3 days prior to surgery as adjunctive
therapy to alpha-adrenergic blockade
Management of Inoperable Tumor: 30 mg orally daily in divided doses as adjunctive therapy to
alpha-adrenergic blockade
Usual Adult Dose for Atrial Fibrillation

Immediate-release: 10 mg to 30 mg orally 3 or 4 times a day before meals and at bedtime
Usual Pediatric Dose for Arrhythmias

Oral: Children: Initial: 0.5 to 1 mg/kg/day in divided doses every 6 to 8 hours; titrate dosage
upward every 3 to 5 days; usual dose: 2 to 4 mg/kg/day; higher doses may be needed; do not
exceed 16 mg/kg/day
IV: Children: 0.01 to 0.1 mg/kg slow IV over 10 minutes; maximum dose: 1 mg (infants); 3 mg
(children)
Usual Pediatric Dose for Hypertension

Children:
Immediate release formulations:
Initial: 0.5 to 1 mg/kg/day in divided doses every 6 to 12 hours; increase gradually every 5 to 7
days
Usual dose: 1 to 5 mg/kg/day
Maximum dose: 8 mg/kg/day
Children and Adolescents 1 to 17 years:

Immediate release formulations:
Initial: 1 to 2 mg/kg/day divided in 2 to 3 doses/day; titrate dose to effect
Maximum dose: 4 mg/kg/day up to 640 mg/day; sustained release formulation may be dosed
29
once daily (National High Blood Pressure Education Program Working Group on High Blood
Pressure in Children and Adolescents).
Usual Pediatric Dose for Thyrotoxicosis

Neonates: Oral: 2 mg/kg/day in divided doses every 6 to 12 hours; occasionally higher doses
may be required
Adolescents: Oral: 10 to 40 mg/dose every 6 hours
Usual Pediatric Dose for Hemangioma

Propranolol oral solution 4.28 mg/mL:
Initiate treatment at ages 5 weeks to 5 months:
Initial dose: 0.15 mL/kg (0.6 mg/kg) orally 2 times a day (at least 9 hours apart)
-After 1 week: Increase the daily dose to 0.3 mL/kg (1.1 mg/kg) orally 2 times a day (at least 9
hours apart)
-After 2 weeks: Increase the dose to 0.4 mL/kg (1.7 mg/kg) orally 2 times a day (at least 9 hours
apart) maintain for 6 months
Comments:
-Dose should be periodically adjusted as the weight of the child increases.
-Administration directly into the mouth of the child is recommended; however, the product may
be diluted in a small quantity of milk or fruit juice, given in a bottle.
-This drug should be administered during or right after a feeding to reduce the risk of
hypoglycemia.
-The dose should be skipped if the child is not eating or is vomiting.
-Heart rate and blood pressure should be monitored for 2 hours after drug initiation or dose
increases.
-If hemangiomas recur, treatment may be reinitiated.
Uses: For the treatment of proliferating infantile hemangioma requiring systemic therapy.
Side effects
Tiredness
Cold extremities
Difficulty in sleeping
Headache
Numbness and spasm in fingers, followed by warmth and pain (Raynauds disease)
Feeling sick
30
Being sick
Diarrhoea
Slow or irregular heart beat
Skin and hair problems, including rash, worsening of psoriasis, hair loss, dry flaky skin
Dizziness
Hallucinations
Mood changes
Pins and needles
Depression or psychoses
Thinning of the hair
Purplish marks on the skin
Difficulty in breathing.
Dry eyes
Visual disturbances.
Increased bruising, nosebleeds, sore throats or infections
Changes in sex drive
Bisoprolol
For management of heart failure, angina pectoris, and mild to moderate hypertension and for secondary
prevention of myocardial infarction (MI).
Pharmacodynamics
Bisoprolol is a competitive, cardioselective 1-adrenergic antagonist. Activation of 1-receptors (located
mainly in the heart) by epinephrine increases heart rate and the blood pressure causing the heart to consume
more oxygen. 1-adrenergic blocking agents such as bisopolol lower the heart rate and blood pressure and
may be used to reduce workload on the heart and hence oxygen demands. They are routinely prescribed in
patients with ischemic heart disease. In addition, 1-selective blockers prevent the release of renin, a
hormone produced by the kidneys causes constriction of blood vessels. Bisoprolol is lipophilic and exhibits no
intrinsic sympathomimetic activity (ISA) or membrane-stabilizing activity.
Mechanism of action
Bisoprolol selectively blocks catecholamine stimulation of 1-adrenergic receptors in the heart and
vascular smooth muscle. This results in a reduction of heart rate, cardiac output, systolic and
diastolic blood pressure, and possibly reflex orthostatic hypotension. At higher doses (e.g. 20 mg and
greater) bisoprolol may competitively block 2-adrenergic receptors in bronchial and vascular
smooth muscle causing bronchospasm and vasodilation.
31
Absorption
Well absorbed. Bioavailability > 80%. Absorption is not affected by food. Peak plasma concentrations
occur within 2-4 hours.
N/A
Protein binding
Binding to serum proteins is approximately 30%
Metabolism
Approximately 50% of the dose is metabolized primarily metabolized by CYP3A4 to inactive metabolites. In
vitro studies have shown that bisoprolol is also metabolized by CYP2D6 though this does not appear to be
clinically significant. Approximately half the administered dose is excreted in unchanged in urine.
Eliminated equally by renal and non-renal pathways. Approximately 50% of the total orally
administered dose is excreted unchanged in urine with the remainder appearing as inactive
metabolites. Less than 2% of the dose is excreted in the feces.
Half life
9-12 hours; prolonged in the elderly and those with decreased renal function
Clearance
N/A
Toxicity
Oral, mouse: LD50 = 100 mg/kg; Skin, rabbit: LD50 = 200 mg/kg; Skin, rat: LD50 = 500 mg/kg. Symptoms
of overdose include congestive heart failure (marked by sudden weight gain, swelling of the legs,
feet, and ankles, fatigue, and shortness of breath), difficult or labored breathing, low blood pressure,
low blood sugar, and slow heartbeat.
Dose

Dose Titration: If desired response is not achieved, may increase the dose to 10 mg, then 20
mg if necessary
Comments:
-Dosage should be individualized to the patient; some patients may benefit from a starting dose
of 2.5 mg once a day.
32
-In clinical trials, blood pressure lowering effects were seen at 1 week and changed little
thereafter.
Side effects
SOPROLOL SIDE EFFECTS
Vomiting
Diarrhoea
Constipation
Tiredness
Dizziness
Headache
Feeling of coldness or numbness in hands and feet.
Slow heart beat (bradycardia)
Irregular heart beat (arrhythmia)
Worsening of heart failure causing increased breathlessness and/or fluid retention
Muscular weakness and cramps
Sleep disturbances
Depression
Bronchospasm (muscle bands around the airways tighten uncontrollably, causing the
airways to narrow) in patients asthma or a history of disease causing obstruction to airways
Feeling faint or dizzy when standing up.
Deafness
Inflammation of the liver (hepatitis)
Nightmares
Hallucinations
Impotence
Dry eyes
Inflammation of the nose (allergic rhinitis).

33
Inflammation of the eye (conjunctivitis)
Hair loss
Causing or worsening the skin condition called psoriasis (a type of skin disease, normally
indicated by red scaly patches).
Amlodipine
For the treatment of hypertension and chronic stable angina.
Pharmacodynamics
Amlodipine belongs to the dihydropyridine (DHP) class of calcium channel blockers (CCBs), the most widely
used class of CCBs. There are at least five different types of calcium channels in Homo sapiens: L-, N-, P/Q-,
R- and T-type. It was widely accepted that DHP CCBs target L-type calcium channels, the major channel in
muscle cells that mediate contraction; however, some studies have indicated that amlodipine also binds to
and inhibits N-type calcium channels (see references in Targets section). Similar to other DHP CCBs,
amlodipine binds directly to inactive L-type calcium channels stabilizing their inactive conformation. Since
arterial smooth muscle depolarizations are longer in duration than cardiac muscle depolarizations, inactive
channels are more prevalent in smooth muscle cells. Alternative splicing of the alpha-1 subunit of the channel
gives amlodipine additional arterial selectivity. At therapeutic sub-toxic concentrations, amlodipine has little
effect on cardiac myocytes and conduction cells
34
Mechanism of action
Amlodipine decreases arterial smooth muscle contractility and subsequent vasoconstriction by
inhibiting the influx of calcium ions through L-type calcium channels. Calcium ions entering the cell
through these channels bind to calmodulin. Calcium-bound calmodulin then binds to and activates
myosin light chain kinase (MLCK). Activated MLCK catalyzes the phosphorylation of the regulatory
light chain subunit of myosin, a key step in muscle contraction. Signal amplification is achieved by
calcium-induced calcium release from the sarcoplasmic reticulum through ryanodine receptors.
Inhibition of the initial influx of calcium decreases the contractile activity of arterial smooth muscle
cells and results in vasodilation. The vasodilatory effects of amlodipine result in an overall decrease
in blood pressure. Amlodipine is a long-acting CCB that may be used to treat mild to moderate
essential hypertension and exertion-related angina (chronic stable angina). Another possible
mechanism is that amlodipine inhibits vascular smooth muscle carbonic anhydrase I activity causing
cellular pH increases which may be involved in regulating intracelluar calcium influx through calcium
channels.
Absorption
Amlodipine is slowly and almost completely absorbed from the gastrointestinal tract. Peak plasma
concentrations are reached 6-12 hour following oral administration. Its estimated bioavailability is 64-
90%. Absorption is not affected by food.
n/a
Protein binding
97.5%
Metabolism
Hepatic. Metabolized extensively (90%) to inactive metabolites via the cytochrome P450 3A4 isozyme.
Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with
10% of the parent compound and 60% of the metabolites excreted in the urine.
Half life
30-50 hours
Clearance
n/a
Toxicity
Gross overdosage could result in excessive peripheral vasodilatation and possibly reflex tachycardia.
Marked and probably prolonged systemic hypotension up to an including shock with fatal outcome
have been reported.
Dose

Maintenance dose: 5 to 10 mg orally once a day
Small or fragile patients may be started on 2.5 mg orally once a day.
35
Chronic stable or vasospastic angina, or angiographically documented coronary artery disease
in patients without heart failure or an ejection fraction less than 40%: 5 to 10 mg orally once a
day
Most patients with chronic stable or vasospastic angina require 10 mg for adequate effect. In
clinical studies, most patients with coronary artery disease required 10 mg.
Usual Adult Dose for Coronary Artery Disease

Chronic stable or vasospastic angina, or angiographically documented coronary artery disease
in patients without heart failure or an ejection fraction less than 40%: 5 to 10 mg orally once a
day
Most patients with chronic stable or vasospastic angina require 10 mg for adequate effect. In
clinical studies, most patients with coronary artery disease required 10 mg.
Usual Geriatric Dose for Hypertension

Initial dose: 2.5 mg orally once a day
Maintenance dose: 2.5 to 10 mg orally once a day
Usual Geriatric Dose for Angina Pectoris

Chronic stable or vasospastic angina: 5 to 10 mg orally once a day
The lower dose is recommended in the elderly; however, most patients require 10 mg for
adequate effect.
Usual Pediatric Dose for Hypertension

6 to 17 years: 2.5 mg to 5 mg orally once a day
Doses in excess of 5 mg daily have not been studied in pediatric patients
Side effects
Amlodipine should be used with caution in: patients with liver problems, those with heart
failure, children under the age of 18 years, or the elderly.
It should not be used in: patients with very low blood pressure making them feel faint or
dizzy, patients who are in shock (including shock because of heart disease, termed
cardiogenic shock), patients with poor heart function because of severe heart disease or a
heart attack, patients with heart failure because of a heart attack, those with narrowing of
the heart valve of the aorta (aortic stenosis), or patients with unstable angina (angina is a
chest pain occurring when the heart muscle is not getting enough blood).
Diltiazem
For the treatment of Hypertension
36
Pharmacodynamics
Diltiazem, a benzothiazepine calcium-channel blocker, is used alone or with an angiotensin-converting
enzyme inhibitor, to treat hypertension, chronic stable angina pectoris, and Prinzmetal's variant angina.
Diltiazem is a non-dihydropyridine (DHP)member of the calcium channel blocker class, along with Verapamil.
Diltiazem is similar to other peripheral vasodilators. Diltiazem inhibits the influx of extra cellular calcium across
the myocardial and vascular smooth muscle cell membranes possibly by deforming the channel, inhibiting
ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum.
The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells,
causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue,
decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload.
Mechanism of action
Possibly by deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with
the release of calcium from the sarcoplasmic reticulum, diltiazem, like verapamil, inhibits the influx of
extracellular calcium across both the myocardial and vascular smooth muscle cell membranes. The
resultant inhibition of the contractile processes of the myocardial smooth muscle cells leads to
dilation of the coronary and systemic arteries and improved oxygen delivery to the myocardial tissue.
Absorption
Diltiazem is well absorbed from the gastrointestinal tract but undergoes substantial hepatic first-pass
effect.
N/A
Protein binding
70%-80%
Metabolism
Diltiazem is metabolized by and acts as an inhibitor of the CYP3A4 enzyme.
N/A
Half life
3.0 - 4.5 hours
Clearance
n/a
Toxicity
Dose

Initial dose: 30 to 60 mg orally 3 to 4 times a day.
Maintenance dose: 180 to 360 mg orally/day in divided doses.
SR initial dose: 60 to 120 mg orally twice a day.
SR maintenance dose: 240 to 360 mg orally/day.
CD or XR initial dose: 120 to 240 mg orally once a day.
37
CD maintenance dose: 240 to 360 mg orally once a day.
XR maintenance dose: 240 to 480 mg orally once a day.
LA initial dose: 120 to 240 mg orally once a day.
LA maintenance dose: 240 to 420 mg orally once a day.
IV Dosing:
Initial bolus doses: 0.25 mg/kg as a bolus administered over 2 minutes. A second bolus of 0.35
mg/kg may be used if necessary.
Initial infusion dose: 5 mg/hr.
Maintenance infusion dose: The infusion rate may be increased in 5 mg/hr increments up to 15
mg/hr.

Initial dose (oral): 30 to 60 mg orally 3 to 4 times a day
SR initial dose: 60 to 120 mg orally twice a day
Initial dose (IV): 0.25 mg/kg actual body weight bolus over 2 minutes. If necessary, a second
bolus of 0.35 mg/kg ABW may be given. In some cases, an infusion of diltiazem 5 mg/hour may
be started, and advanced in 5 mg/hour increments to 15 mg/hour for up to 24 hours.
Usual Adult Dose for Atrial Flutter

38
Usual Adult Dose for Supraventricular Tachycardia


Initial dose: 30 to 60 mg orally 3 to 4 times a day

Initial dose: 30 to 60 mg orally 3 to 4 times a day
Side effects
Upset stomach
39
Feeling sick
Dizziness
Headache
Tiredness
Swelling of the legs
Flushing (redness of the face).
Low blood pressure (feeling dizzy, light-headed or faint when you stand or sit up quickly)
Allergic reaction (a rash, swallowing or breathing problems, swelling of your lips, face,
throat or tongue)
Skin problems, including blistering or peeling of the skin, or severe blistering rash in which
layers of the skin may peel off to leave large areas of raw exposed skin over the body, or
skin lesions with a pink/red ring and a pale centre, more sensitive to the sun than usual
Slow or uneven heartbeat
Very fast, uneven or forceful heartbeat (palpitations)
Shortness of breath, feeling tired along with swollen ankles and legs (possible signs of heart
failure)
Unusual movements of the tongue, muscle spasms in your face, rolling eyes and trembling
High temperature, feeling tired, loss of appetite, stomach pain, feeling sick (possible signs
of a liver problem, hepatitis)
Breast enlargement in men
Digoxin
For the treatment and management of congestive cardiac insufficiency, arrhythmias and heart failure.
Pharmacodynamics
Digoxin, a cardiac glycoside similar to digitoxin, is used to treat congestive heart failure and supraventricular
arrhythmias due to reentry mechanisms, and to control ventricular rate in the treatment of chronic atrial
fibrillation.
40
Mechanism of action
Digoxin inhibits the Na-K-ATPase membrane pump, resulting in an increase in intracellular sodium.
The sodium calcium exchanger (NCX)in turn tries to extrude the sodium and in so doing, pumps in
more calcium. Increased intracellular concentrations of calcium may promote activation of contractile
proteins (e.g., actin, myosin). Digoxin also acts on the electrical activity of the heart, increasing the
slope of phase 4 depolarization, shortening the action potential duration, and decreasing the maximal
diastolic potential.
Absorption
Absorption of digoxin from the elixir pediatric formulation has been demonstrated to be 70% to 85%
complete (90% to 100% from the capsules, and 60% to 80% for tablets).
N/A
Protein binding
25%
Metabolism
Hepatic (but not dependent upon the cytochrome P-450 system). The end metabolites, which include
3 b-digoxigenin, 3-keto-digoxigenin, and their glucuronide and sulfate conjugates, are polar in nature
and are postulated to be formed via hydrolysis, oxidation, and conjugation.
Following intravenous administration to healthy volunteers, 50% to 70% of a digoxin dose is excreted
unchanged in the urine.
Half life
3.5 to 5 days
Clearance
Not Available
Toxicity
Toxicity includes ventricular tachycardia or ventricular fibrillation, or progressive bradyarrhythmias,
or heart block. LD50 = 7.8 mg/kg (orally in mice).
Dose

Rapid Digitalization with a Loading Dose:
Peak digoxin body stores of 8 to 12 mcg/kg generally provide a therapeutic effect with minimum
risk of toxicity in most patients with heart failure and normal sinus rhythm.
The loading dose should be administered in several fractions, with approximately half the total
given as the first dose. Additional fractions of the total dose may be given at 6 to 8 hour
intervals. Careful assessment of the patient's clinical response should be considered before
each additional dose. If the patient's response necessitates a change from the calculated
loading dose of digoxin, then calculation of the maintenance dose should be based upon the
amount actually given.
41
Tablets:
Initial: 500 to 750 mcg usually produces a detectable effect in 0.5 to 2 hours with a maximal
effect in 2 to 6 hours. Additional doses of 125 to 375 mcg may be given at 6 to 8 hour intervals
until clinical evidence of an adequate effect is noted. The usual amount of digoxin tablets that a
70 kg patient requires to achieve 8 to 12 mcg/kg peak body stores is 750 to 1250 mcg.
Capsules:
Initial: 400 to 600 mcg of digoxin capsules generally produces a detectable effect in 0.5 to 2
hours with a maximal effect in 2 to 6 hours. Additional doses of 100 to 300 mcg may be given
cautiously at 6 to 8 hour intervals until clinical evidence of an adequate effect is noted. The
usual amount of digoxin capsules that a 70 kg patient requires to achieve 8 to 12 mcg/kg peak
body stores is 600 to 1000 mcg.
Injection:
Initial: 400 to 600 mcg of digoxin intravenously usually produces a detectable effect in 5 to 30
minutes with a maximal effect in 1 to 4 hours. Additional doses of 100 to 300 mcg may be given
cautiously at 6 to 8 hour intervals until clinical evidence of an adequate effect is noted. The
usual amount of digoxin injection that a 70 kg patient requires to achieve 8 to 12 mcg/kg peak
body stores is 600 to 1000 mcg. The injectable route is frequently used to achieve rapid
digitalization, with conversion to digoxin tablets or digoxin capsules for maintenance therapy.
Maintenance Dose:
The doses of digoxin tablets used in controlled trials in patients with heart failure have ranged
from 125 to 500 mcg once daily. In these studies, the digoxin dose has been generally titrated
according to the patient's age, lean body weight, and renal function. Therapy is generally
initiated at a dose of 250 mcg once daily in patients under age 70 with good renal function.

Peak digoxin body stores larger than the 8 to 12 mcg/kg required for most patients with heart
failure and normal sinus rhythm have been used for control of ventricular rate in patients with
atrial fibrillation. Doses of digoxin used for the treatment of chronic atrial fibrillation should be
titrated to the minimum dose that achieves the desired ventricular rate control without causing
undesirable side effects.
Usual Pediatric Dose for Atrial Fibrillation

Do not give full total digitalizing dose at once. Administer loading doses in several portions, give
roughly half the total as the first dose. Give additional fractions of the total dose at 6 to 8 hour
42
intervals (oral) or 4 to 8 hour intervals (parenteral). Divided daily dosing is recommended for
infants and young children under 10 years of age.
Parenteral administration should be used only when the need for rapid digitalization is urgent or
when the drug cannot be taken orally. Intravenous administration is preferred over intramuscular
injection as it can lead to severe pain at the injection site. If it is necessary to administer the
drug by the intramuscular route, it should be injected deep into the muscle followed by
massage. No more than 500 mcg should be injected into a single site.
Calculated doses should be based on lean body weight.
Premature:
Digitalizing (Loading) dose: Oral elixir: 20 to 30 mcg/kg; Intravenous: 15 to 25 mcg/kg
Maintenance dose: oral 5 to 7.5 mcg/kg; intravenous 4 to 6 mcg/kg
Full Term:
Maintenance dose: oral 6 to 10 mcg/kg; intravenous 5 to 8 mcg/kg
1-24 months:
Maintenance dose: 10 to 15 mcg/kg oral; intravenous 7.5 to 12 mcg/kg
3 to 5 years:
Maintenance dose: oral 7.5 to 10 mcg/kg; intravenous 6 to 9 mcg/kg
6 to 10 years:
Maintenance dose: oral 5 to 10 mcg/kg; intravenous 4 to 8 mcg/kg
11 years and older:

Maintenance dose: oral 2.5 to 5 mcg/kg; intravenous 2 to 3 mcg/kg
Side effects
Palpitations,
chest pain,
43
shortness of breath,
sweating,
slow or irregular heart beat,
nausea, vomiting or diarrhoea,
rash that may be itchy,
drowsiness or dizziness,
visual disturbances, with blurred or yellow-green sight,
depression.
Diabetic Drugs
Metformin
For use as an adjunct to diet and exercise in adult patients (18 years and older) with NIDDM. May also be
used for the management of metabolic and reproductive abnormalities associated with polycystic ovary
syndrome (PCOS). Jentadueto is for the treatment of patients when both linagliptin and metformin is
appropriate.
Pharmacodynamics
Metformin is an oral antihyperglycemic agent that improves glucose tolerance in patients with NIDDM,
lowering both basal and postprandial plasma glucose. Metformin is not chemically or pharmacologically
related to any other class of oral antihyperglycemic agents. Unlike sulfonylureas, metformin does not produce
hypoglycemia in either patients with NIDDM or healthy subjects and does not cause hyperinsulinemia.
Metformin does not affect insulin secretion.
44
Mechanism of action
Metformin's mechanisms of action differ from other classes of oral antihyperglycemic agents.
Metformin decreases blood glucose levels by decreasing hepatic glucose production, decreasing
intestinal absorption of glucose, and improving insulin sensitivity by increasing peripheral glucose
uptake and utilization. These effects are mediated by the initial activation by metformin of AMP-
activated protein kinase (AMPK), a liver enzyme that plays an important role in insulin signaling,
whole body energy balance, and the metabolism of glucose and fats. Activation of AMPK is required
for metformin's inhibitory effect on the production of glucose by liver cells. Increased peripheral
utilization of glucose may be due to improved insulin binding to insulin receptors. Metformin
administration also increases AMPK activity in skeletal muscle. AMPK is known to cause GLUT4
deployment to the plasma membrane, resulting in insulin-independent glucose uptake. The rare side
effect, lactic acidosis, is thought to be caused by decreased liver uptake of serum lactate, one of the
substrates of gluconeogenesis. In those with healthy renal function, the slight excess is simply
cleared. However, those with severe renal impairment may accumulate clinically significant serum
lactic acid levels. Other conditions that may precipitate lactic acidosis include severe hepatic disease
and acute/decompensated heart failure.
Absorption
Absorbed over 6 hours, bioavailability is 50 to 60% under fasting conditions. Administration with food
decreases and delays absorption. Some evidence indicates that the level of absorption is not dose-
related, suggesting that absorption occurs through a saturable process. Limited data from animal and
human cell cultures indicate that absorption occurs through a passive, non-saturable process,
possibly involving a paracellular route. Peak action occurs 3 hours after oral administration.
654 L for metformin 850 mg administered as a single dose. The volume of distribution following IV
administration is 63-276 L, likely due to less binding in the GI tract and/or different methods used to determine
volume of distribution.
Protein binding
Metformin is negligibly bound to plasma proteins.
Metabolism
Metformin is not metabolized.
Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted
unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been
identified in humans) nor biliary excretion. Approximately 90% of the drug is eliminated in 24 hours in
those with healthy renal function. Renal clearance of metformin is approximately 3.5 times that of
creatinine clearance, indicating the tubular secretion is the primary mode of metformin elimination.
Half life
6.2 hours. Duration of action is 8-12 hours.
Clearance
718-1552 mL/minute following single oral dose of 0.5-1.5 g. Metformin is removed by hemodialysis at a rate of
approximately 170 ml/min under good hemodynamic conditions.
45
Toxicity
Acute oral toxicity (LD50): 350 mg/kg [Rabbit]. It would be expected that adverse reactions of a more
intense character including epigastric discomfort, nausea, and vomiting followed by diarrhea,
drowsiness, weakness, dizziness, malaise and headache might be seen.
Dose
Usual Adult Dose for Diabetes Type 2

Immediate-release:
Initial dose: 500 mg orally twice a day or 850 mg orally once a day
Dose titration: Increase in 500 mg weekly increments or 850 mg every 2 weeks as tolerated
Maintenance dose: 2000 mg daily
Comments: Take in divided doses 2 to 3 times a day with meals. Titrate slowly to minimize
gastrointestinal side effects. In general, significant responses are not observed with doses less
than 1500 mg/day.
Extended-release:
Initial dose: 500 to 1000 mg orally once a day
Dose titration: Increase in 500 mg weekly increments as tolerated
Comments: If glycemic control is not achieved with once a day administration of an extended-
release product, consider dividing doses. If higher doses are required, may switch to immediate-
release product.
Use: To improve glycemic control in adults with type 2 diabetes mellitus as an adjunct to diet
and exercise.
Usual Pediatric Dose for Diabetes Type 2

10 years or older:
Immediate-release:
Initial dose: 500 mg orally twice a day
Dose titration: Increase in 500 mg weekly increments as tolerated
Comments: Take in divided doses 2 to 3 times a day with meals. Titrate slowly to minimize
46
gastrointestinal side effects.
Safety and effectiveness of metformin extended-release has not been established in pediatric
patients less than 18 years of age.
Use: To improve glycemic control in children with type 2 diabetes mellitus as an adjunct to diet
and exercise.
Side effects
Most common:
Loss of appetite
Nausea (feeling sick)
Vomiting
Diarrhoea (temporary)
Stomach pain
Metallic taste
Rarely:
Lactic acidosis (symptoms of deep and rapid breathing, vomiting, stomach pain, feeling of
being very weak and unwell)
Itching
Redness of the skin
Itchy skin rash
Gliclazide
For the treatment of NIDDM in conjunction with diet and exercise.
Pharmacodynamics
Gliclazide is a second generation sulphonylurea which acts as a hypoglycemic agent. It stimulates cells of
the islet of Langerhans in the pancreas to release insulin. It also enhances peripheral insulin sensitivity.
Overall, it potentiates insulin release and improves insulin dynamics.
47
Mechanism of action
Gliclazide binds to the cell sulfonyl urea receptor (SUR1). This binding subsequently blocks the
ATP sensitive potassium channels. The binding results in closure of the channels and leads to a
resulting decrease in potassium efflux leads to depolarization of the cells. This opens voltage-
dependent calcium channels in the cell resulting in calmodulin activation, which in turn leads to
exocytosis of insulin containing secretorty granules.
Absorption
Rapidly and well absorbed but may have wide inter- and intra-individual variability. Peak plasma
concentrations occur within 4-6 hours of oral administration.
n/a
Protein binding
94%, highly bound to plasma proteins
Metabolism
Extensively metabolized in the liver. Less than 1% of the orally administered dose appears
unchanged in the urine. Metabolites include oxidized and hydroxylated derivates, as well as
glucuronic acid conjugates.
Metabolites and conjugates are eliminated primarily by the kidneys (60-70%) and also in the feces (10-
20%).
Half life
10.4 hours. Duration of action is 10-24 hours.
Clearance
n/a
Toxicity
LD50=3000 mg/kg (orally in mice). Gliclazide and its metabolites may accumulate in those with severe
hepatic and/or renal dysfunction. Symptoms of hypoglycemia include: dizziness, lack of energy,
drowsiness, headache and sweating.
Dose
Initially, 4080 mg daily, adjusted according to response; up to 160 mg as a single dose, with
breakfast; higher doses divided; max. 320 mg daily
Side effects
Low blood sugar (hypoglycaemia, seek medical attention if severe or prolonged even if
temporarily controlled by eating sugar)
Blood disorders (e.g. anaemia, bruising or bleeding caused by a decrease in the number of
cells in the blood)
Liver disorders (jaundice, contact your doctor immediately if this happens)
Skin disorders (rash, redness, itching, hives, photosensitivity skin reactions)
Digestive disorders (stomach pain or discomfort, nausea, indigestion, diarrhoea,

constipation)
Eye disorders
48
Headache
Fever or sore throat
TZD-Pioglitazone
Treatment of Type II diabetes mellitus
Pharmacodynamics
Pioglitazone, a member of the drug group known as the thiazolidinediones or "insulin sensitizers", is not
chemically or functionally related to the alpha-glucosidase inhibitors, the biguanides, or the sulfonylureas.
Pioglitazone targets insulin resistance and, hence, is used alone or in combination with insulin, metformin, or
asulfonylurea as an antidiabetic agent.
49
Mechanism of action
Pioglitazone acts as an agonist at peroxisome proliferator activated receptors (PPAR) in target
tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPAR-
gamma receptors increases the transcription of insulin-responsive genes involved in the control of
glucose production, transport, and utilization. In this way, pioglitazone both enhances tissue
sensitivity to insulin and reduces hepatic gluconeogenesis. Thus, insulin resistance associated with
type 2 diabetes mellitus is improved without an increase in insulin secretion by pancreatic cells.
Absorption
Following oral administration, in the fasting state, pioglitazone is first measurable in serum within 30
minutes, with peak concentrations observed within 2 hours. Food slightly delays the time to peak
serum concentration to 3 to 4 hours, but does not alter the extent of absorption.
0.63 0.41 L/kg
Protein binding
> 99%
Metabolism
Hepatic
Following oral administration, approximately 15% to 30% of the pioglitazone dose is recovered in the
urine. Renal elimination of pioglitazone is negligible, and the drug is excreted primarily as metabolites
and their conjugates. It is presumed that most of the oral dose is excreted into the bile either
unchanged or as metabolites and eliminated in the feces.
Half life
3-7 hours
Clearance
apparent cl=5 7 L/h [oral administration]
Toxicity
Hypogycemia; LD50=mg/kg (orally in rat)
Dose

Initial dose:
-Patients without congestive heart failure: 15 mg or 30 mg orally once a day
-Patients with congestive heart failure (New York Heart Association [NYHA] Class I or II): 15 mg
orally once a day
Maintenance dose: 15 mg to 45 mg orally once a day based on glycemic response as
determined by HbA1c
Maximum dose: 45 mg orally once a day
Comments:
-This drug can be taken without regard to meals.
50
Use: As an adjunct to diet and exercise to improve glycemic control in adults with type 2
diabetes mellitus in multiple clinical settings
Side effects
Swelling of the legs and ankles
Abnormal vision
Weight gain
Reduced sense of touch
Chest infection
Decrease in red blood cell count
Joint pain
Headache
Abnormal urine tests (blood in urine)
Difficulty with having or maintaining an erection (impotence)
Dizziness
Back pain
Inflammation of the sinuses (sinusitis)
Difficulty sleeping
Wind (flatulence)
Tiredness
Increase in appetite
Low blood sugar (hypoglycaemia)
Abnormal urine tests (sugar in urine, protein in urine)
Sweating
Swelling to the back of the eye causing blurred vision (macular oedema)
Eye disorders
Shortness of breath
Heart failure
Abnormal blood tests (increases in liver enzymes)
Broken bones in women
51
DPP4 inhibitors-Sitagliptin
For use as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes
mellitus. Also for use in patients with type 2 diabetes mellitus to improve glycemic control in combination with
metformin or a PPAR agonist (e.g., thiazolidinediones) when the single agent alone, with diet and exercise,
does not provide adequate glycemic control.
Pharmacodynamics
Sitagliptin is an orally-active member of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs. The
benefit of this medicine is expected to be its lower side-effects of hypoglycemia in the control of blood glucose
values. The drug works to diminish the effects of a protein/enzyme (by the inhibition of this protein/enzyme)
on the pancreas at the level of release of glucagon (diminishes its release) and at the level of insulin
(increases its synthesis and release) until blood glucose levels are restored toward normal, in which case the
protein/enzyme-enzyme inhibitor becomes less effective and the amounts of insulin released diminishes thus
diminishing the "overshoot" of hypoglycemia seen in other oral hypoglycemic agents.
Mechanism of action
Sitagliptin is a highly selective DPP-4 inhibitor, which is believed to exert its actions in patients with
type 2 diabetes by slowing the inactivation of incretin hormones, thereby increasing the
concentration and prolonging the action of these hormones. Incretin hormones, including glucagon-
like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the
intestine throughout the day, and levels are increased in response to a meal. These hormones are
rapidly inactivated by the enzyme, DPP-4. The incretins are part of an endogenous system involved in
the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal
or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by
intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from
pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging
active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in the
circulation in a glucose-dependent manner. These changes lead to a decrease in hemoglobin A1c
(HbA1c)levels, as well as a lower fasting and postprandial glucose concentration. Sitagliptin
demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at
concentrations approximating those from therapeutic doses.
Absorption
Rapidly absorbed following oral administration, with an absolute bioavailability of 87%.
198 L [healthy subjects]
Protein binding
The fraction of sitagliptin reversibly bound to plasma proteins is low (38%).
Metabolism
Sitagliptin does not undergo extensive metabolism. In vitro studies indicate that the primary enzyme
responsible for the limited metabolism of sitagliptin was CYP3A4 (oxidation), with contribution from CYP2C8.
52
Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor
pathway of elimination. Following administration of an oral [14C]sitagliptin dose to healthy subjects,
approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%)
within one week of dosing. Elimination of sitagliptin occurs primarily via renal excretion and involves
active tubular secretion.
Half life
12.4 hours
Clearance
renal cl=350 mL/min [Healthy subjects receiving 100 mg oral dose]
Toxicity
Not Available
Dose

Usual dose: 100 mg orally once a day
Comments: When used in combination with an insulin secretagogue (e.g. sulfonylurea) or

insulin, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of
hypoglycemia.
Use: As an adjunct to diet and exercise to improve glycemic control in patients with type 2
diabetes mellitus.
Side effects
Low blood sugar
Constipation
Headache
Weight loss
Loss of appetite
Stomach pain
Diarrhoea
Drowsiness
Dizziness
Cough
53
Vomiting
Fungal skin infection
Chest infection
Swelling of the legs and ankles (due to fluid retention)
Swelling of the feet
Wind (flatulence)
Sore throat
Blocked or runny nose
Pain in the arms and legs
Osteoarthritis
Allergic reaction including rash, hives, swelling of the face, lips, tongue and throat, and
difficulty breathing or swallowing
GLP-1 receptor agonist-Exenatide

Indicated as adjunctive therapy to improve glycemic control in patients with Type 2 diabetes mellitus who are
taking metformin, a sulfonylurea, or a combination of both, but have not achieved adequate glycemic control.
Pharmacodynamics
Exenatide is an incretin mimetic, which has glucoregulatory effects. While it is has blood-sugar lowering
actions alone, it can also be combined with other medications such as pioglitazone, metformin, sulfonylureas,
and/or insulin to improve glucose control. The approved use of exenatide is with either sulfonylureas,
metformin and thiazolinediones. The medication is injected twice per day using a pre-filled pen device. Typical
human responses to exenatide plus eating include improvements in the initial rapid release of endogenous
insulin, suppression of glucagon release by the pancreas, regulation of gastric empyting and reduced
appetite; all behaviors more typical of individuals without blood sugar control problems. Exenatide is self-
regulating in that in lowers blood sugar when levels are elevated but does not continue to lower blood sugar
when levels return to normal, unlike with sulfonylureas or insulins.
Mechanism of action
Exenatide is a functional analog of the human incretin Glucagon-Like Peptide-1 (GLP-1). Incretins
enhance glucose-dependent insulin secretion and exhibit other antihyperglycemic actions following
their release into the circulation from the gut. The GLP-1 system increases insulin secretion only in
the presence of elevated plasma glucose levels, avoiding inappropriately high insulin levels during
fasting. The drug also moderates peak serum glucagon levels during hyperglycemic periods following
meals, but does not interfere with glucagon release in response to hypoglycemia. Secondary effects
of drug administration reduces the rate of gastric emptying and decreases food intake, mitigating the
potential severity of hyperglycemic events after meals.
Absorption
Following subcutaneous administration to patients with type 2 diabetes, exenatide reaches median
peak plasma concentrations in 2.1 hours.
54
28.3 L
Protein binding
n/a
Metabolism
n/a
Nonclinical studies have shown that exenatide is predominantly eliminated by glomerular filtration
with subsequent proteolytic degradation.
Half life
Mean terminal half-life is 2.4 hours.
Clearance
Apparent cl=9.1 L/hr
Toxicity
Effects of the overdoses included severe nausea, severe vomiting, and rapidly declining blood
glucose concentrations.
Dose

Immediate-release:
-Initial dose: 5 mcg subcutaneously twice a day for at least 1 month
-Maintenance dose: Based on clinical response, may increase to 10 mcg subcutaneously twice
a day
-Maximum dose: 10 mcg twice a day
-Administer within the 60-minute period before the morning and evening meals; alternatively,
may give before the two main meals of the day provided dosing is 6 hours or more apart; do not
administer after a meal.
Extended-release:
-Dose: 2 mg subcutaneously once every seven days; administer at any time of day, with or
without meals
-Patients may switch from immediate-release to extended-release, although prior treatment with
immediate-release exenatide is not necessary.
-For patients who do switch, discontinue immediate-release exenatide on initiation of extended-
release; transient elevations in blood glucose may occur and generally improve within the first 2
weeks of initiation.
Comments:
55
-For patients concomitantly receiving a sulfonylurea, a lower dose of the sulfonylurea may be
required to reduce the risk of hypoglycemia.
Use: As an adjunct to diet and exercise to improve glycemic control in adults with type 2
diabetes mellitus
Side effects
Incidence not known: Agitation
bloated or full feeling
chills
coma
confusion
constipation
cough
darkened urine
decreased urination or urine output
depression
difficulty with swallowing
dizziness
dry mouth
fainting
fast heartbeat
fever
headache
hives or welts, itching, or skin rash
hostility
increase in heart rate
indigestion
irritability
large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex
organs
lethargy
56
lightheadedness
loss of appetite
muscle twitching
nausea
pains in the stomach, side, or abdomen, possibly radiating to the back
puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
rapid breathing
rapid weight gain
seizures
shortness of breath
stupor
sunken eyes
swelling of the face, ankles, or hands
thirst
tightness in the chest
unusual tiredness or weakness
vomiting
wrinkled skin
yellow eyes or skin
SGLT-2 inhibitors-Dapaglifloxin
Dapagliflozin is indicated for adjunct management of glycemic control in patients with type 2 diabetes mellitus,
in combination with diet and exercise.
Pharmacodynamics
Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in patients
with type 2 diabetes mellitus following the administration of dapagliflozin. A Dapagliflozin dose of 10 mg per
day in patients with type 2 diabetes mellitus for 12 weeks resulted in excretion of approximately 70 grams of
glucose in the urine per day at week 12. A near maximum glucose excretion was observed at the
dapagliflozin daily dose of 20 mg. This urinary glucose excretion with dapagliflozin also results in increases in
urinary volume.
Mechanism of action
A competitive inhibitor of the sodium-glucose transport subtype 2 protein, dapagliflozin blocks
glucose reabsorption into the kidney, resulting in the elimination of blood glucose through the urine.
57
Absorption
Cmax is about 1 hour. (Obtained from 6 adult men in a fasted state administered a 50mg dose). 1.6%
of unchanged dapagliflozin was found in the urine. A high-fat meal (52% caloric content) had no
significant effect on previous pharmacokinetic parameters.
n/a
Protein binding
91%.
Metabolism
Dapagliflozin 3-O-glucuronide is the primary metabolite of dapagliflozin, with 61% of the dapagliflozin
dose recovered in the urine as this metabolite. The metabolism of dapagliflozin is primarily mediated
by UGT1A9-dependent glucuronide conjugation. The major metabolite, dapagliflozin 3-O-glucuronide,
is not an SGLT2 inhibitor.
n/a
Half life
13.8 hours with the consumption of a 50 mg dose.
Clearance
Oral plasma clearance of 4.9 mL/min/kg, and a renal clearance of 5.6 mL/min.
Toxicity
Compared to placebo-treated patients, patients with moderate renal impairment treated with
dapagliflozin did not have improvement in glycemic control and had more renal-related adverse
reactions and more bone fractures; therefore, dapagliflozin should not be initiated in this population.
Based on its mechanism of action, dapagliflozin is not expected to be effective in patients with severe
renal impairment (eGFR less than 30 mL/min/1.73 m2) or ESRD.
Dose

Maximum dose: May increase to 10 mg orally once a day in patients tolerating therapy with 5
mg and requiring additional glycemic control
Comments:
-If used in combination with insulin or an insulin secretagogue, a lower dose of insulin or the
insulin secretagogue should be considered to reduce the risk of hypoglycemia.
58
Use: As an adjunct to diet and exercise to improve glycemic control in patients with type 2
diabetes mellitus.
Side effects
More common:
Anxiety
bladder pain
bloody or cloudy urine
blurred vision
chills
cold sweats
coma
confusion
cool, pale skin
decreased frequency or amount of urine
depression
difficult, burning, or painful urination
dizziness
fast heartbeat
frequent urge to urinate
headache
increased hunger
increased thirst
itching of the vagina or genitals
loss of appetite
lower back or side pain
nausea
nightmares
seizures
shakiness
slurred speech
swelling of the face, fingers, or lower legs
thick, white vaginal discharge with mild or no odor
troubled breathing
59
vomiting
weight gain
Less common:
Foul smelling discharge from the penis
pain in the skin around the penis
rash of the penis
redness, itching, or swelling of the penis
Rare:
Cough
dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting
position
dry mouth
fainting
increase in heart rate
large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex
organs
lightheadedness
rapid breathing
skin rash, hives, or itching
sunken eyes
sweating
wrinkled skin
Insulins
rapid- Humalog
For the treatment of Type 1 or 2 diabetes mellitus. To be used in conjunction with an intermediate or long-
acting insulin except when used in a continuous insulin infusion pump.
Pharmacodynamics
Insulin is a natural hormone produced by beta cells of the pancreas. In non-diabetic individuals, a basal level
of insulin is supplemented with insulin spikes following meals. Increased insulin secretion following meals is
responsible for the metabolic changes that occur as the body transitions from a postabsorptive to absorptive
state. Insulin promotes cellular uptake of glucose, particularly in muscle and adipose tissues, promotes
60
energy storage via glycogenesis, opposes catabolism of energy stores, increases DNA replication and protein
synthesis by stimulating amino acid uptake by liver, muscle and adipose tissue, and modifies the activity of
numerous enzymes involved in glycogen synthesis and glycolysis. Insulin also promotes growth and is
required for the actions of growth hormone (e.g. protein synthesis, cell division, DNA synthesis). Insulin lispro
is a rapid-acting insulin analogue used to mimic postprandial insulin spikes in diabetic individuals. The onset
of action of insulin lispro is 10-15 minutes. Its activity peaks 60 minutes following subcutaneous injection and
its duration of action is 4-5 hours. Compared to regular human insulin, insulin lispro has a more rapid onset of
action and a shorter duration of action. Insulin lispro is also shown to be equipotent to human insulin on a
molar basis.
Mechanism of action
Insulin lispro binds to the insulin receptor (IR), a heterotetrameric protein consisting of two
extracellular alpha units and two transmembrane beta units. The binding of insulin to the alpha
subunit of IR stimulates the tyrosine kinase activity intrinsic to the beta subunit of the receptor. The
bound receptor autophosphorylates and phosphorylates numerous intracellular substrates such as
insulin receptor substrates (IRS) proteins, Cbl, APS, Shc and Gab 1. Activation of these proteins leads
to the activation of downstream signaling molecules including PI3 kinase and Akt. Akt regulates the
activity of glucose transporter 4 (GLUT4) and protein kinase C (PKC), both of which play critical roles
in metabolism and catabolism. In humans, insulin is stored in the form of hexamers; however, only
insulin monomers are able to interact with IR. Reversal of the proline and lysine residues at positions
B28 and B29 of native insulin eliminates hydrophobic interactions and weakens some of the
hydrogen bonds that contribute to the stability of the insulin dimers that comprise insulin hexamers.
Hexamers of insulin lispro are produced in the presence of zinc and m-cresol. These weakly
associated hexamers quickly dissociate upon subcutaneous injection and are absorbed as
monomers through vascular endothelial cells. These properties give insulin lispro its fast-acting
properties.
Absorption
Rapidly absorbed following subcutaneous administration. It is also absorbed more quickly than
regular human insulin. Peak serum levels occur 30-90 minutes after injection in healthy subjects.
Absorption also differs depending on the site of injection. After insulin lispro was administered in the
abdomen, serum drug levels were higher and the duration of action was slightly shorter than after
deltoid or thigh administration. Bioavailability, 0.1 - 0.2 unit/kg = 55% - 77%.
When administered intravenously as bolus injections of 0.1 and 0.2 U/kg dose in two separate groups of
healthy subjects, the mean volume of distribution of insulin lispro appeared to decrease with increase in dose
(1.55 and 0.72 L/kg, respectively).
Protein binding
n/a
Metabolism
Insulin is predominantly cleared by metabolic degradation via a receptor-mediated process.
61
n/a
Half life
SubQ administration = 1 hour
Clearance
Clearance is dose dependent. When a dose of 0.1 unit/kg and 0.2 unit/kg were administered intravenously,
the mean clearance was 21.0 mL/min/kg and 9.6 mL/min/kg respectively.
Toxicity
Inappropriately high dosages relative to food intake and/or energy expenditure may result in severe
and sometimes prolonged and life-threatening hypoglycemia. Neurogenic (autonomic) signs and
symptoms of hypoglycemia include trembling, palpitations, sweating, anxiety, hunger, nausea and
tingling. Neuroglycopenic signs and symptoms of hypoglycemia include difficulty concentrating,
lethargy/weakness, confusion, drowsiness, vision changes, difficulty speaking, headache, and
dizziness. Mild hypoglycemia is characterized by the presence of autonomic symptoms. Moderate
hypoglycemia is characterized by the presence of autonomic and neuroglycopenic symptoms.
Individuals may become unconscious in severe cases of hypoglycemia. Rare cases of lipoatrophy or
lipohypertrophy reactions have been observed.
Side effects
Severity: Major
You should check with your doctor immediately if any of these side effects occur when
taking insulin lispro:
More common:
Anxious or nervous feeling

behavior change similar to being drunk
blurred vision
cold sweats
confusion or difficulty thinking
convulsions (seizures)
depression
dizziness or lightheadedness
drowsiness
excessive hunger
fast heartbeat
fever or chills
headache
irritability or abnormal behavior
62
lower back or side pain
nightmares
painful or difficult urination
restless sleep
shakiness
slurred speech
tingling in the hands, feet, lips, or tongue
unconsciousness
Less common:
Dry, red, hot, or irritated skin
Less common or rare:
Depression of the skin at the injection site
dryness of the mouth
fast or weak pulse
itching, redness, or swelling at the injection site
muscle cramps or pain
nausea or vomiting
skin rash or itching over the whole body
sweating
thickening of the skin at the injection site
trouble breathing
Incidence not known:
Bloating or swelling of the face, arms, hands, lower legs, or feet
decreased urine
dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
fast, pounding, or irregular heartbeat or pulse
hives or itching skin
redistribution or accumulation of body fat
unusual weight gain or loss
63
Intermediate-Humulin I
Pharmacodynamics
Mechanism of action
Absorption
Protein binding
Metabolism
Half life
Clearance
Toxicity
Dose
Side effects
Long-Glargine
Pharmacodynamics
64
Mechanism of action
Absorption
Protein binding
Metabolism
Half life
Clearance
Toxicity
Dose
Side effects
BD mix- Novomix 30
Pharmacodynamics
65
Mechanism of action
Absorption
Protein binding
Metabolism
Half life
Clearance
Toxicity
Dose
Side effects
Steroids
Betamethasone
Pharmacodynamics
66
Mechanism of action
Absorption
Protein binding
Metabolism
Half life
Clearance
Toxicity
Dose
Side effects
Deflazacort
Pharmacodynamics
67
Mechanism of action
Absorption
Protein binding
Metabolism
Half life
Clearance
Toxicity
Dose
Side effects
Dexamethasone
Pharmacodynamics
68
Mechanism of action
Absorption
Protein binding
Metabolism
Half life
Clearance
Toxicity
Dose
Side effects
Hydrocortisone
Pharmacodynamics
69
Mechanism of action
Absorption
Protein binding
Metabolism
Half life
Clearance
Toxicity
Dose
Side effects
Methylprednisolone,
Pharmacodynamics
70
Mechanism of action
Absorption
Protein binding
Metabolism
Half life
Clearance
Toxicity
Dose
Side effects
Prednisolone
Pharmacodynamics
71
Mechanism of action
Absorption
Protein binding
Metabolism
Half life
Clearance
Toxicity
Dose
Side effects
72
Fludrocortisone acetate
Pharmacodynamics
Mechanism of action
Absorption
Protein binding
Metabolism
Half life
Clearance
Toxicity
Dose
Side effects
Antidepressants
Citalopram
Pharmacodynamics
73
Mechanism of action
Absorption
Protein binding
Metabolism
Half life
Clearance
Toxicity
Dose
Side effects
Fluoxetine
Pharmacodynamics
74
Mechanism of action
Absorption
Protein binding
Metabolism
Half life
Clearance
Toxicity
Dose
Side effects
Fluoxetine
Pharmacodynamics
75
Mechanism of action
Absorption
Protein binding
Metabolism
Half life
Clearance
Toxicity
Dose
Side effects
Phenalzine
Pharmacodynamics
76
Mechanism of action
Absorption
Protein binding
Metabolism
Half life
Clearance
Toxicity
Dose
Side effects
Amitriptyline
Pharmacodynamics
77
Mechanism of action
Absorption
Protein binding
Metabolism
Half life
Clearance
Toxicity
Dose
Side effects
http://www.drugbank.ca/drugs/DB00945
http://drugs.webmd.boots.com/drugs/drug-316-Morphine+Sulphate.aspx?
drugid=316&drugname=Morphine%2bSulphate&source=1&isTicTac=false
http://www.drugs.com/sfx/morphine-side-effects.htm
78

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Analgesics

Diclofenac free acid capsules: 35 mg orally 3 times a day

Diclofenac sodium extended-release tablets: 100 mg orally once a day

Use: For the relief of signs and symptoms of osteoarthritis.

Usual Adult Dose for Dysmenorrhea

Diclofenac potassium immediate-release tablets: 50 mg orally 3 times a day

Use: For the relief of signs and symptoms of primary dysmenorrhea.

Usual Adult Dose for Rheumatoid Arthritis

Diclofenac potassium immediate-release tablets: 50 mg orally 3 or 4 times a day

Diclofenac sodium extended-release tablets: 100 mg orally once a day

For the relief of signs and symptoms of rheumatoid arthritis

Usual Adult Dose for Migraine

Diclofenac potassium for oral solution packets: 50 mg (1 packet) orally once

Use: For acute treatment of migraine with or without aura.

Usual Adult Dose for Pain

20% bound to plasma proteins.

5.9 mL/min/Kg [Healthy Adults, 100 mg qid, MD p.o]

8.5 mL/min/Kg [Healthy Adults, 100 mg SD p.o]

6.89 mL/min/Kg [Geriatric, (<75 yr), 50 mg SD p.o.]

4.23 mL/min/Kg [Hepatic Impaired, 50 mg SD p.o.]

4.23 mL/min/Kg [Renal Impaired, Clcr10-3mL/min, 100 mg SD i.v.]

3.73 mL/min/Kg [Renal Impaired, CLcr<5 mL/min, 100 mg SD i.v.]

6.4 mL/min/Kg [Male following a 100 mg IV dose]

LD50=350mg/kg (orally in mice)

For the relief and treatment of severe pain.

Bioavailability is approximately 30%.

1852 +/- 116 mL/min [Chinese]

1495 +/- 80 mL/min [Caucasian]

Immediate release tablets:

IV:-For relief of pain and as preanesthetic:

Usual Adult Dose for Osteoarthritis

Usual Adult Dose for Rheumatoid Arthritis

Usual Adult Dose for Systemic Lupus Erythematosus

Usual Adult Dose for Fever

Usual Adult Dose for Pain

Usual Adult Dose for Rheumatic Fever

80 mg/kg/day orally in 4 equally divided doses, up to 6.5 g/day.

Usual Adult Dose for Myocardial Infarction

Usual Adult Dose for Ischemic Stroke

50 to 325 mg orally once a day. Therapy should be continued indefinitely.

Usual Adult Dose for Angina Pectoris

Usual Adult Dose for Angina Pectoris Prophylaxis

75 mg to 325 mg orally once a day, continued indefinitely.

Usual Adult Dose for Thromboembolic Stroke Prophylaxis

75 mg to 325 mg orally once a day, continued indefinitely.

Usual Adult Dose for Myocardial Infarction - Prophylaxis

75 mg to 325 mg orally once a day, continued indefinitely.

75 mg to 325 mg orally once a day, continued indefinitely.

Usual Adult Dose for Revascularization Procedures - Prophylaxis

For coronary artery bypass graft (CABG):

For percutaneous transluminal coronary angiography (PTCA):

For carotid endarterectomy:

Commonly: Dyspepsia (indigestion), feeling sick (nausea), vomiting.

Usual Adult Dose for Acute Coronary Syndrome

ST-Elevation Myocardial Infarction (STEMI):

Uses: Prevention of atherothrombotic events in patients with non-ST-segment elevation acute

Usual Adult Dose for Ischemic Stroke

Uses: Prevention of atherothrombotic events in patients with a history of recent myocardial

Usual Adult Dose for Myocardial Infarction

Uses: Prevention of atherothrombotic events in patients with a history of recent myocardial

Usual Adult Dose for Peripheral Arterial Disease

Glyceryl trinitrate (GTN)

For the prevention of angina