PEDIATRICS II

Pediatric Therapeutics EXIMIUS

Dean Ramirez, MD September 2019 2021
DEVELOPMENTAL PHARMACOLOGY C. Risks to the patient
- A Physician must possess a basic understanding of the
factors affecting variability of pharmacologic effects and Proven Teratogens (High Risk)
pharmacokinetics of drugs at different stages of the child’s
Drug Defect
development.
Antineoplastic Agents: - Hydrocephalus
- He must foresee the possible adverse effects of drugs on
(Antimetabolites) - MeningoencephalocoeleCl
maturation and development of the child.
a. Aminopterin eft palate /lip

b. Methotrexate - Anencephaly
Interference of Drugs with Normal Development

- The drug effects may not be seen grossly but may exert its
(Alkylating)
effect at the biochemical level, causing great harm to the - Hand and feet defects
a. Cyclophosphamide
young, as this may later lead to behavioral and mental - bilateral inguinal hernia

maldevelopment. - Hard palate grooves on

- E.g. hormonal agents each uvula


Sex hormones - Neural tube defects and
Drugs Affecting Maturation, Development and Behavior
o Clomiphene other fetal abnormalities
- Antihypertensives
o Methyltestosterone - Masculinization of female
o Beta adenoreceptor blockers o 17-ethynyl-19 fetus
§ Intrauterine growth retardation
nortestosterone
- Antimicrobial
o 17-ethinyl testosterone
o Tetracyclines
Sedatives - Extremities: amelia,
§ Retarded bone growth
Thalidomide phocomelia, hemimelia
Radiocontrast media
- Skeleton: rudimentary
o (Diatrizoate,Ethiodized oil,metrizamide)
scapula and maldeveloped
§ Impaired thyroid function
sacrum

- Digestive tract: esophageal
GENERAL CARE OF THE PATIENT
atresia, duodenum, anus,
Caring for children
renal agenesis, GUT abn
- Illness can be frightening and unpleasant
Alcohol - Fetal alcohol syndrome:
They should be told about their illness
microcephaly, short
Parents need objective advice from the physician
palpebral fissures, maxillary
Parents have a legal and ethical right to be informed of the
hypoplasia, prognathism,
benefits and risks of therapy and to be included in the
joint anomalies, post natal
decision-making
growth deficiency and

developmental delay.
PRINCIPLES OF THERAPEUTICS
Cigarette Smoking - Growth retardation:
- Therapeutic intervention is either irrelevant or worse.
increased spontaneous
Before intervention is made, consider:
abortion and perinatal
• accuracy of diagnosis
mortality
• effectiveness of therapies
Vitamin A Derivatives - Syndrome: Absent or low
• risks to the patient
a. Etretinate set ears; CHD;
• discomfort to the patient
b. Isoretinoic Acid microcephaly;
• costs hydrocephalus; facial
A. Accuracy of diagnosis dysmorphia
- A working diagnosis should be constantly reassessed.
- No therapy should be completed because it has been Proven Teratogens (Low Risk)
started.
Drug Defect
- The most common error in diagnosis is attributing
Antibiotics
pathogenicity to an associated but not causative finding.
Streptomycin Impaired hearing
- When a dx depends on a lab test, one should make sure of
Anti-cancer Agents
the accuracy of that test in that laboratory.
- Alkylating agents
- It is prudent to obtain the results of diagnostic tests first
o Busulfan Absent kidney and ureters
hand.
o Chlorambucil
B. Effectiveness of therapies
Septal defects in the heart,
- Few therapeutic regimens are completely effective in all
- Metaphase inhibitors extra thumb and radius,
cases.
o Podophyllum(sli malformed ear, skin tags(ear
- “Cures” are usually a combination of therapy and the
mming tablets and cheeks
patient’s own defenses.
and stool
- The general application of an effective technique is not
softener)
necessarily appropriate in all cases.


TRANSCRIBERS WILMA, JOSH, MARK 1

 PEDIATRICS II
Pediatric Therapeutics EXIMIUS
Dean Ramirez, MD September 2019 2021
Anti-coagulant Possible Teratogens
- Coumadin Nasal hypoplasia, abnormal Drug Defect
terminal phalanges, dysplastic Anticonvulsants
nails Diazepam Cleft lip,cleft palate
Anticonvulsants Antithyroid Drugs
- Diphenylhydantoin Fetal hydantoin syndrome: - Carbimazole Aplasia cutis(scalp
craniofacial abnormalities- defects),goiter
broad, low nasal ridge,
epicanthic folds, short - Methimazole Goiter
upturned nose, hypertelorism,
ocular abnormalities, - Potassium iodide Goiter
prominent and slightly Corticosteroids Cleft palate
malformed ears, wide mouth Hallucinogen
with prominent lips, variations - LSD(Lysergic acid Chromosomal damage
in head size and shape with diethylamide)
sutural ridging or wide
fontanels; alterations in - Phencyclidine Skeletal defects
growth or mental deficiencies Psychotropic Drugs
Anti-epileptic Drugs Lithium Clubfoot
- Carbamazepine Cranial defects, finger nail Antimicrobials
hypoplasia and developmental - Pyrimethamine Cleft palate
delay
- Trimethoprim Cleft palate
- Valproic acid Neural tube defects,
microcephaly, cardiac - Rifampicin Cleft palate,spina bifida
abnormalities, varied minor
bony and soft tissue
abnormalities
Adverse Perinatal Effects of drugs

Drug Defect
- Trimethadione Fetal trimethadione syndrome-
Analgesic-antipyretic
low set ears, cleft lip or palate;
mental retardation, V-shaped - Acetophenetidin Methemoglobinemia
eyebrows; teeth irregularities - Salicylates Hemolysis, platelet
dysfunction; decreased factor

XII; fetal death


Anti malarials
- Quinacrine Agenesis of the kidneys; Anesthetics Neonatal depression
Hydronephrosis; Spina bifida - General;barbiturates Methemoglobinemia
- Local-Mepivacaine, Bradypnea;bradycardia;convul

Procaine sion;Methemoglobinemia
Abnormal retinal
- Chloroquine pigmentation, Bilateral
vestibular paresis Anticoagulants
Sedatives - Coumarine Hemorrhage; perinatal death

- Bromides Polydactily, GI malformations,
- Phenindiones Hemorrhage or hematoma
clubfoot, congenital hip
dislocation
Sex hormones Anti-epileptics
- Phenytoin Vitamin K related coagulation
- Danazol Virilization of female fetus
defect


Virilization of fetus and other
- Hormone pregnancy tests congenital abnormalities - Primidone Neonatal bleeding

- Sodium valproate Increased incidence of
Masculinization of female
neonatal jaundice
- Progesterone fetus

Vaginal adenocarcinoma Anti-diabetics
- Stilbestrol(DES) - Insulin Perinatal death


- Sulfonylureas Perinatal death;

thrombocytopenia; severe
hypoglycemia

TRANSCRIBERS WILMA, JOSH, MARK 2

 PEDIATRICS II
Pediatric Therapeutics EXIMIUS
Dean Ramirez, MD September 2019 2021
Antihistamines Mental and Behavioral Development
- Diphenhydramine Generalized tremulousness; o Infants born to mothers who were on phenytoin
diarrhea therapy during pregnancy –failure to thrive;
o slow mental development
- Hydroxyzine Hypotonia; myoclonic jerks - Alcoholic mothers - low birth weight babies, metabolic
disturbances in the neonates; learning difficulties later
Antihypertensive agents - Mothers on antidepressant drugs- babies have slow
Beta adenoreceptor blockers Intrauterine growth adaptation to breastfeeding, diminished attentiveness,
retardation prolonged period of disorganized activity
Antimicrobial
Tetracycline Retarded bone growth Other drugs that interfere with Normal Development
Sedatives, hypnotic, tranquilizers: Post natal growth retardation - Anti cancer agents-Anti metabolites such as
- Alcohol Slow mental development methotrexate,5 fluorouracil, cyclophosphamide,
cyclosporine
Anticonvulsant(Phenytoin, Slow mental development - Anticoagulants-Phenindione
trimethadione, Paramethadione) - Anti-depressants Amytriptylline, amoxapine, desipramine,
Barbiturates, mephrobamate, Decreased adaptive and fluoxetin, imipramine, trazodone
minor tranquilizers, learning capacity; decreased - Antihistamine - Clemastine, diphenhydramine
antidepressants, drug of abuse somatic growth - Antipsychotic agents Haloperidol, chlorpromazine and
other phenothiazines
Steroids Virilization; advanced bone - Antithyroid agents – Thiouracils
Androgens age - Cathartics- Phenolphthalein
Estrogens Feminization of male - Drugs of abuse: Amphetamine, cocaine, heroin,
marijuana, nicotine, phencyclidine
Diethylstilbestrol Adenocarcinoma of vagina - Ergot alkaloids-Bromocriptine,ergotamine
- H2 receptor blocker-Cimetidine
Stimulants Poor weight gain and height; - Radioactive drugs
- Amphetamine; reversible and with catch-up - Vitamin D
Dextroamphetamine; growth upon cessation of
Methylphenidate therapy DRUGS CONTRAINDICATED TO BREASTFEEDING
1. Alcohols
Thyroid agents 2. Analgesics(Opiates )
- Iodides Goiter 3. Anti-anxiety drugs(diazepam and other benzodiazepines)
4. Antimicrobials-Ciprofloxacin and other
- Thioureas, methimazole Goiter, hypothyroidism fluoroquinolones;Metronidazoles and other imidazoles;
Vitamin A excess Retardation of bone growth Trimethoprim
with early closure of epiphysis 5. Chloramphenicol
6. Tetracyclines
Cigarette smoking Low birth weight, fetal growth

retardation, minimal cerebral
dysfunction, abnormal reading
DEVELOPMENTAL PHARMACOKINETICS AND
retardation; SIDS
PHARMACODYNAMICS

Developmental pharmacokinetics

INTERFERENCE OF DRUGS WITH NORMAL DEVELOPMENT - the study of the processes of drug absorption, distribution,
- Drugs may exert its effect at the biochemical level, causing protein binding, metabolism and excretion at different
great harm to the young as this later lead to behavioral stages of development.
and mental maldevelopment.
- Ex. Hormonal agents-adverse effect on linear growth and ABSORPTION
skeletal maturation Absorption of a drug is dependent on 2 main factors:
- Tetracyclines - deposited in the epiphyses, inhibiting 1. characteristics of the drug or active ingredient such as
growth; causes enamel hypoplasia and teeth discoloration lipid solubility,molecular size, degree of ionization and
concentration and the inactive components of the
Sexual development formulation affecting its disintegration time and /or
- Administration to the pregnant woman of androgens, dissolution rate
progestins and stilbestrol can produce varied genital 2. Host factors such as the state of the absorbing surface,
changes on the fetus depending on the stages of fetal blood flow of the area and for orally administered drug,
development, e.g. clitoral enlargement when given after the gastro-intestinal peristalsis.
the stage of complete differentiation of sexual organs.
- Pseudo hermaphroditism –when given to the mother
during first few weeks of gestation

TRANSCRIBERS WILMA, JOSH, MARK 3

 PEDIATRICS II
Pediatric Therapeutics EXIMIUS
Dean Ramirez, MD September 2019 2021
PHYSIOLOGIC DIFFERENCES IN THE GIT OF CHILDREN o Drugs that can displace bilirubin from albumin
A. Gastrointestinal Absorption binding sites: Sulfonamides, diazepam, caffein,
- Gastric pH at birth-alkaline salicylates, mefenamic acid, phenytoin, valproic
- After 24 hours- acidic acid.
- Gastric emptying time –delayed in neonates and infants o Toxicity of drugs in neonates is aggravated by
th
until the 6-8 month of life greater passage of most drugs through:
- Absorbing surface of GIT in neonates-reduced, poor 1. Blood-brain barrier
absorption in infants of orally administered antibiotics 2. Blood-ocular barrier
Other physiologic differences in the GIT of children
- Sterile intestinal tract in neonate. Absence of bacteria may Factors Facilitating passage of drugs in neonate and infants:
affect the intestinal absorption of drugs requiring prior 1. Incomplete anatomic development of the barrier
hydrolysis. 2. Increased permeability of the membrane
- Biliary function is not fully developed in neonates such 3. Incomplete myelinization in the brain
that drugs which undergo biliary secretion and entero- 4. Acidosis
hepatic reabsorption will show altered absorption. 5. Hypoglycemia
- Blood flow in the intestinal smooth muscle of neonates is
decreased. DRUG METABOLISM
Metabolism
B. Percutaneous Absorption - Is the mechanism by which the chemical or drug is altered
- Drugs and chemicals in are percutaneously absorb more in usually converting these substances into more polar and
neonates and infants. When applied topically, some drugs more water soluble compounds to facilitate excretion.
has systemic adverse effects: most antibiotics,
corticosteroids, hexachlorophene, boric acid and aniline 2 Phases of Drug Metabolism
dyes. A. Phase 1 Reactions
- may activate or inactivate the drug/ chemical by
C. Parenteral Absorption processes of oxidation, reduction and hydroxylation
- Neonates showed unstable peripheral circulation and - Oxidation: leads to removal from or attachment to drugs
altered rate of parenteral drug absorption. such as hydroxyl, amino, hydrogen, alkyl or halogen groups
- Subcutaneous and IM administration resulted in erratic - Hydrolysis: involves the splitting of water or amide
absorption but faster rate. linkages
- Reduction: reactions result in the conversion of nitro- or
D. Rectal Absorption azo-compounds into amino group.
- More used in children. It can result in efficacy equal to that - Cytochrome P450-most drugs are metabolized
of oral route but with delayed absorption and onset of - Birth- cytochrome P450 content of the liver is 28% of adult
effect. - Monooxygenase activity is decreased by 50% of the adult
- In the neonate-hydroxylation and oxidation are depressed.
E. Inhalational Absorption - Drugs such as mephobarbital which have to be oxidized to
phenobarbital will not be very effective in neonates.
- The inhalational route for the therapy of reactive airway
disease in infants and children are effective. B. Phase II metabolism
- results in conjugation and inactivation of drug through
DRUG DISTRIBUTION glucuronidation, glycine coupling or sulphation.
- In term infants: Total Body Water: 80%, due to higher ECF - Deficient glucuronidation and glycine conjugation result in
volume, more in preterm (50%), infants 6-8months greater toxicity in neonates and infants of many drugs
(35%),after 1 year(20-25%). such as salicylates, chloramphenicol and para-
o Sulfonamides- mainly distributed in body water aminobenzoic acid.
in preterms.
RENAL ELIMINATION
- Protein Binding - Processes of Renal Elimination
1. glomerular filtration
o Neonates and infants exhibit lower protein
2. tubular reabsorption
binding of drugs due to:
3. tubular secretion
1. lower levels of albumin
2. presence of fetal albumin - Neonates –GFR and effective renal plasma flow is only 30-
40% of the adult
3. presence of endogenous substances wich
- Tubular secretion is decreased by 70-80%
compete for protein binding sites th
- 17 day of life- improved renal function
4. increased capacity of neonatal protein
binding with bilirubin. - Tubular excretion result of increased rate of elimination of
Penicillin and dreivatives, cephalosporins and
o Increased capacity of neonatal protein to bind
aminoglycosides
with bilirubin is a protective mechanism
- Tubular secretion takes longer to mature
preventing diffusion of free bilirubin to the brain
- Tubular reabsorption of Na, Cl, amino acid, and glucose is
(kernicterus).
increased in the newborn.
TRANSCRIBERS WILMA, JOSH, MARK 4

 PEDIATRICS II
Pediatric Therapeutics EXIMIUS
Dean Ramirez, MD September 2019 2021
Effect of Disease states on Drug kinetics Penicillin G and Penicillin V
a. Renal Failure - Pen G- drug of choice for infections due to :
- Most important pathologic states that require 1. Gram-positive cocci such as
modification of drugs since most drugs are eliminated streptococci,susceptible pneumococci and
through the renal route. susceptible staphylococci
- Dosage adjustments are needed for drugs with narrow 2. Gram-negative cocci such as meningococci and
margin of safety and mainly excreted unchanged in the susceptible gonococci
urine. 3. 3. Gram-positive bacilli such as bacillus anthracis,
diphtheria
b. Malnutrition 4. Gram-negative bacilli (bubonic plague, spirillum
- Severe protein-calorie malnutrition(PCM) can alter drug minus)
disposition by these patho-physiologic changes: 5. Spirochetes such as
o hypoalbuminemia, hypolipo-proteinemia, leptospira,treponema(syphilis,yaws)
increased total body water, decreased body fat, 6. Anaerobic bacteria cocci, fusobacteria,
reduced muscle mass, reduced hepatic actinomyces, Clostridia (gas gangrene,tetanus),
biotransformation, reduced biliary excretion, bacteroides spp.
reduced cardiac output and altered renal
function. - Serum Pen G-with increased dosage: penetrates the blood
brain barrier when inflamed.
ANTIBACTERIAL AGENTS
A. Betalactam antibiotics Phenoxymethylpenicillin
B. Penicillins - preferred oral preparation for therapy of mild to moderate
C. Cephalosporins infections of the skin, subcutaneous tissue and respiratory
D. Monobactams tract by susceptible Gram-positive cocci.
E. Carbapenems
Procaine Penicillin G
Antibacterial Agents - Single daily dose of 50,000 units/kg for mild to moderate
infections
- Exert bactericidal effect through inhibition of
transpeptidation reaction required for the synthesis of the - High dose leads to hallucinations, disorientation, agitation,
cell wall peptidoglycan and subsequent inactivation of an bizarre behavior and neurological reactions.

inhibitor of autolytic enzymes in the cell wall leading to
Benzathin Penicillin
lysis of the bacteria.
- For IM injection, prolonged blood levels of Pen G up to 3

A. Penicillins weeks . A single injection of 1.2 M u is satisfactory for the
treatment of B-hemolytic streptococcal tonsillopharyngitis.
- No Longer the “Wonder Drug”
- Provide secondary prophylaxis in patients with Rheumatic
- A class of antibiotics that comes from mold.
fever
- Discovered by accident in 1928 by Alexander Fleming, is
the first antibiotic.
- Penicillin antibiotics include ampicillin,
st th
phenoxymethylpenicillin, amoxicillin, 1 -4 generations. NASO-MENINGOCOELE
- 50 drugs that are now classified as penicillin.
- Use in WWII and after.

How Penicillin Works
- Resembles a protein needed for production of cell wall.
- Penicillin binds to cell wall of bacteria, prevents peptide
chains from linking, and lyses it.

Bacteria
- Can reproduce in 20 minutes.
- Have a single chromosome and plasmids which contain
spare genes.
- Make copies of plasmids with resistant gene on them,
passed on to offspring or other bacteria through
conjugation.

TRANSCRIBERS WILMA, JOSH, MARK 5

 PEDIATRICS II
Pediatric Therapeutics EXIMIUS
Dean Ramirez, MD September 2019 2021
ANENCEPHALY FETAL ALCOHOL SYNDROME

HYDROCEPHALUS

CLEFT LIP AND PALATE

CLEFT LIP
GOITER

CLUB FOOT

Antistaphylococcal Penicillins
Ø Less active against pneumococci and streptococci
Ø Parenteral use- Nafcillin,oxacillin
Ø Orally absorbed-Cloxacillin, dicloxacillin or fluocloxacillin

Extended spectrum Penicillins- Aminopenicillins
Ø Ampicillin
PHOCOMELIA
o Has a broader spectrum of antibacterial activity
vs. H. influenzae,E.coli,salmonella,
shigella,Listeria monocytogenes and Proteus
mirabilis.
o Drug of choice for enterococcal infections.

Ø Amoxicillin
o Same as Ampicillin except it has no effect against
shigella, more effective against salmonella,good
absorption in the presence of food


TRANSCRIBERS WILMA, JOSH, MARK 6

 PEDIATRICS II
Pediatric Therapeutics EXIMIUS
Dean Ramirez, MD September 2019 2021
Ø Co- amoxiclav(amoxicillin+clavulanic), IMIPENEM / CILASTATIN
o active against H. influenzae, E. coli, Ø Pharmacokinetics
Proteus,Klebsiella,S. aureus,S. epidermidis, B. o Not absorbed orally ( i.v infusion )
catarrhalis, N. gonorrhea,Legionella o Partly broken down by dehydropeptidase in the
pneumophilia, and B. fragilis but not proximal tubule- given with cilastatin (
Pseudomonas. dihydropeptidase inhibitor )
Treatment for : o Excreted primarily by the kidney
o Otitis media,sinusitis, infections of the lower o Doses must be reduced in renal failure
respiratory tract, skin soft tissues and urinary o Half- life about 1 hr
tract. Ø Disadvantages of Imipenem / cilastatin vs Meropenem
o High incidence of seizures, whereas meropenem
Ø Sulbactam +ampicillin is not.
o Useful in the treatment of intra abdominal or o A 1g of imip./cilas require 200 ml saline to
pelvic infections. dissolve, whereas A 1g of meropenem dissolves
o Not use to treat meningitis. in only 20 ml saline.
o Hence, meropenem can be given either by i.v
Antipseudomonal Penicillins bolus or i.v infusion, Whereas, Imip./cilas should
Ø Carboxypenicillins be given only by i.v infusion, so:
Ø Carbenicillin o Less suitable for fluid restricted pts
Ø Ticarcillin o Not suitable for outpatients- need
o with bactericidal activity vs. gram-negative hospitalization
Ø Side effects
bacteria, Pseudomonas and Proteus spp.
o Similar to those seen with B- lactams
Ø Ureidopenicillins- piperacillin,mezlopenicillin
o Nausea & vomiting are frequent
o CSF penetration is better.
o Excessive levels with renal failure may lead to
o Active against Pseudomonas
seizures
o Should be use with antipseudomonal
o Pts allergic to penicillins may be allergic to
aminoglycoside for synergistic effect.
imipenem


Carbapenems
MONOBACTAMS
Ø Imipenem; Meropenem;Cilastatin
AZTREONAM
Ø Broad spectrum of activity against enteric Gram –negative
Ø Mechanism of action
rods and P. aeruginosa.
o Similar to other B- lactams
Ø Has excellent activity vs. Anaerobes, including Bacteroides
Ø Antibacterial spectrum
fragilis and many Gram-positive organism.
Ø Does not cover MRSA. o Active only against G- aerobic bacteria
(pseudomonads, N. gonorrhea, N. meningitidis,
Ø It has good penetration in the CSF but can cause seizures.
H. influenzae and enterobacteriaceae )
Ø Clinical uses of imipenem / cilastatin
o Inactive against G+ and anaerobic bacteria
o Infections require multiple antibiotics ( useful in
Ø Pharmacokinetics
nosocomial infections )
o Not used alone for serious pseud.infections o Poorly absorbed orally( i.v / 8 hr )
o Limited penetration into the CSF
o Not used for MRSA infections
o Excreted primarily by the kidney

o Half- life 2 hr

Ø Side effects
o Similar to other B- lactams.
o Pts allergic to penicillins and cephalosporins can
receive aztreonam
Ø Clinical uses of aztreonam
o Active against G- aerobes only
o Alternative for penicillins ( piperacillin ) and
cephalosporins ( ceftazidime ) allergic pts for G-
infections
o Safe alternative to aminoglycosides, esp. in
elderly and pts with renal impairements









TRANSCRIBERS WILMA, JOSH, MARK 7

 PEDIATRICS II
Pediatric Therapeutics EXIMIUS
Dean Ramirez, MD September 2019 2021
Cephalosporin Kanamycin,gentamicin,tobramycin,netilmicin,amikacin.
st
1 Generation Ø Kanamycin-not effective vs. P aeruginosa
Ø cefazolin,cephalothin,cephalexin,and cephradin. Ø Gentamicin-drug of choice concurrent with Pen G or
Ø Most active vs. Gram-positive cocci except and aerobic Ampicillin in the treatment of neonatal sepsis and or
Gram-negative bacilli such as E. coli, K. pneumoniae and P. meningitis
mirabilis Ø Tobramycin- greater activity vs. P. aeruginosa but less
Ø Excellent anti-staphylococcal agents but not vs. MRSA active vs. serratia
Ø Do not penetrate blood brain barrier. Ø Amikacin-effective vs. coliform bacilli including P.
aeruginosa resistant with gentamicin and netilmicin
nd
2 Generation
st
Ø Cefuroxime-equal activity as the 1 generation but more Aminoglycosides
activity vs. E. coli,K. pneumoniae and P. mirabilis Ø It has dose –related toxicity and narrow range between
Ø Active vs. H. influenzae, S. aureus,S. pneumoniae,and grp toxic levels
A streptococci,enterobacter, serratia,anaerobes,Neisseria Ø 2 major toxicities:
Ø Not active vs. Pseudomonas o 1. irreversible ototoxicity(vestibular and auditory
Ø Better penetration into CSF but not sufficient for optimal damage)
treatment o 2. reversible renal damage
Ø Oral form-cefaclor ,curoxime axetil
Macrolides and Azalides
rd Ø Bacteriostatic effect through inhibition of protein synthesis
3 Generation
Ø Cefotaxime,ceftriaxone,ceftizoxime,moxalactam Ø Activity vs. Gram-positive cocci,
Ø Cefixime,cefetamet,cefdinir- oral forms legionella,bordetella,corynebacteria,Gram-positive
Ø Most active vs. Gram-positive organism,useful vs. Gram- cocci,mycoplasma, chlamydia, and both Gram-positive and
negative bacillary infections like meningitis Gram-negative anaerobes.
Ø Ceftriaxone –longest duration of effect,can be given once Ø Inactive vs. Enterobacteriaceae and Pseudomonas spp.
or twice daily, use for treatment of MDR S. typhi and Erythromycin,clarithromycin,roxythromycin,spiramycin.
gonorrhea. Ø Erythromycin-base is destroyed by gastric acid
Ø Antipseudomonal cephalosporin o Insufficient concentration in the CSF
Ø Ceftazidime-has the greater activity vs. Pseudomonas o Penicillin substitute in the treatment of
rd
Ø 3 gen ceph-lack activity vs. enterococci,L. streptococcal and pneumococcal infections
monocytogenes and MRSA. outside CNS who are allergic to penicillin.
o Drug of choice for pertussis,diphtheria,and
TH
4 Generation pneumonia caused by Mycoplasma
Ø Cefepime pneumoniae,Chlamydia trachomatis and
Ø Greater activity vs. Gram-positive cocci Legionella pneumophilia.
Ø Increased activity vs. Enterobacteriaceae and P. Ø Clarithromycin-same indication with Erythromycin. It has
aeruginosa activity vs. Mycobacterium avium
Ø Azithromycin-an azalide,active vs. H. influenzae,Moraxella
Cephalosporin and gonococci
Ø Adverse effects: thrombophlebitis with iv use o Good oral bioavailability,rapid and sustained
Ø Cefaclor- diarrhea uptake by the tissues allowing once a day dosing
Ø Ceftriaxone-bile sludging or “pseudocholelithiasis” and shorter duration of treatment.
Ø Moxalactam,cefoperazone,cefamandole-bleeding o Most common side effects:
problems nausea,vomiting,diarrhea, abdominal cramps.

Lincosamides
Aminoglycosides Ø Clindamycin and lincomycin
Ø Bactericidal Ø Bacteriostatic
Ø Act on microbial ribosomes to irreversibly inhibit protein Ø Active vs. Gram-positive cocci such as
synthesis staphylococci,pneumococci, S. pyogenes and S. viridans
Ø Active vs. aerobic Gram-negative bacilli and S. aureus and against most anaerobes.
Ø Ineffective against streptococci,meningococci, and Ø Used for the treatment of staph infections who are allergic
anaerobic bacilli and cocci to penicillin,an alternative antibiotics for anaerobic
Ø Given parenterally infections outside the CNS.
Ø Minimal CSF penetration Ø Side effect: Antibiotic associated diarrhea
Ø Excreted unchanged by Glomerular filtration Pseudomembranous colitis with toxic megacolon due to C.
difficile

TRANSCRIBERS WILMA, JOSH, MARK 8

 PEDIATRICS II
Pediatric Therapeutics EXIMIUS
Dean Ramirez, MD September 2019 2021
Chloramphenicol Ø Metabolized in the liver and the metabolites and
Ø Inhibits bacterial protein synthesis by reversibly binding to unchanged drugs are excreted through the urine and
the larger 50 S subunit of the 70 S ribosome which feces.
prevents formation of peptide bonds. Ø Side effects:headache,nausea,dry mouth and metallic
Ø Active vs. Spirochetes,rickettsia, chlamydia and taste
mycoplasmas, Salmonella, including S. typhi,H. influenzae,
S. pneumoniae and N. meningitides Sulfonamides
Ø Active vs. anaerobes including B. fragilis Ø Bacteriostatic
Ø Rapidly absorb after oral administration than iv or im. Ø Inhibit the incorporation of p-aminobenzoic acid(PABA)
Ø Penetrates well into all tissues including CSF, into tetrahydropteroic acid,thus inhibiting folic acid
brain,aqueous humor and breastmilk. synthesis
Ø Side effect: hematologic effect-suppression of the bone Ø Active vs. Gram-positive and Gram-negative bacteria, as
marrow well as actinomyces, chlamydia,plasmodia and
Ø Gray syndrome-in neonates due to deficient glucuronyl toxoplasma.
st
transferase during 1 3-4 weeks of life Ø Sulfamethoxazole-use in the treatment of respiratory and
urinary tract infections
Tetracyclines Ø Cotrimoxazole
Ø Inhibit protein synthesis o Active vs. S. aureus, S. pneumoniae,E. coli,P.
Ø Bacteriostatic mirabilis,Shigella spp.,Salmonella spp.,
Ø Active vs. Gram-positive cocci and E. coli,N. Pseudomonas cepacia,Yersinia enterocolitis and
gonorrhea,Pseudomonas , Brucella spp.,Vibrio N. gonorrhea.
cholerae,Mycobacterium marinum o Clinically active vs. Pneumocystis carinii
Ø Incompletely absorb from the oral route Ø Well absorbed from the GIT
Ø Absorption is impaired by milk intake,milk products Ø Well distributed throughout body fluids including the CSF
Ø Widely distributed in the tissues and fluids except the CSF Ø Metabolized by acetylation and glucuronidation in the liver
Ø Cross the placental barrier and are deposited in the bones Ø Cotrimoxazole
and teeth buds of the fetus. o Adverse effects:
Ø Primary route of excretion is through the kidneys,except • Allergic reactions (rash, photosensitivity,
Doxycycline which is excreted in the liver and kidneys. drug fever) and kernicterus in newborns
Ø Side effects: dose and duration related • Renal and liver damage, Steven –Johnson
o Gi disturbances,bone lesions staining and syndrome
hypoplasia of the teeth in infants and children up • Blood dyscrasia and vasculitis
to 8 years old and when given to pregnant
th
women after the 4 month of pregnancy Quinolone Antimicrobial Agents
Vancomycin Ø Nalidixic acid
Ø Bactericidal, acts by inhibiting biosynthesis of the major o Was the first commercially available compound of
structural cell wall polymer, peptidoglycan this class and was approved for treatment of urinary
Ø Active vs. Gram-positive organisms tract infections in 1964.
Ø Poorly absorbed from the GIT
Ø Widely distributed to all body tissues including CSF when First-generation quinolones
meninges are inflamed.
Ø Norfloxacin
Ø Drug of choice for the treatment of serious staphylococcal o Fluoroquinolone with a broad spectrum of
infections resistant to the usual anti staph antibacterial activity; was patented in 1978.
antibiotics(MRSA)
Second-generation quinolones
Ø Alternative drug for the treatment of enterococcal
endocarditis and endocarditis caused by Strep viridans
Ø Adverse effects
o Thrombophlebitis, fever and chills
th
o 8 nerve deafness

Nitro-imidazoles
Ø Metronidazole-a very potent and effective agent vs.
anaerobic including B. fragilis and clostridia and
anaerobic protozoa including Trichomonas vaginalis,
Giardia lamblia and Entamoeba histolytica.
Ø Metronidazole
o Used in the treatment of intra abdominal and
female pelvic infections
o Treatment of choice for bacterial vaginosis and
of C.difficile related diarrhea.
Ø Well absorbed by oral ,rectal and iv route

Ø Distributed to all tissues and body fluids including the CSF
TRANSCRIBERS WILMA, JOSH, MARK 9

 PEDIATRICS II
Pediatric Therapeutics EXIMIUS
Dean Ramirez, MD September 2019 2021
Third-generation quinolones Isoniazid
Ø A third advance was made in early 1990s. All third- Ø The central drug in tuberculosis management and
generation fluoroquinolones have significantly improved preventive therapy.
activity against gram-positive bacteria, notably Ø Highly effective, safe, well tolerated and inexpensive.
streptococcus pneumonia. Ø MOA: acts through inhibition of mycolic acid of the
Ø Some of them have good activity against anaerobes and mycobacterial cell wall and is bactericidal to both
atypical pathogens. extracellular and intracellular rapidly growing tubercle
bacilli.
Mechanism of action Ø Extensively metabolized by cytosolic N-acetyl transferase
Ø Quinolones enter the cell by passive diffuse. Intracellularly, mainly in the liver and small intestine.
they inhibit the synthesis of bacterial DNA by interfering Ø Asians are rapid acetylators.
with the action of DNA gyrase ,topoisomerase. Ø Fast acetylators produce more monoacetylhydrazine than
slow acetylators=increased risk of hepatotoxicity
The Metabolism of Quinolone
Ø The quinolones are often well absorbed following oral Pyrazinamide
administration and are highly serum-protein bound. Ø A synthetic analogue of nicotinamide.
Ø Peak value is 1-2 h after oral administration and keep high Ø MOA: bactericidal,sterilizing effect on slowly and
concentration in urea for most quinolones. intermittently multiplying organisms intracellularly located
Ø Most metabolic reactions occur at the piperazine rings. macrophages at acidic Ph.
Ø Readily absorbed from the GIT and is distributed to all
Norfloxacin tissues and fluids including the CSF.
Ø It is a broad-spectrum antimicrobial agent, active against Ø Side effects: Hyperuricemia; hypersensitivity, severe
both Gram-positive and Gram-negative bacteria, as well as hepatic impairment, gout.
Pseudomonas aeruginosa.
Ethambutol hydrochloride
Ciprofloxacin Hydrochloride Ø Ethambutol is not recommended for use alone, but in
combinations with other antitubercular drugs in the
Ø The antibacterial spectrum of Ciprofloxacin is familiar with
chemotherapy of pulmonary tuberculosis.
that of Norfloxacin, but the MIC values against E.coli,
Bacillus blue-pus, Streptococcal infection, Staphylococcal Ø MOA: inhibit the incorp
infection, Bacillus anthracis are lower other quinolones as
Rifampin
well as antibiotics.
Ø Rifampin, a semisynthetic derivative of rifamycin B, was

released as an antitubercular agent in US in 1971.
Levofloxacin
Ø Chemical name: 3-[[（4-methy- 1-piperazinyl
Ø The drug was marketed in 1991, it is the optical isomer of
imino]methyl]rifamycin
Ofloxacin, and the antibacterial activity is two times as
Ø An inhibitor of DNA-dependent RNA polymerase
high as that of Ofloxacin.
Ø Toxic effects
Ø It exhibits activities for both Gram-negative and Gram-
o Interfere with liver function in some patients
positive bacteria .
o The incidence of hepatotoxicity was significantly

higher when rifampin was combined with
Tuberculostatics
isoniazid than when either agent was combined
Ø Synthetic drugs
with ethambutol.
o p-Amino-salicylic acid (PAS)
o Allergic and sensitivity reactions to rifampin have
o Isoniazid
been reported, but they are infrequent and
o Ethambutol
usually not serious.
Ø Antibiotics

o Streptomycin
Antifungal Agents
o Rifampin
Ø Fungal infections classification:

Combination therapy o Superficial infections: Ringworm (tinea) → skin
and mucous membrane. Incidence rate is high.
Ø A major advance in the treatment of tuberculosis was
o Systemic infections: Candida albicans →
signaled by the introduction of the antibiotic rifampin into
opportunist infections. Fatality rate is high.
therapy.
Ø Antifungal agents classification:
Ø Clinical studies indicated that when rifampin is included in
the regimen, particularly in combination with isoniazid o Antibiotics: Amphotericin B
and ethambutol (or pyrazinamide), the period required for o Azole: Ketoconazole
successful therapy is shortened significantly (6-9 months, 2 o Allylamine: Terbinafine
ys without rifampin). o Pyrimidine: Flucytosine

TRANSCRIBERS WILMA, JOSH, MARK 10

 PEDIATRICS II
Pediatric Therapeutics EXIMIUS
Dean Ramirez, MD September 2019 2021
Antibiotic Antifungal Drugs Ketoconazole
Ø Polyenes: Amphotericin B, Nystatin Ø The first oral azole introduced into clinical use.
Ø Non-polyenes: Griseofulvin Ø Less selective for fungal P450
o Inhibition of human P450 interferes with
Amphotericin B biosynthesis of adrenal and gonadal steroid
Ø Produced by Streptomyces nodosus. Amphoteric polyene hormones;
macrolide. o Alter the metabolism of other drugs.
Ø Pharmacological Effect: broad-spectrum Ø Best absorbed at a low gastric pH.
Ø Mechanism: binds to ergosterol in fungi (cholesterol in
humans and bacteria) to form pores Miconazole, Econazole, Clotrimazole
Ø Pharmacokinetics: Ø Bioavailability is low by taking orally.
o Poorly absorbed from the gastrointestinal tract. Ø Used topically.
o More than 90% bound by serum proteins. Bifonazole
o Metabolized in liver, excreted slowly in the
Ø Double inhibition, antifungal action is more powerful.
urine.

Ø Adverse Effects:
Itraconazole
o Infusion-Related Toxicity: fever, chills, muscle
Ø Its absorption is increased by food and by low gastric pH.
spasms, vomiting, headache, hypotension.
Ø Treatment of dermatophytoses and onychomycosi.
o Slower Toxicity:
Ø The only agent with significant activity against aspergillus
§ Renal toxicity
+ 2+ species.
§ K ↓, Mg ↓

§ Anemia: erythropoietin ↓
Fluconazole
§ Abnormalities of liver function
§ Neurologic sequel Ø Water solubility and good cerebrospinal fluid penetration.
Ø The widest therapeutic index of the azoles.
o Announcements: Ø Treatment and secondary prophylaxis of cryptococcal
§ Administration in advance of NSAIDs meningitis.
and Antihistamine drug, Glucocorticoid
§ Periodic Monitoring Vorionazole
Nysfungin Ø Available in an intravenous and an oral formulation.
Ø Like Amphotericin B and has same mechanism of action. Ø Metabolism is predominantly hepatic, but the propensity
Ø Too toxic for parenteral administration, and is only used for inhibition of mammalian P450 appears to be low.
topically Ø Similar to itraconazole in tits spectrum of action, having
Ø Not absorbed from skin, mucous membranes, or the good activity against candida species.
gastrointestinal tract, so little significant toxicity. Ø More effective than itraconazole.

Griseofulvin
Ø Derived from a species of penicillium. Acrylamide
Ø Fungistatic drug Ø Include Naftifine and Terbinafine.
Ø Insoluble. Ø non-competitive and reversible inhibitor of Squalene
Ø Administered in a microcrystalline form only using in the epoxidase.
systemic treatment of dermatophytosis. Ø Terbinafine is synthetic, oral formulation.
Ø Deposited in newly forming skin where it binds to keratin, o Fungicidal
protecting the skin from new infection. o Treatment of dermatophytoses, especially
onychomycosis, more effective than griseofulvin
Azoles or itraconazole.
Ø Synthetic compounds.
Ø Classification: according to the number of nitrogen atoms Pyramine
in the five-membered azole ring Ø Flucytosine （5-FC）is a water-soluble pyrimidine analog.
o Imidazoles: Ketoconazole, Miconazole, Ø Its spectrum of action is much narrower than that of
Econazole, Clotrimazole, Bifonazole amphotericin B.
o Triazoles: Itraconazole, Fluconazol, Vorionazole Ø Poorly protein-bound and penetrates well into all body
→ systemic treatment fluid aompartments, including the cerebrospinal fluid.
Ø Mechanism of Action Ø Mechanism
o Reduction of ergosterol synthesis by inhibition of o 5-FC (taken up by fungal cells via the enzyme
fungal cytochrome P450 enzymes. cytosine permease) → 5-FU → F-dUMP and
o Greater affinity for funfal than for human FUTP → inhibit DNA and RNA synthesis,
cytochrome P450 enzymes. respectively.
o Imidazoles exhibit a lesser degree of specificity o Synergy with amphotericin B
than the triazoles, accounting for their higher o Spectrum of action: Cryptococcus neoformans,
incidence of drug interactions and side effects. some candida species, and the dematiaceous
molds that cause chromoblastomycosis.
TRANSCRIBERS WILMA, JOSH, MARK 11

 PEDIATRICS II
Pediatric Therapeutics EXIMIUS
Dean Ramirez, MD September 2019 2021
o Not used as a single agent because of its Ø Adverse effects:
demonstrated synergy with other agents and to o Dose-limiting toxicity is a dose-related peripheral
avoid the development of secondary resistance. sensory neuropathy.
Ø Adverse effects: result from metabolism to 5-FU o Pancreatitis, arthralgias, elevation in serum
o Bone marrow toxicity with anemia, leukopenia, aminotransferases.
and thrombocytopenia

Antiretroviral (Anti-HIV) Agents Nucleoside Antiviral Agents
Ø The first available agents: Nucleoside analog class → Ø Including Purine-nucleoside and Pyrimidine-nucleoside
competitive inhibition of the viral reverse transcriptase Ø Drugs requires intracytoplasmic activation---
Ø Nonnucleoside reverse transcriptase inhibitors phosphorylation → triphosphate form → competitive
Ø The protease inhibitors inhibition of viral DNA polymerase.
Ø The combination of at least two antiretroviral agents Ø Incorporated into the growing viral DNA chain → cause
(cocktail therapy) → enhancing potency and delaying termination
resistance
Ø Mechanism of Action Acyclovir (ACV)
1. Competitive inhibition of HIV-1 reverse Ø An acyclic guanosine derivative
transcriptase; Ø Pharmacological effects:
2. Incorporated into the growing viral DNA chain → o Against HSV-1 and HSV-2 and against varicella-
cause termination zoster virus, Epstein-Barr virus and
o Drugs requires intracytoplasmic activation--- cytomegalovirus.
phosphorylation → triphosphate form Ø Mechanism:
o Most have activity against HIV-2 as well as HIV-1. o Three phosphorylation steps for activation.
§ First converted to the monophosphate
Zidovudine derivative by the virus-specified
Ø Azidothymidine , AZT thymidine kinase（selective activation）
Ø Deoxythymidine analog § Then to the di- and triphosphate
Ø Anti-HIV-1 and HIV-2 compounds by host’s cellular enzymes.
Ø Well absorbed from the gut and distributed to most body
tissues and fluids, including the cerebrospinal fluid. Ø Acyclovir triphosphate inhibits viral DNA synthesis by two
Ø Eliminated primarily by renal excretion following mechanisms:
glucuronidation in the liver. o Competitive inhibition of deoxyGTP for the viral
Ø Decrease the rate of clinical disease progression and DNA polymerase, with binding to the DNA
prolong survival. template as an irreversible complex;
Ø Treatment HIV-associated dementia and o Incorporation into the viral DNA → chain
thrombocytopenia. termination
Ø neutropenia; gastrointestinal intolerance, headaches,
insomnia Ø Pharmacokinetics
Ø Reduce the rate of vertical (mother-to-newborn) o Available in oral, intravenous, and topical
transmission of HIV. formulations.
Ø Adverse effect: Myelosuppression → anemia o Oral bioavailability is 15-20%.
o Plasma protein binding is low, diffuses into most
tissues and body fluids.
Zalcitabine o Cleared primarily by glomerular filtration and
Ø Cytosine analog tubular secretion.
Ø Anti-HIV-1
Ø Zalcitabine + Zidovudine + one protease inhibitor Ø Clinical uses
Ø Long intracellular half-life of 10hs. o Treatment of HSV infection —— first selection
Ø Dose-dependent peripheral neuropathy. Contraindication o Topical acyclovir is much less effective than oral
to use with other drugs that may cause neuropathy. therapy for primary HSV infection. It is of no
benefit in treating recurrences.
Stavudine o VZV is less susceptible to acyclovir than HSV,
Ø Thymidne analog (d4T), not used with AZT because AZT high doses are required.
may reduce the phosphorylation of d4T.
Ø Anti-HIV-1 and HIV-2 Ø Adverse reactions
Ø High oral bioavailability (86%) that is not food-dependent. o Nausea, diarrhea, headach
Ø Plasma protein binding is negligible, mean cerebrospinal o Intravenous infusion → renal insufficiency or
fluid concentrations are 55% of those of plasma. neurologic toxicity
Ø Excretion is by active tubular secretion and glomerular
filtration.

TRANSCRIBERS WILMA, JOSH, MARK 12

 PEDIATRICS II
Pediatric Therapeutics EXIMIUS
Dean Ramirez, MD September 2019 2021
Valacyclovir
Ø The L-valyl ester of acyclovir
Ø It is rapidly converted to acyclovir after oral
administration, achieving serum levels three to five times
greater than those achieved with oral acyclovir.


Ganciclovir
Ø An acyclic guanosine analog
Ø Against CMV is up to 100 times greater than that of
acyclovir.
Ø Adverse reactions:
o Myelosuppression, particularly neutropenia

TRANSCRIBERS WILMA, JOSH, MARK 13