2. Opioid receptorsOpioid receptors
• All opioid receptors are GGii-protein coupled-protein coupled
receptors (receptors (↓ cAMP)↓ cAMP)
• Opioid receptor activation leads to:
– Opening of K+
channels → neuronal membrane
hyperpolarization
– Closing of voltage-gated Ca2+
channels on presynaptic
terminals → reduce NT release (glutamate, substance
P)
3. The majority of currently available opioid
analgesics are μ receptor agonists
• Full agonistsFull agonists::
• MorphineMorphine
• MethadoneMethadone
• FentanylFentanyl
• HeroinHeroin
• Metabolism: CYP3A4
oxidation followed by
glucoronide conjugation
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4. Organ system effects of full agonistsOrgan system effects of full agonists
• CNS effects:
• Analgesia (they reduce both the pain and its emotional
component; continuous dull pain is relieved more
effectively than sharp pain)
• Euphoria (dopamine pathways involved)
• Sedation
• Respiratory depression (occurs even with therapeutic
doses; dose-related; a problem during management of
severe pain)
• Cough suppression
• Constriction of the pupils – valuable in the diagnosis of
opioid overdose
• Nausea and vomiting
5. Organ system effects of full agonistsOrgan system effects of full agonists
• Peripheral effects:
• Orthostatic hypotension (peripheral vascular dilation)
• Decreased GI tract motility (constipation)
• Contraction of biliary smooth muscle (can result in biliary
colic)
• Stimulation of ADH and prolactin release
• Histamine release from mast cells causes itching, flushing
of the skin, urticaria + bronchoconstriction
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• When a partial
agonist is given to a
patient also receiving
a full agonist, there is
a risk of diminishing
analgesia or even
inducing withdrawal
symptoms
• Partial and full
agonists shouldn’t be
combined
7. • Effective when given orally
• Weak analgesic on its own, but metabolized by CYP2D6
to morphine
– Genetic polymorphism in CYP2D6 makes codeine ineffective as
an analgesic for 10% of the Caucasian population
• Combined in formulations with caffeine and
acetaminophen
• Effective antitussive action at doses lower than required
for analgesia
CodeineCodeine
8. • Partial μ receptor agonist + κ receptor antagonist
• Long duration of action
• Maintenance of opioid dependence
BuprenorphineBuprenorphine
10. OpioidOpioid
antagonistsantagonists
• Used in treatment of
acute opioid overdose
• Short duration of action
of naloxone (1-2 hours);
repeated administration
necessary when treating
opioid overdose
• Administration of an
opioid antagonist to an
opioid-dependent person
would precipitate severe
withdrawal symptoms
11. Cocaine
• Stimulant and local anesthetic
• Leaves of the Erythroxylon coca plant have 0.5 to 1%
cocaine
• Potent vasoconstrictor properties
• Administered orally, intranasally, IV, inhalation
through smoking
• Cocaine increases synaptic conc. of dopamine,
norepinephrine, and serotonin
– Binds to transporter proteins in presynaptic neurons and
blocks reuptake(negative feedback)
12. Cocaine
• Brief, dose-related stimulation and enhancement of
mood
• Tolerance develops
• Affects almost every organ system
• Increases heart rate, blood pressure, body
temperature
• Pyrexia or hypertension could be lethal
• Also respiratory depression, cardiac arrhythmias,
seizures, hepatic cirrhosis
13. PCP
• Diagnosis of overdose is difficult because the
symptoms resemble a psychotic episode
• PCP remains in urine 1 to 5 days following
high-dose intake
• Overdose requires life-support measures,
including treating respiratory depression
• Psychiatric emergency – risk for suicide or
extreme violence
14. Acetaminophen
• Toxicity
– Ethanol is an inducer of CYP2E1, which is the main P450
enyme that converts acetaminophen to the toxic
metabolite
– Treat with N-acetylcysteine to increase glutathione
synthesis
– Also thought that Kupffer cells play an important role in
toxicity
– A different toxic metabolite can bind to cellular proteins in
the kidney medulla and cause damage
– Nephrotoxicity is characterized by proximal tubular
necrosis
15. Ethylene Glycol
• Toxicity
– Clinical presentation
• Initial asymptomatic phase (EG is metabolized)
• A period of inebriation – duration and degree depends on dose
• Cardiopulmonary phase – 12-24 h after exposure – tachycardia and
tachypnea – may progress to cardiac failure and pulmonary edema
• Renal toxicity phase – 24-72 h after exposure
• Increasing severity of metabolic acidosis during last two stages
– Metabolism – ethylene glycol to glycolaldehyde (by alcohol
dehydrogenase) and on to glycolic acid
• Ethanol is given as an antidote because it effectively competes with EG for
alcohol dehydrogenase
– Rapid metabolism, so no bioaccumulation upon repeated exposure
17. Cancer Terminology
• Benign vs. Malignant
– Malignant: a tumor that can result in death
and is capable of metastasis = breaking the
boundaries of the initial organ to colonize in
other organs.
• Naming of tumor is cell of origin, plus
“carcinoma”, if epithelial in origin; or
“sarcoma”, if originating from connective
tissue.
• Ex: colorectal carcinoma, pancreatic
carcinoma; leiomyosarcoma,
chondrosarcoma,
18. Principles of Oncology
• Fig. 55-1. The log-
kill hypothesis.
– Relationship of
tumor cell number to
time of diagnosis,
symptoms,
treatment, and
survival. Three
alternative
approaches to drug
treatment are shown
for comparison with
the course of tumor
growth when no
treatment is given
(dashed line). Surgery +
5 trtmts with
short recovery
No surgery,
14 trtmts with
short recovery
No surgery +
trtmts with
long recovery
19. Choice of Cancer Treatment• Tumors are heterogenous cell
masses.
– Initial cell is mutated = initiation
– cell growth of the mutated cell is
promoted = promotion
– cell becomes
immortalized/transformed (loss of
control of the cell cycle) =
conversion or transformation
– progeny cells continue to
accumulate mutations =
progression
– cells spread out of local boundaries
into surrounding tissues = local
invasion
– cells break off, circulate and
colonize in other tissues to form
new tumors = metastasis.
http://en.wikipedia.org/wiki/Cancer
apoptosis
clonal
evolution
20. Cancer Chemotherapy
• Chemo is not usually the first treatment choice.
– Can be first choice for some cancer types
– Can be used in combination with other therapies.
• Systemic treatment for systemic cancers.
– Leukemias
– Inoperable tumors
– Advanced cancer – multiple metastases
• Adjuvant therapy
– Systemic treatment to prevent micrometastases after local
treatment (surgery, radiation)
• Palliative treatment
– Shrinking of tumors that cause blockage or constriction
– Relief of bone pain
21. Alkylating Agents
• General Mechanism of action (two modes):
– Alkylation of DNA
• primarily at N7 position of guanine, resulting in
transfer of a group that blocks the replication
machinery, preventing tumor growth and, ideally,
promoting apoptosis (programmed cell death).
• also, guanine O6
• also alkylate other bases, including adenine N1 and
N3, cytosine N3
– Alkylation of cellular proteins
• react with cellular nucleophiles, such as sulfhydryl,
amino, hydroxyl, carboxyl and phosphate groups of
various cellular proteins.
– Most are bifunctional = 2 reactive groups 1
agent molecule can alkylate 2 different target
molecules.
23. Alkylating Agents
• Bis(chloro-ethyl)amines
– Each chloro-ethylamine group
can alkylate the N7 of 2
adjacent purines, (intrastrand)
resulting in cross-linked DNA
strands.
– Cross-linked DNA is stable and
cannot be replicated or
degraded by normal cellular
means.
bendamustine
24. Alkylating Agents
• Platinum Analogs
–Platinum-containing complexes
–Mechanism of action:
• Same manner as alkylating agents –
forms interstrand and intrastrand DNA
cross-links, inhibiting DNA synthesis and
function.
25. Alkylating Agents
• Platinum Analogs
– Cisplatin – first-generation drug
– Carboplatin – second generation
• significantly less renal and GI toxicity
• IV hydration is not required
• has replaced cisplatin in combo therapies
– Oxaliplatin – third generation
• cisplatin- and carboplatin-resistant cancer cells are
not cross-resistant to oxaliplatin
• Part of FOLFOX regimen = 5-fluoruracil + leucovorin
+ oxaliplatin = most widely used regimen in first-
line treatment of advanced colorectal cancer.
26. Antimetabolites
• Methotrexate
– = folic acid antagonist
– Binds to active catalytic site of dihydrofolate
reductase (DHFR), competing with binding of
DHF, inhibiting conversion to THF (active folic
acid)
– Interferes with production of DNA, RNA and
key cellular proteins.
• Pemetrexed and Raltitrexed (Tomudex)
– = TS antagonists
– Target DHFR activities, but their main action is
through inhibition of thymidylate synthase
(TS), the methyltransferase that converts
dUMP to dTMP.
5,10-methylenetetrahydrofolate + dUMP + TS -> dTMP + dihydrofolate
dihydrofolate + DHFR -> tetrahydrofolate dTMP dTTP
27. Antimetabolites
•Pyrimidine Antagonists
–5-FU and capecitabine
–5-FU = 5-fluorouracil
•Metabolized to ribosyl and deoxyribosyl
metabolites that produce cytotoxicity via combined
DNA- and RNA-mediated events.
28. Antimetabolites
• Pyrimidine Antagonists
– Capecitabine
• Also leads to inhibition of DNA synthesis and “thymine-
less death” because it is a prodrug that is metabolized
to 5-FU. Thus, cytotoxicity is identical to 5-FU.
• Difference: capecitabine is converted to 5-FU by
thymidine phosphorylase, which has significantly
higher expression in solid tumor cells than in normal
cells.
• Result: main side effects of myelosuppression,
mucositis, nausea and vomiting are less frequent and
severe with capecitabine, compared to 5-FU = selective
toxicity.
29. Antimetabolites
• Pyrimidine Antagonists
– Cytarabine
• Inhibits DNA polymerase α and β
– (like purine antagonists
fludarabine & cladribine)
– Gemcitabine
• = deoxycytidine analog
• Mimics cytidine, is incorporated into
DNA, preventing elongation
• Inhibits ribonucleotide reductase,
preventing production of dNTPs
necessary for DNA synthesis
30. Antimetabolites
•Purine antagonists
–6-thiopurines: 6-
mercaptopurine (6-MP), 6-
thioguanine (6-TG)
•Both inhibit several enzymes in
the de novo purine nucleotide
biosynthetic pathway.
•Decreases DNA and RNA
synthesis by way of reducing
available functional purines.
–Fludarabine and cladribine
•Inhibit DNA polymerase α and
β
–(like pyrimidine antagonist cytarabine)
31. Plant Alkaloids
• Vinblastine and vincristine
– Vinca (periwinkle) alkaloids
– MOA: Inhibit tubulin polymerization, halting cell cycle,
leading to cell death
• Vinorelbine
– Synthetic version of the vinca alkaloids
• All have the same mechanism of action, but
different spectrum of clinical activity and toxicity.
32. Plant Alkaloids
• Taxanes
– Paclitaxel, docetaxel
– Alkaloid derivatives of Pacific and European yew
• paclitaxel is natural; docetaxel is semisynthetic
– MOA: Enhance abnormal microtubule assembly
• Occurs in absence of regulatory proteins and GTP that
are necessary for cell division, thus inhibits cell division
33. Antitumor Antibiotics
• Anthracyclines
– Doxorubicin, daunorubicin, idarubicin, epirubicin
– Exert their effects through 4 major mechanisms:
• Inhibition of topoisomerase II
• High-affinity binding to DNA through intercalation (=binding
in the groove of the double helix), blocking the replication
machinery
• Binding to cell membranes, altering fluidity and transport
• Generation of semiquinone free radicals and oxygen free
radicals through an iron-dependent, enzyme-mediated
reductive process. (Estrogen can also mediate this reaction.)
– This is the cause of cardiotoxicity from these drugs.
34. Antitumor Antibiotics
• Anthracene
– Mitoxantrone
• Resembles anthracycline ring structure
• Binds to DNA to produce strand breakage, inhibiting DNA and
RNA synthesis
• Dactinomycin
– Intercalating agent, between adjacent guanine and cytosine base
pairs, blocking replication machinery
• Mitomycin
– An alkylating agent that cross-links DNA
• Bleomycin
– A small peptide with a DNA-binding domain and an iron-binding
domain at opposite ends of the molecule.
– Binds to DNA at one end and produces hydroxyl radicals with the
other end, in close proximity to the DNA, ensuring more DNA
damage.
35. Hormonal Agents
• Gonadotropin-releasing hormone agonists &
antagonists
– MOA: bind to the GnRH receptors and prevent
gonadal release of estrogens and androgens.
– Antagonists
• “Relix” drugs = cetrorelix, ganirelix, abarelix, degarelix
– Agonists:
• Leuprolide, & “Relin” drugs” = buserelin, nafarelin, histrelin,
deslorelin
• Initial increase in gonadal hormone release followed by
inhibition through negative feedback.
40. Radiation Therapy
• Ionizing radiation
= the kind of radiation used in cancer treatment
– Forms ions by dislodging electrons as it passes
through cells.
– Two major types:
• Photons – gamma and x-rays; most widely used
• Particle radiation – electrons, protons, neutrons, alpha
particles, and beta particles
– Higher energy types penetrate tissue better, but
also cause more damage to normal cells.
41. Radiation Therapy
• Common types of cancer radiation treatments:
– High-energy photons
• Come from radioactive sources such as cobalt, cesium, or a
machine called a linear accelerator (or linac, for short.)
• By far, the most common type of radiation treatment in use
today.
– Electron beams
• Produced by a linear accelerator.
• Less tissue penetration, so it is used for tumors close to a
body surface.
42. Radiation Therapy
• Common types of cancer radiation treatment:
–Protons
• A newer form of treatment.
• Cause little damage to tissues they pass through, but are very
good at killing cells at the end of their path – may be able to
deliver more radiation to the cancer while causing fewer side
effects to normal tissues nearby.
• Used routinely for certain types of cancer, but still need more
study in treating others.
• Some of the techniques used in proton treatment can also
expose the patient to neutrons (see below).
• Proton beam radiation therapy requires highly specialized
equipment and is currently only offered in certain medical
centers.
43. Radiation Therapy
• Common types of cancer radiation
treatment:
– Neutrons
• Used for some cancers of the head, neck, and
prostate.
• Can sometimes be helpful when other forms of
radiation therapy don't work.
• Use has declined over the years because of severe
long-term side effects.
44. Radiation Therapy
• Radiation delivery methods:
– External beam radiation
• the most widely used type of radiation therapy.
• Linear accelerator emits focused beam on the area
affected by cancer.
• The beam is aimed at the tumor, but also affects the
normal tissue it passes through on its way into and out
of the body.
• Allows large areas of the body to be treated and allows
treatment of more than one area such as the main
tumor and nearby lymph nodes.
• Usually given in daily treatments over several weeks.
45. Radiation Therapy
• Internal radiation therapy
– = brachytherapy, which means short-distance therapy.
– Radioactive containers are placed into the tumor or into a
cavity close to the tumor.
– Advantage: the ability to deliver a high dose of radiation to a
small area – useful in cases that need a high dose of radiation
or a dose that would be more than the normal tissues could
stand if given externally.
– The main types of internal radiation are:
• interstitial radiation: the radiation source is placed directly into or
next to the tumor using small pellets, seeds, wires, tubes, or
containers.
• intracavitary radiation: a container of radioactive material is placed in
a cavity of the body such as the chest, uterus, or vagina.
– May be temporary or permanent
46. Radiation Therapy
• Radiopharmaceuticals
– Radiopharmaceuticals are drugs containing
radioactive materials.
– Systemic radiation therapy.
– Can be given intravenously (IV), orally, or into a
body cavity.
– Depending on the drug and how it is given, these
materials travel to various parts of the body to
treat cancer.
47. Intravenous Anesthetics
• Primarily used for the induction of
anesthesia
• Reduce Stage II (excitatory phase) of
general anesthesia
• IV anesthetics:
– Barbiturates (thiopental)
– Propofol
– Ketamine
– Benzodiazepines (midazolam)
48. Inhaled Anesthetics
• Used for maintenance of anesthesia after administration
of an intravenous agent
• Volatile agents (halogenated hydrocarbons)
– Halothane
– Isoflurane
– Sevoflurane
– Enflurane
– Desflurane
• Anesthetic gases
– Nitrous oxide (N2O)
Halothane Enflurane
49. Organ System Effects
• Respiratory system
– All (except nitrous oxide) cause respiratory depression –
reduce or eliminate ventilatory drive and reflexes that
maintain airway patency – must assist breathing
– Gag reflex lost
– Stimulus to cough is blunted
– Lower esophageal sphincter tone is reduced
• Kidney
– Decreased renal blood flow and GFR
• Hepatotoxicity – halothane (toxic metabolites)
50. Organ System Effects
• Postoperative Issues
– N/V
– Hypertension
– Shivering
– Airway obstruction – particularly of concern in
patients who snore or have sleep apnea
• Potential for creation of negative pressure leading to
pulmonary edema
– Pain – opioids can be problematic due to additive
respiratory depression
51. Mechanism of Action:
Local anesthetics block voltage-gated Na+
channels (need to access
those channels from inside the cell)
DOES NOT INCREASE GABA OR NMDA EFFECTS
Charged (BH+) form
binds at the inside of
Na+
channels
Unionized, lipid soluble
form (B) enters the cell
52. Local Anesthetics
• Drug of choice – depends on duration of action
– Procaine (short-acting)
– Lidocaine (intermediate-acting)
– Tetracaine (long-acting)
• Vasoconstrictor (epinephrine) needed with short- and
intermediate-acting local anesthetics (procaine, lidocaine) to
prolong their duration of action
• Other local anesthetics – articaine, etidocaine, mepivacaine,
prilocaine, ropivacaine, dibucaine, dyclonine hydrochloride,
pramoxine hydrochloride, benzocaine
53. Why is it important that patients
have an empty stomach prior to
surgery?
– Answer: General anesthetics act on the chemoreceptor
trigger zone and the vomiting center of the brain stem.
Because vomiting is a possibility while under general
anesthesia, it is important that the patient’s stomach be
empty to minimize the vomiting. Also, when anesthesia
is given, it is common for normal reflexes to relax. The
horizontal position of the patient may allow for stomach
contents to travel from the gastrointestinal tract into
the esophagus, mouth, or even the windpipe and lungs.
The foreign matter in the lungs may cause aspiration
pneumonia.
54. Which over-the-counter anesthetics are
available for dental issues? What are their
mechanisms of action and indications?
• Benzocaine is the active ingredient used in the
majority of dental issues. The mechanism of
action is blocking the voltage gated Na+
channels which causes a decrease in Na+
permeability. As a result, the conduction of
nerve impulses is blocked. Alcohols are also
used, which are inactive ingredients that have
some local anesthetic effect.
55. What is the main ingredient in the OTC urinary
anesthetics/analgesics available? What is the
mechanism of action and indications?
• Ingredient - phenazopyridine
• Mechanism of action – unknown – mostly
listed as an analgesic, but may also have local
anesthetic properties; acts on the urinary tract
as it is excreted
56. What anesthetics are available for
sore throats?
• Lozenges
• Cepacol Sore Throat Sugar (Benzocaine 15mg;
Pectin 5 mg)
• Chloraseptic Sore Throat (Benzocaine 5mg;
Menthol 10 mg)
• Sucrets Classic Sore Throat (Dyclonine
hydrochloride 2 mg)
59. Staining
• Cell walls
– Cytoplasmic membrane covered with peptidoglycan
cell wall (both gram neg and gram pos)
– Amino acids from neighboring peptidoglycans will
cross-link, stabilizing the structure
• Enzyme that catalyzes crosslinks is a target for penicillin
– Gram positive cell wall is thick with many complex
crosslinks
– Gram negative cell wall is thin with few simple
crosslinks
– Bacterial cytoplasmic membrane has no cholesterol or
other sterols
60. Staining
• Gram negative
– Have inner cytoplasmic membrane, small space, thin
peptidoglycan cell wall (no teichoic acid), unique outer
membrane that contains lipopolysaccharide (LPS)
• Outer membrane is anchored to cell wall by murein lipoprotein
• LPS contains three components, including lipid A, which is toxic to
humans (endotoxin)
• When bacterial cells are lysed by a properly functioning immune
system, fragments of membrane containing lipid A are released
into the circulation, causing fever, diarrhea, and possibly fatal
septic (endotoxic) shock
– Outer LPS-containing layer blocks out molecules (Gram
negative), including antibiotics and lysozyme
61. Staining
• Gram positive
– Extensive crosslinking of cell wall outside cytoplasmic
membrane
– Peptidoglycan, TEICHOIC ACID, polysaccharides,
proteins
– Inner surface of cell wall touches outer surface of
cytoplasmic membrane
– Thickly meshed peptidoglycan layer does not block
the passage of small molecules, so dyes can enter
(Gram positive) – large enough to become trapped
62. Gram Positive
• 6 main gram positive organisms that cause
disease in humans – most of the other disease
causing organisms are gram negative
– Streptococcus sp.– chains of cocci
– Staphylococcus sp. – clumps of cocci
– Bacillus sp. – rods that form spores
– Clostridium sp. – rods that form spores
– Corynebacterium sp. – rods (no spores)
– Listeria sp. – rods (no spores) – only gram positive
organism that has endotoxin
63. Growth Requirements
• Oxygen requirement
– Obligate aerobes – require oxygen
– Anaerobes – do not require oxygen
• Aerotolerant anaerobes – can survive in the presence
of small amounts of oxygen, but thrive without oxygen
– Facultative anaerobes – can grow under aerobic
or anaerobic conditions
• Temperature – most pathogenic bacteria grow
best at body temperature (35-37° C)
64. Virulence
• Enzyme-mediated tissue damage
– Bacterial metabolites, degradative enzymes, cytolytic
exotoxins
• Adherence
– Pili or adhesion molecules – allows for colonization
• Toxin-induced localized and systemic effects
– LPS (endotoxin) is in cell wall of gram negative
bacteria – initiates complement and clotting cascade
– can lead to shock
• Resistance to antibiotics
65. Virulence
• Invasion and growth in normally sterile sites –
even normal flora can cause disease when
invading sites such as CSF, blood, lung
• Circulation via the blood or other means of
spreading from primary infection site
– Tissue damage promotes the spread of bacteria
• Evasion of host immune response by capsule,
catalase production, intracellular growth and
other mechanisms
66. Gram Positive Bacteria
• Staphylococcus spp.
– S. aureus, S. epidermidis, S. saprophyticus
– Normal flora
– S. aureus is most virulent
• MRSA – Methicillin resistant staph aureus
• Toxin-mediated diseases – food poisoning (salted or smoked
meats or creamy foods), toxic shock syndrome
• Inflammatory diseases with pyogenic and necrotic functions –
range from mild skin lesions to life-threatening systemic diseases
and bacteremia
– S. epidermidis – can colonize prosthetic heart valves,
stents, prosthetic joints
– S. saprophyticus – frequent cause of UTIs in sexually active
young women
67. Gram Positive Bacteria
• Streptococcus spp.
– S. pyogenes, S. pneumoniae, and others (causes of
serious neonatal disease, endocarditis, dental
caries)
– S. pyogenes
• Group A strep – causes strep throat, skin infections,
postsurgical cellulitis,
– Toxin-mediated diseases – also causes TSS, scarlet fever
– Nonsuppurative autoimmune sequelae – acute
glomerulonephritis, rheumatic fever
68. Gram Positive Bacteria
• Clostridium spp.
– C. botulinum, C. difficile, C. perfringens, C. tetani
– Gram positive (rods) anaerobes that form spores
and produce potent exotoxins
– Produce serious diseases – gas gangrene, tetanus,
food poisoning (botulism), necrotizing
enterocolitis
• Corynebacterium diphtheriae
– Cause of respiratory and cutaneous diphtheria
69. Gram Negative Bacteria
• Neisseria spp.
– Neisseria meningitidis – causes meningitis, usually
in children under 5 and among those living in
close quarters, such as college students and
military personnel
– Neisseria gonorrhoeae – causes acute gonorrhea,
pelvic inflammatory disease, infection of female
reproductive organs
70. Gram Negative Bacteria
• Haemophilus influenzae
– Type b (Hib) is the most virulent – can cause
meningitis, epiglottis, arthritis, otitis, etc.
• Pseudomonas aeruginosa
– Causes opportunistic infections
• UTI, burn wound infections, ear infections, skin
infections, pulmonary infections (particularly in CF pts.)
72. Viral Replication
• DNA viruses
– DNA enters host cell nucleus
– Is transcribed to messenger RNA
– mRNA is translated into viral proteins
• RNA viruses
– Host cell could use enzymes contained in viral particle to
synthesize mRNA
– Or the viral RNA could serve as its own mRNA – the mRNA is
translated into viral proteins, such as RNA polymerase, and more
mRNA and genomic RNA is made
• Retroviruses
– Contain reverse transcriptase enzyme that makes DNA from viral
RNA and then the DNA inserts into the host genome
73. Clinical Course of Disease
• Incubation period – site of disease and time needed
for damage to occur determines incubation period
– Diseases that manifest at site of entry usually have
incubation periods less than 1 week – exception is
papillomaviruses (7-21 weeks)
– Diseases that manifest in tissues distant from the site of
entry have incubation periods ranging from 1 week to
several months
– Diseases that result from damage to the immune system
or from slow accumulation of tissue damage may have
incubation periods ranging from several weeks (HBV, EBV)
to years (HIV)
74. DNA Viruses
• Noneveloped DNA viruses
– Human papillomavirus
• Infect and replicate in cutaneous and mucosal
epithelial tissue
• Leads to production of proteins that inactivate tumor
suppressor proteins Rb and p53, leading to hyperplasia
of host cells
• Transmission occurs through direct contact with skin
warts or genital warts, or through mother/child
transmission during birth
• HPV can lead to cervical cancer
75. DNA Viruses
• Enveloped DNA viruses
– Varicella zoster virus – still in Herpesviridae family
– Double-stranded DNA virus
– Human herpesvirus 3 – commonly called varicella zoster virus (VZV)
and causes two common diseases
• Chickenpox – called varicella
• Shingles – called herpes zoster
– Chickenpox is result of primary infection – one of the most common
communicable diseases worldwide
• Highly contagious
• Common in children, but can have serious consequences in adults and
immunocompromised patients
– Shingles is result of VZV reactivation – not life-threatening, but causes
severe pain and neuralgia
76. DNA Viruses
• Enveloped DNA viruses
– Epstein-Barr virus (EBV)
• Herpes virus
• Double-stranded DNA virus
• Viral envelope is derived from cellular membranes of host cells through
budding process – envelope is essential for infectivity
• Infects B lymphocytes – establishes a latent infection with immortalization of
the cell with restricted expression of viral proteins
• Latent infection can be activated to lytic infection
• Only B cells are infected
• Transmission is through oral secretions – often through kissing
• About 90% of adults have been exposed to EBV – two peaks of transmission
(ages 1-6 and ages 14-20)
• Diseases associated with EBV
– Infectious mononucleosis, Burkitt’s lymphoma, nasopharyngeal carcinoma (NPC),
Hodgkin’s disease, other lymphoid and epithelial tumors
77. RNA Viruses
• Nonenveloped RNA viruses
– Includes poliovirus, coxsackieviruses, hepatitis A virus,
rhinoviruses (common cold), rotoviruses, Norwalk virus
– Poliovirus binds to receptors on muscle cells and neurons
• Different disease outcomes – paralytic, nonparalytic, may also
cause minor illness
– Coxsackievirus A – hand-foot-and-mouth disease – self-
limiting disease of young children with vesicular lesions
and mild fever
– Rotovirus – infection of GI epithelial cells leading to watery
diarrhea and vomiting
• Fecal-oral transmission
• Most serious in infants (dehydration can be fatal)
78. RNA Viruses
• Influenza
– Large antigenic shifts occur every 10-40 years historically
to cause pandemic influenza outbreak – because it is so
different from previous strains large segments of
population is susceptible
– Transmission – inhalation of respiratory droplets from
infected person
– Vaccine is available – made based on strains prevalent
during the previous flu season
– The major site of infectivity is ciliated columnar cells
– No explanation for many of the symptoms, such as
myalgia
79. RNA Viruses
• Respiratory syncytial virus (RSV)
– Enveloped RNA virus with non-segmented, single-
stranded, negative-sense genome
– Leading viral agent causing death in children under 5
years old (worldwide)
– Common agent causing pneumonia and bronchiolitis
in infants and trachobronchitis and upper RTIs in
older children and adults
– RSV is highly contagious
– Lower respiratory tract disease associated with
primary infection is almost entirely confined to the
child under 3 years of age
80. RNA Viruses
• RSV
– Transmission – requires contact with large particles of respiratory
secretions
– Eyes and nose are major portals of entry
– RSV will remain infectious on hands long enough to be transmitted to
self or others – handwashing is essential to limit transmission
– Healthcare workers may be important carriers of RSV, as they may
have mild symptoms and continue to work
– Early bronchiolitis – inflammation
– Progresses to necrosis and sloughing of bronchiolar epithelia – dead
cells will plug up small airways, blocking airflow
81. Nucleoside/Nucleotide Analogs
• Similar mechanisms of action
• Similar indications for clinical use
• All are well tolerated – side effects uncommon
• Analogs are incorporated into the viral nucleic
acid, which is then nonfunctional
– Insert themselves into DNA and make
nonfunctional viral components
• Converted by viral enzymes
– For example, acyclovir is converted to acyclovir
monophosphate by a viral enzyme
82. Nucleoside/Nucleotide Analogs
• Acyclovir (Valtrex)
– Mechanism of Action
• Viral thymidine kinase converts acyclovir to acyclovir-
monophosphate
• Further phophorylated to triphosphate
• Competes with endogenous compounds for DNA
polymerase and binds irreversibly to DNA template
• Chain termination when incorporated into viral DNA
– Clinical Uses
• HSV-1, HSV-2, and VZV
• Weaker activity against EBV, CMV, HHV-6
83. Nucleoside/Nucleotide Analogs
• Acyclovir
– ADME
• Oral, IV, and topical formulations
• Excreted in urine
• Diffuses in most fluids and tissues, including CSF (levels
are 50% of serum levels)
– Resistance
• Occurs through mutation of viral thymidine kinase or
DNA polymerase
• Cross-resistance in other analogs that require
thymidine kinase activation
84. Nucleoside/Nucleotide Analogs
• Other NS/NT analogs
– Valacyclovir (HSV and VZV)
– Famciclovir (HSV and VZV)
– Penciclovir (topical) (HSV)
– Trifluridine (HSV, vaccinia, and some adenoviruses)
– Ganciclovir (HSV, VZV, EBV, HHV-6, CMV, and KSHV)
• Oral, IV, or intraocular implant
• Adverse effects – myelosuppression, retinal detachment
85. Preventing Viral Entry
• Docosanol
– Saturated 22-carbon aliphatic alcohol
– Inhibits fusion between the plasma membrane
and the HSV envelope, preventing viral entry into
the cells
– Available without prescription (topical) for
treatment of herpes viral infection – Abreva
http://www.abreva.com/
86. Antiretroviral Therapy
• HAART – highly active anti-retroviral therapy
– Multiple drug therapy – 3 or 4 drugs
– Reduces viral replication to the lowest possible
level
– Decreases likelihood of resistance
87. NRTIs and
NNRTIs
Fusion inhibitors
Protease Inhibitors-
block release of viral
particles (can still form,
just don’t bud off)
http://www.mcat45.com/image
s/HIV-replication-cycle.png
Integrase Strand
Transfer Inhibitors
88. NRTIs
• Act by competitive inhibition of HIV-1 reverse
transcriptase
• Can be incorporated into the growing viral
DNA chain to cause termination
• Each requires intracytoplasmic activation via
phosphorylation by cellular enzymes to the
triphosphate form
• Most have activity against HIV-2
89. NRTIs
• Abacavir (Ziagen) – guanosine analog
– Metabolism – glucuronidation and carboxylation
– 50% protein-bound
– Hypersensitivity syndrome
• Didanosine (Videx)– adenosine analog
– Degraded at low gastric pH – must be taken with antacid
– Food decreases bioavailability
– Renal secretion – little metabolism
– Not extensively protein-bound
– Main side effects – peripheral neuropathy and pancreatitis
• Emtricitabine (Emtriva) – cytosine analog
– Renal secretion – little metabolism
– Not extensively protein-bound
– Few adverse effects and no effect on mitochondrial DNA
90. Protease Inhibitors
• Adverse Effects
– Redistribution and accumulation of body fat
(except atazanavir)
– Increases in blood lipids levels
– Glucose intolerance and insulin resistance
– Causes of these adverse effects is unknown
– Increased bleeding in pts. with Hemophilia A or B
– May be inducers or inhibitors of P450 enzymes
91. Fusion Inhibitors
• Enfuvirtide (Fuzeon)
– First agent in this new class of antiretroviral drugs
– Synthetic peptide
– Blocks viral entry into the cell
– Binds to the gp41 viral envelope glycoprotein
– Prevents fusion of virus with plasma membrane
– SC injection
– Adverse effects - local reactions at the injection site
92. Anti-influenza Agents
• Zanamivir (Relenza) and Oseltamivir (Tamiflu)
– Neuraminidase inhibitors
– Interfere with the release of progeny virus from infected cells to new
host cells
– Effective against influenza A and B
– Early administration is required
– Zanamivir is administered via inhalation
– Oseltamivir is administered orally
– Avoid near vaccination times – noted exceptions
– Look up adverse effects and warnings on Lexicomp
93. Categories
• Superficial mycoses – surface of hair, nails, skin
• Cutaneous mycoses – involve epidermis and deeper layers of
hair, skin, and nails
• Subcutaneous mycoses – involves dermis, and subcutaneous
tissues and muscles - cause chronic nodules or ulcers in
subcutaneous tissues
• Systemic mycoses – inhaled from the environment (soil, etc.)
and produce lung infections that spread in
immunocompromised host
• Candidiasis – caused by Candida albicans – opportunistic
pathogen
94. Fungal Infections
• Cutaneous mycoses
– Caused by about 30 different fungi called dermatophytes
– Includes ringworm, jock itch, athlete’s foot, scalp infection
(common in children), nail infection
– Also includes cutaneous candidiasis – oral thrush
(neonates, diabetics, AIDS pts., pts. taking antibiotics or
steroids) and vulvovaginitis (antibiotic use, pH increase,
diabetes) – in immunocompromised cancer and transplant
pts will present as disseminated disease
– Topical treatment
95. Fungal Infections
• Subcutaneous mycoses
– Often caused by organisms in the soil – may be
melanin-containing
– Enter into breaks in the skin – may remain local or
travel through lymphatic system
– Sporothrix schenckii – causes sporotrichosis in
gardeners, from thorn prick
96. Fungal Infections
• Systemic mycoses
– Aspergillus spp. – appears as ‘fungus ball’ on X-ray –
induces allergic reactions and becomes systemic in
immunocompromised patients
– Pneumocystis jiroveci (sometimes classified as a
protozoan) – interstitial pneumonia in AIDS patients
– Coccidioides immitis – endemic in desert areas of
southwestern US
• San Joaquin Valley fever – acute, self-limiting flu-like illness
97. Fungal Infections
• Systemic mycoses
– Cryptococcus neoformans – found in pigeon droppings and
nests
• May appear as a single nodule resembling a tumor
• Can spread to CSF – AIDS patients
– Histoplasma capsulatum – endemic in Ohio and
Mississippi River valleys
• Found in bird and bat droppings
• Pulmonary granulomas visible on X-ray
98. Parasitic Infections
• Blood and tissue protozoa
– Leishmania spp.
• Endemic to tropical and subtropical regions
• Transmitted by sandfly
• Infects macrophages leading to cutaneous, mucocutaneous, and
visceral disease
– Plasmodium spp.
• Endemic to tropical regions
• Transmitted by female Anopheles mosquito
• Causes malaria
• Life cycle takes place in mosquito, human liver, and human red
blood cells
99. Parasitic Infections
• Blood and tissue protozoa
– Toxoplasma gondii – acquired from cat litter, ingestion of
undercooked meat, or in utero
• Mononucleosis-like syndrome in healthy individuals
• Potentially fatal encephalitis in immunocompromised patients
– Trypanosoma cruzi
• Endemic to South America
• Transmitted by reduviid bug
• Causes Chagas’ disease – cardiomyopathy, megacolon,
megaesophagus)
100. Parasitic Infections
• Helminthic parasites
– Roundworms
• Trichinella spiralis
– Transmitted by eating undercooked meat, especially pork
– Encysted larvae in muscle – extreme muscle pain
– Fever, diarrhea, eye edema, hemorrhages under nails
101. Parasitic Infections
• Helminthic parasites
– Flukes and flatworms
• Schistosoma spp. – blood and bladder flukes
– Transmitted through skin penetration by motile larvae – snails are
intermediate hosts
– Fibrosis of liver and ascites
– Bladder granulomas and hematuria
– Eggs are covered with spines – stool or urine
• Taenia spp. – beef and pork tapeworms (up to 10 m)
– Suckers and hooks on larvae
– Abdominal pain, diarrhea, weight loss
– Brain, eye, and muscle involvement (cysts and inflammation) due to
ingestion of eggs rather than larvae – rare in US
102. β-lactams inhibit peptidoglycan
cross-linking
• Peptidoglycan:
polymers of glycan
units, joined by
peptide cross-links
(transpeptidation)
mediated by a
transpeptidase
enzyme AKA-Penicillin
Binding Protein (PBP)
• Cross linking give cell
wall its structural
rigidity
• Peptidoglycan is not
found in mammalian
cells
NAG=N-acetyl glucosamine
NAM=N-acetyl muramic aci
103. β-lactams
Mechanism of Action
- As structural analogs of terminal D-Ala—D-Ala on
the peptidoglycan strand, β-lactams bind to PBPs
and competitively block its activity (competitive
inhibitor)
- Prevent the formation of an intact cell wall,
resulting in bacterial lysis (bactericidal)
- For β-lactam antibiotics to work, bacteria must be
synthesizing cell walls thus β-lactams should not
be combined with bacteriostatic drugs
104. Mechanisms of bacterial resistance to
β-lactams
1. Production of β-lactamases (most common)
2. Alteration of PBPs
105. Inactivation of β-lactams by β-lactamases
Hundreds of bacterial β-lactamases identified
–Differ between species and in selectivity
• S. aureus, Haemophilus sp. and E. coli beta lactamases
– Relatively narrow substrate specificity with preference for
penicillins
• P. aeruginosa and Enterobacter sp. produce AmpC
beta-lactamase
– Hydrolyzes both penicillins and cephalosporins
• Several species produce Extended-Spectrum Beta-
Lactamases (ESBL)
– Both penecillin and cephalosporin selectivity
106. Penicillins
1- Natural penicillins: Penicillin G , Penicillin V
Pharmacokinetics:
Penicillin G: Acid labile; administered parenterally
Procaine and benzathine penicillin G: Water
insoluble depot or repository forms
administered IM
Penicillin V: Acid stable (oral)
107. Penicillins
1- Natural penicillins: Penicillin G , Penicillin V
Major therapeutic use:
PenG:
Drug of choice for infections caused by streptococci (e.g
pharyngitis), meningococci (e.g meningitis), and T.
pallidum (syphilis)
PenV:
Indicated only in minor infections because of:
– Poor oral bioavailability
– qid dosing
– Less active than Pen G
108. Penicillins
1- Natural penicillins: Penicillin G , Penicillin V
Bacterial resistance:
Mainly by production of penicillinases (a β-lactamase
that inactivates penicillins)
110. Penicillins
2. Antistaphylococcal (penicillinase resistant) penicillins
Major therapeutic use:
• Used exclusively in treatment of Staphylococcal infections
• Unfortunately, now there is Methicillin-Resistant
Staphylococcus aureus (MRSA), Methicillin-Resistant
Staphylococcus epidermidis (MRSE) as a source of serious
hospital-acquired infections
– Mechanism of resistance: PBP alteration (have lower affinity
to β-lactams)
– Treatment: MRSA and MRSE infections are treated with
vancomycin
111. Penicillins
2. Antistaphylococcal (penicillinase resistant) penicillins
Pharmacokinetics:
- Dicloxacillin, and oxacillin are acid stable (given orally
for mild staph. infection)
- Nafcillin is somewhat less stable in acidic media
(given IV for serious systemic staph. infection)
- Oxacillin can also be given IV for serious systemic
staph. infection
113. Penicillins
3. Extended spectrum penicillins
Major therapeutic uses:
Amoxicillin, ampicillin:
– Treatment of infections due to susceptible Gm- microbes
(e.g RTI, UTI, Otitis, sinusitis )
– Drug of choice for treating infections caused by enterococci
– Treatment of mixed infections caused by susceptible Gm+
and Gm- organisms
– Treatment of penicillin-resistant pneumococci
114. Penicillins
3. Extended spectrum penicillins
Major therapeutic uses:
Piperacillin
Treatment of serious systemic infections caused by
Gram(-) bacteria
• Hospital-acquired infections (Immunocompromised patients)
• Sepsis
• Pneumonias
• Infected burns
• Treatment of P. aeruginosa infections: usually in combination
with an aminoglycoside
115. Penicillins
Pharmacokinetics
• Absorption of most oral penicillins (except for
amoxicillin) is impaired by food; should be
administered 1-2 h before or after meal
• Excretion of most penicillins (except for
Antistaphylococcal penecillins) is by kidney;
need to adjust dose in renal failure
117. Cephalosporins
Grouped into 5 generations based on their
spectra of activity:
– First generation
Drug Administration Elimination
Cefadroxil p.o Renal
Cefazolin IV Renal
Cephalexin p.o Renal
118. Cephalosporins
Grouped into 5 generations based on their
spectra of activity:
– Second generation
Drug Administration Elimination
Cefaclor p.o Renal
Cefprozil p.o Renal
Cefuroxime IV, IM Renal
Cefoxitin IV Renal
Cefotetan IV, IM Renal
Red: Cephamycins
119. Cephalosporins
– Third-generation
Drug Administration Elimination
Cefixime p.o Renal
Cefdinir p.o Renal
Cefpodoxime p.o Renal
Ceftibuten p.o Renal
Cefotaxime IV Renal
Ceftazidime IV, IM Renal
Ceftizoxime IV Renal
Ceftriaxone IV, IM Biliary/renal
120. Cephalosporins
Grouped into 5 generations based on their
spectra of activity:
– Fourth-generation
– Fifth generation
Drug Administration Elimination
Cefepime IV, IM Renal
Drug Administration Elimination
Ceftaroline IV Renal
121. Cephalosporins
Third generation cephalosporins
Spectrum of activity:
– Much less effective than 1st
generation against Gm+
– Compared with 2nd
generation, these drugs have expanded
Gm- coverage
– Resistant to some Gm- β-lactamases but susceptible to
enterobacter β-lactamase (Amp C)
– Ceftriaxone and cefotaxime: Anti-pneumococcal activity
– Ceftazidime : Active against P. aeruginosa
122. Cephalosporins
Fourth generation cephalosporin (Cefepime)
Spectrum of activity:
- Extensive Gm- coverage plus better Gm+ coverage than 3rd
generation
- Better resistance to Gm- β-lactamases than 3rd
generation
(esp. of enterobacter and penicillin resistant streptococci)
- Active against P. aeruginosa
Major therapeutic use:
– Similar to 3rd
generation
– Useful in treatment of enterobacter infections
– Used for severe infections (Pneumonia, sepsis, meningitis)
123. Cephalosporins
Fifth generation cephalosporin (Ceftaroline)
Spectrum of activity:
• Gm- coverage similar to 4rd
generation
• Gm+ coverage including methicillin-resistant
Staphylococcus aureus (MRSA)
Major therapeutic use:
• Community-acquired pneumonia
• Complicated skin and skin structure infection
124. Cephalosporins
Adverse effects of cephalosporins
– Select 2nd generation drugs (cephamycins) contain
N-MethylThioTetrazole side chain (MTT side chain)
• Cephamycins (Cefoxitin, cefotetan)
• These agents cause
– Disulfiram-like reaction
– Hypoprothrombinemia and bleeding
(anti-vitamin K effect)
N-Methylthiotetrazole
126. β-lactam antibiotics
Carbapenems
Pharmacokinetics:
– IV administration
– IM: Ertapenem is formulated with 1% lidicaine
– Renal excretion
- Imipenem is inactivated by dehydropeptidases in the renal
tubule; therefore administered with equal quantity of cilastatin
- Cilastatin is a dehydropeptidase inhibitor and must be co-
administered with imipenem to ensure its efficacy.
127. β-lactam antibiotics
Carbapenems
Major therapeutic use
– Drug of choice for ESBL infections
– Plays a role in empirical therapy
– Treatment of choice of Enterobacter infections
– With/out an aminoglycoside for P. aeruginosa infections
Adverse effects (More common with imipenem)
– Hypersensitivity
– NVD
– Local reactions
– Seizures
128. β-lactam antibiotics
Monobactams
Aztreonam (given IV)
Spectrum of activity:
– Relatively resistant to β-lactamases
– No significant cross-reactivity with penicillins
– Narrow spectrum of activity (Active against Gm-
aerobes including Pseudomonas ; inactive against
Gm+ bacteria or anaerobes)
129. Non-β-lactam Cell Wall Synthesis
Inhibitors
Fosfomycin (p.o)
Mechanism of action:
– Inhibits step 1 in cell wall synthesis
– Structural analog of phosphoenol pyruvate (PEP)
– Inhibit enol pyruvate transferase: block the formation of N-
acetyl-muramic acid
Fosfomycin Phosphoenol pyrovate
130. Non-β-lactam Cell Wall Synthesis
Inhibitors
Fosfomycin (p.o, IV)
Spectrum of activity:
– Broad spectrum
Excretion:
– Renal
Major therapeutic use
– Uncomplicated lower UTI
131. Non-β-lactam Cell Wall Synthesis
Inhibitors
Bacitracin
Mechanism of action:
– Inhibits Step 3 in cell wall synthesis
– Blocks dephosphorylation of isoprenyl pyrophosphate, a lipid
which carries the building blocks of peptidoglycan outside the
plasma membrane
Spectrum of activity:
– Gram +; Neisseria; T. pallidum
Major therapeutic use
– Topical application ONLY (renal failure)
– Localized skin infections
– Prevention of wound infections
Bacitracin: a cyclic polypeptide
132. Non-β-lactam Cell Wall Synthesis Inhibitors
Vancomycin
Mechanism of action:
– Bind with high affinity to the D-Ala—D-Ala terminus of pentapeptide
– Block transglycosylase (elongation of peptidoglycan) and transpeptidation (cross
linking)
Spectrum of activity:
– Active only against Gram(+) bacteria, including MRSA, MRSE (bactericidal)
– Enterococci (bacteriostatic)
Major therapeutic use
– Used in treatment of serious infections with β-lactam resistant Gram(+) bacteria or in
cases of allergy to β-lactams
– Treatment of MRSA, MRSE infections (sepsis, endocarditis)
133. Non-β-lactam Cell Wall Synthesis
Inhibitors
Vancomycin
Pharmacokinetics
– Administered IV (Slow infusion)
– Administered orally only for the treatment of pseudomembranous
colitis caused by Clostridium difficile (local effect in colon);
metronidazole is preferred as initial therapy.
Adverse effects:
– Vancomycin: Red Man Syndrome: flushing, shock in severe cases
(caused by vancomycin-induced histamine release due to rapid
infusion)
– Phlebitis at the site of injection
– Ototoxicity
– Nephrotoxicity
134. Non-β-lactam Cell Wall Synthesis
Inhibitors
Vancomycin
Bacterial resistance
– Vancomycin Resistant Enterococci (VRE) synthesize
pentapeptide with D-ala-D-lactate or D-ala-D-serine
terminus, (reduced affinity for drug)
– Vancomycin Resistant S. Aureus (VRSA) can overexpress
D-ala-D-ala (competitor to bind up the drug)
135. Sulfonamides
Mechanism of action
• Structural analogues of para-aminobenzoic
acid (PABA)
• Inhibit dihydropteroate synthase (which
produces dihydrofolic acid); competitive
inhibitor
• Bacteriostatic
• High concentrations of PABA inhibit sulfa
activity
136. Sulfonamides
Spectrum of activity
• Broad Spectrum
• Active against many Gm+ bacteria including MRSA,
Streptococci, Nocardia, and Clostridium perfringens.
• Active against Gm- organisms (E Coli, Klebsiella,
Proteus, Salmonella, Shigella)
• Active against some protozoa (Plasmodium,
Toxoplasma gondii) and atypical bacteria (Chlamydia
trachomatis)
137. Sulfonamides
Major therapeutic use
• Not typically used alone for common bacterial
infections
• Treatment of malaria
• Treatment of CNS toxoplasmosis
138. Sulfonamides
Adverse effects
• Hypersensitivity (cross reactivity with other
sulfonamides, diuretics (thiazides,
acetazolamide), and sulfonylurea antidiabetic
agents
– Steven’s Johnson syndrome (SJS)
• GI distress
• Crystalluria: drink plenty of fluids (sulfadiazine)
• Bone marrow suppression
• Hepatotoxicity and nephrotoxicity
• Photosensitivity
• Kernicterus in infants -competes for bilirubin
binding sites on albumin and increases levels of
unconjugated bilirubin- CNS toxicity
139. Sulfonamides
Mechanism of bacteria resistance:
• Overproduction of PABA
• Reduced enzyme affinity
(dihydropteroate synthase)
• Reduced cell permeability to
sulfonamides
140. Trimethoprim
Mechanism of action
• Acts sequentially with sulfonamindes in the
synthesis of purines
• Inhibit dihyrofolate reductase (DHFR) (which
produces tetrahydrofolic acid)
• 50,000X more active against bacterial DHFR
than human DHFR
141. Trimethoprim-Sulfamethoxazole
Spectrum of activity
• Broad spectrum: Many Gm+ (including MRSA)
and Gm- (including E, coli, H. influenza, Moraxella
catarrhalis, Klebsiella pneumonia)
• Not active against Pseudomonal spp, anaerobes,
or atypical bacteria
Major therapeutic use
• UTIs (decreased efficacy with increasing E.coli
resistance rates)
• Pneumocystis pneumonia
• Sinusitis, otitis media
142. Trimethoprim-Sulfamethoxazole
Adverse effects
• Same as sulfa
• Folinic acid supplement?
Bacterial resistance to trimethoprim
• Overproduction of DHFR
• Reduced enzyme affinity (DHFR)
• Reduced cell permeability to trimethoprim
143. Mechanism of action
• Inhibit bacterial DNA synthesis (DNA replication)
• Inhibit bacterial topoisomeraseII (DNA gyrase) and
topoisomeraseIV
– TopoisomeraseII : responsible for DNA unwinding needed for initiation of
DNA replication
– TopoisomeraseIV: responsible for separation of replicated chromosomal
DNA into the respective daughter cells during cell division.
• Bactericidal
• Killing is concentration dependent, significant PAE
FLUOROQUINOLONES
144. Fluoroquinolones
Major therapeutic uses
• Complicated UTIs, community acquired UTIs
(Ciprofloxacin)
• Pneumonia (Levofloxacin, moxifloxacin)
• Gm- coverage of abdominal infections, hospital
acquired infections
• Nosocomial infections esp. pseudomonas or
complicated gram negative infections
• Combination therapy: fluoroquinolone + a β-lactam
(additive)
145. Fluoroquinolones
Drug-drug interaction
• Certain fluroquinolones inhibit CYP1A2
enzyme: decrease metabolism of xanthine
derivatives (theophylline) and warfarin
(Cipro>levo>moxi)
• Increased risk of torsade de points in
combination with agents that increase the QT
interval (class IA or III antiarrhythmic agents)
146. Post Antibiotic Effect (PAE): Persistent
suppression of bacterial growth that results
from drug exposure after the drug has been
completely removed.
147. Combination Antimicrobial Therapy
Some mechanisms of antibiotic synergism:
1. Each antibiotic affects a different step in a biochemical
pathway (trimethoprim + sulfamethoxazole)
2. One drug may enhance the uptake of a second drug by
the microorganism (penicillin + aminoglycoside)
3. One drug may prevent the enzymatic degradation of
another drug (amoxicillin + clavulanic acid)
151. Chloroquine
• Synthetic 4-aminoquinoline
• Drug of choice since the 1940s
• Resistance is a common problem in P. falciparum, and
increasing in P. vivax
• Drug of choice for treatment and prophylaxis of sensitive
malaria
• Mechanism of action
– Blood schizonticide (moderately effective gametocide against all
species but falciparum)
– Not active against liver stage parasites
– May act by concentrating in the parasite food vacuoles and
preventing the polymerization of heme into hemozoin – toxic due
to buildup of free heme
152. Amodiaquine
• Closely related to chloroquine
• Most likely shares mechanism of action and
resistance
• Low cost, limited toxicity, in some areas effective
against chloroquine-resistant malaria
• Heme to hemozosin
• Adverse effects
– Agranulocytosis, aplastic anemia, hepatotoxicity
– Not used prophylactically because of toxicity with long-
term use
153. Quinine and Quinidine
• First-line therapy for falciparum malaria, esp. in
severe disease
• Toxicity may affect therapy
• Resistance is uncommon but increasing
• Derived from bark of cinchona tree
• Quinidine is the D stereoisomer of quinine
• Mechanism of action
– Blood schizonticide for all four species
– Gametocide for P. vivax and P. ovale
– Not active against liver stage parasites
– Mechanism of action unknown
154. Primaquine
• Clinical Uses
– Given in conjunction with chloroquine for radical cure
– Given after completion of travel in endemic area
– Could be used prophylactically, but toxicity of concern, so
not used routinely
– Used in the treatment of Pneumocystis jiroveci
• Adverse Effects
– Rare – hematological and cardiac dysfunction
• Contraindications
– Patients with hematological problems or receiving
myelosuppressive drugs
155. Other Antimalarial Agents
• Atovaquone
– Effective prophylaxis with proquanil (Malarone)
– Mechanism unknown
• Inhibitors of Folate Synthesis
– Pyrimethamine and proquanil
– Fansidar (combination of sulfadoxine and pyrimethamine)
– Effective against RBC forms of all four species
– Also used to treat toxoplasmosis and pneumocystosis
– Well tolerated
156. Other Antimalarial Agents
• Antibiotics
– Folate antagonists
– Sulfonamides
– Tetracycline and doxycycline – RBC form
– Clindamycin – RBC form – given to children
• Artemisinin
– Oral administration only
– More soluble analogs (artesunate, artemether)
– Widely available in other countries
– Blood schizonticide
– Not effective against hepatic stages
157. Amebiasis
• Amebiasis
– Infection with Entamoeba histolytica
– Luminal or extraintestinal infection
• Metronidazole and Tinidazole
– Metronidazole – drug of choice for extraintestinal
infection
• Eradicates intestinal and extraintestinal inf.
• Also drug of choice for giardiasis and trichomoniasis
– Tinidazole
• Similar activity and less toxicity
– Mechanism of action – reduction of nitro group to reactive
product
158. Amebiasis
• Iodoquinol
– Luminal amebicide – commonly used with metronidazole
– Mechanism of action unknown
– 90% of drug retained in intestine
• Diloxanide furoate
– Luminal amebicide
– Mechanism of action unknown
• Paromomycin sulfate
– Luminal amebicide
– Less toxicity than other agents
159. Antihelminthic Drugs
• Albendazole
– Drug of choice for hydatid disease and
cysticercosis
– Also used for pinworms, hookworms, ascariasis,
trichuriasis, and strongyloidiasis
– Undergoes first pass metabolism to the active
metabolite
– Inhibits microtubule synthesis
– Well tolerated
160. Bithionol
• Drug of choice for fascioliasis (sheep liver
fluke)
• Also used for paragonimiasis
• Up to 40% of patients experience mild side
effects – GI effects, headache, dizziness
161. Ivermectin
• Drug of choice for strongyloidiasis and onchocerciasis
• Alternate drug for a number of other helminth infections
• Paralyzes nematodes and arthropods by increasing GABA
signaling
• Also effective against other parasites
• Adverse effects
– Strongyloidiasis treatment – infrequent
• Fatique, dizziness, N/V, abdominal pain, rash
– Onchocerciasis treatment
• Mazotti reaction – due to killing of microfilariae
• Fever, headache, rash, weakness, hypotension, peripheral edema
162. Piperazine
• Alternative treatment for ascariasis
• Not recommended for other helminth
infections
• Blocks acetylcholine at the neuromuscular
junction – causes paralysis of worm
• Contraindicated in pregnancy, patients with
impaired renal or liver function, and in
patients with a history of epilepsy or chronic
neurological disease
163. Pyrantel Pamoate
• Poorly absorbed from the GI tract, so most
effective against luminal parasites
• Neuromuscular blocking agent – paralyzes
worm, followed by expulsion of worms
• Available in the US without a prescription for
treatment of pinworm infection
• Also used for ascariasis and hookworm
infections
• Adverse effects similar to other agents
164. First-Line Therapy
• Combine the greatest level of efficacy with an
acceptable degree of toxicity
– Isoniazid
– Rifampin (and related drugs)
– Ethambutol
– Pyrazinamide
165. Isoniazid
• The primary drug for treatment of TB
– Used if patient has isoniazid-sensitive strain and if patient
can tolerate the medication
• Bacteriostatic for ‘resting’ bacilli
• Bacteriocidal for rapidly dividing microorganisms
• Highly selective for mycobacteria
• Can penetrate macrophages, so effective against
intracellular and extracellular bacteria
166. Isoniazid
• Adverse Reactions
– Pyridoxine (vitamin B6) should be administered
with isoniazid to minimize risk of peripheral
neuropathy and CNS toxicity
• Indicated for malnourished patients and those
predisposed to neuropathy (elderly, pregnant women,
HIV-infected patients, diabetics, alcoholics, patients
with anemia, and uremics – also slow acetylators)
167. Isoniazid – Adverse Effects
• Common
– Drug-induced hepatitis –
requires immediate
discontinuation of drug
– Increase in liver enzymes – does
not require discontinuation of
drug
– Peripheral neuropathy
– Occasional
– Clinical hepatitis with N/V,
jaundice, and RUQ pain – can
be fatal
• Risk increases with age, in
alcoholics, and during
pregnancy
• Fever
• Skin rashes
• Drug-induced SLE
• Hematologic abnormalities
• Tinnitus
• GI discomfort
• Reduces the metabolism of
phenytoin
• CNS toxicity – memory loss,
psychosis, seizures
168. Rifampin
• ADME
– Distributed throughout the body to most organs and tissues
– May turn body fluids orange-red (sweat, urine, saliva, tears, etc.)
– Following oral administration, peak levels are reached in 2 to 4 hours
– Elimination is through bile, and then undergoes enterohepatic circulation
– The drug is progressively deacetylated, and retains full pharmacological
activity
– The deacetylated drug is not reabsorbed as easily, so excretion is facilitated by
deacetylation
– Half-life 1.5-5 hrs
– During the first 14 days of treatment – liver enzymes are induced, so half-life
is reduced by about 40%
– Half-life is increased in patients with hepatic insufficiency and patients that
are also taking isoniazid and are slow inactivators of isoniazid
– Incidence of adverse effects is low
169. Ethambutol Adverse Effects
• Most Significant
– Retrobulbar neuritis – results
in loss of visual acuity and
red-green color blindness
(rare at lower doses)
– Contraindicated in children
too young for vision testing
– Increased urate in the blood
due to decreased renal
excretion of uric acid –
important to note in patients
with gout
• Occasional
– Hypersensitivity
– Rash
– Fever
– Joint pain
– GI upset
– Headache
– Mental confusion
– Disorientation
– Possible hallucinations
170. Streptomycin
• Only features relevant to treating TB will be discussed here –
streptomycin has broader uses
• The oldest and least used of the first-line agents
• Does not enter cells, so only effective against extracellular
bacteria
• Most strains of tubercle bacilli are sensitive
• Mechanism of action - aminoglycoside
– Inhibits protein synthesis
• Adverse Effects (Review)
– Ototoxic
– Nephrotoxic
– Vertigo and hearing loss are most common and may be permanent
171. Interferon-γ
• Activates macrophages to kill M. tuberculosis
• Aerosol delivery of IFN-γ to the lungs of
patients with multi-drug resistant TB – results
in enhanced local immune stimulation
172. Membrane-active agents
Polymyxins
Spectrum of activity
• Selectively toxic for Gm- bacteria
• Active against Pseudomonas aeruginosa
and enterobacteriaceae spp
Adverse effects
• Neurotoxicity
• Nephrotoxicity
173. Membrane-active agents
Daptomycin
Mechanism of action
• Binds to cell membrane (in a Ca-dependent
manner) via insertion of its lipid tail.
• Forms complexes (pores) in the cell membrane
causing rapid loss of cellular K+ and membrane
depolarization, which results in loss of membrane
potential
• This inhibits DNA, RNA, and protein synthesis
resulting in cell death
• Bactericidal
174. Membrane-active agents
Daptomycin
Spectrum of activity
• Active against Gm+ only
• Activity similar to vancomycin plus active
against vancomycin –resistant spp (VRSA,
VRE)
Major therapeutic use
• Skin and soft tissue infection
• Alternative to vancomycin
• Should not be used for the treatment of
pneumonia (pulmonary surfactants
antagonize its effect)
175. Membrane-active agents
Daptomycin
Adverse effects
• Rash
• Local reactions at injection site
• Musculoskeletal effects: can progress to
rhabdomyolysis (weekly CPK monitoring
is recommended)
• Nephrotoxicity
• Hepatotoxicity
176. Tetracyclines
Spectrum of activity
– Broad spectrum
– Generally more active against Gm+ than Gm-
– Active against MRSA
– Active against atypical bacteria: rickettsia, Chlamydia,
Mycoplasma pneumoniae, Yersinia pestis, Vibrio
cholera, Borrelia
– Inactive against proteus and pseudomonas spp.
(express efflux pumps)
Inhibitors of Bacterial Protein Synthesis
177. Inhibitors of Bacterial Protein Synthesis
Tetracyclines
Pharmacokinetics
• Distribution
– Wide; accumulation in liver, spleen, bone marrow,
and in newly formed bone, dentine, and enamel
of unerupted teeth
– Good penetration into CNS
– Crosses the placenta
178. Inhibitors of Bacterial Protein Synthesis
Tetracyclines
Adverse effects
– Gastrointestinal irritation (N/V/D) and superinfections
(may include pseudomembranous colitis) – Controlled by
• Drug administration with food
• Carboxymethylcellulose
• Reduce dose
• Discontinue therapy
– Photosensitivity
– Hepatotoxicity
– Renal toxicity
– Permanent discoloration of teeth, decreased rate of
enamel growth, bone deformity, growth inhibition –fetal
and childhood risks (should NOT be given to pregnant
women or to children <8 years of age)
– http://www.tmj.ro/article.php?art=4646654684124440
tetracycline dyschromia
179. Inhibitors of Bacterial Protein Synthesis
Aminoglycosides
Mechanism of action
– Bind irreversibly to the 30S ribosomal subunit and
inhibit protein synthesis at several levels:
• Interferes with the initiation complex
• Misreading of mRNA
• Block translocation of ribosomes on mRNA
– Bactericidal
– Concentration-dependent killing with significant PAE
180. Inhibitors of Bacterial Protein Synthesis
Aminoglycosides
Antibacterial spectrum
– Primarily aerobic Gm- including P. aeruginosa (tobramycin)
– No activity against anaerobes
Major therapeutic use
– Combination therapy with penicillin or vancomycin: acts
synergistically on Staphylococcus aureus and S. epidermidis
– Gentamycin (IV): Severe Gm- infections (sepsis, pneumonia)
– Gentamycin (topical): infected burns
– Tobramycin (inhalation): P. aeruginosa LRTI in cystic fibrosis
– Amikacin: TB
– Neomycin: Preoperative bowel preparation(p.o), skin infections
(topical)
181. Inhibitors of Bacterial Protein Synthesis
Aminoglycosides
Adverse effects
– Ototoxicity (irreversible)
• Tinnitus and loss of hearing
• Vestibular toxicity (e.g., dizziness, vertigo, loss of balance)
• Ototoxicity in the fetus (avoid in pregnancy)
– Renal toxicity (reversible): Gentamycin, tobramycin
– Neuromuscular blockade (reversible) when used in
very high doses (curare like effect)
182. Inhibitors of Bacterial Protein Synthesis
Spectinomycin (IM) (aminocyclitol not an
aminoglycoside)
Mechanism of action
– Binds reversibly to the 30S ribosomal subunit
– Bacteriostatic
• Spectrum of activity
– Mostly Gm-
Major therapeutic use
– antibiotic resistant gonorrhea, or gonorrhea in
penicillin-allergic patients
Adverse effects
– Nephrotoxiciy, anemia (rare)
183. Inhibitors of Bacterial Protein Synthesis
Macrolide antibiotics
Mechanism of action
– Bind reversibly to 50S subunit
– Bacteriostatic
– Blocks aminoacyl translocation (step 4)
– The site of action of macrolides is very close to
that of clindamycin, and streptogramin type B
184. Inhibitors of Bacterial Protein Synthesis
Macrolide antibiotics
Spectrum of activity
– Active against Gm+ including penicillin-resistant
streptococci
– Clarithromycin and azithromycin are more
effective than erythromycin against anaerobes
– Azithromycin is highly active against chlamydia
185. Inhibitors of Bacterial Protein Synthesis
Macrolide antibiotics
Adverse effects
– Gastrointestinal disturbances: Stimulate GI motility
leading to abdominal pain, cramping, NVD
– Hypersensitivity
– Local reaction at injection site (erythromycin
lactobionate)
– Cardiac effects: QT prolongation
– Ototoxicity
– Telithromycin (Ketek)
• Hepatotoxicity (FDA bloded warning)
• Worsen the symptoms of myasthenia gravis (Should not be
used in patients with myasthenia gravis (FDA boxed
warning))
186. Inhibitors of Bacterial Protein Synthesis
Macrolide antibiotics
Bacterial resistance
– Efflux pump
– Modification of the bacterial ribosome, rendering it
unable to bind the antibiotic (MLSB resistance)
– Enzymatic inactivation of the drug
Many macrolide-resistant strains are susceptible to
telithromycin
– Poor substrate for efflux pump
– Bind ribosomes with higher affinity than macrolides
187. Inhibitors of Bacterial Protein Synthesis
Lincosamides - Clindamycin
Mechanism of action (similar to macrolides)
– Bind reversibly to 50S subunit
– Bacteriostatic
– Blocks aminoacyl translocation (step 4)
Spectrum of activity
– Most Gm+ are susceptible; anaerobes (esp. B. Fragilis)
– No activity against aerobic Gm-
188. Inhibitors of Bacterial Protein Synthesis
Lincosamides – Clindamycin
Bacterial resistance
– Modification of the bacterial ribosome, rendering it
unable to bind the antibiotic (e.g MLSB resistance)
– Enzymatic inactivation of the drug
189. Inhibitors of Bacterial Protein Synthesis
Streptogramins
Quinupristin/dalfopristin (30:70) (Synercid)
Mechanism of action
– Quinupristin binds the 50S ribosomal subunit, same
site as macrolides; dalfopristin binds nearby,
synergistically enhances quinupristin binding
Spectrum of activity
– Mostly Gm+ including VRSA, VRE
– Individually: Bacteriostatic
– Combined: Bactericidal (due to synergistic effect)
190. Inhibitors of Bacterial Protein Synthesis
Chloramphenicol
Adverse effects
–Toxicity for newborn infants (Gray baby syndrome)
• Infants have inadequate levels of liver glucuronyl
transferase=> can’t metabolize the drug
• Vomiting, flaccidity, gray color, hypothermia, shock,
and collapse (death of 40% of patients within 2 days)
• Chloramphenicol should not be used in infants
191. Flucytosine
• Clinical Use
– Cryptococcus neoformans, some candida spp.,
dematiaceous molds that cause
chromoblastomycosis
– Not used as a single agent – resistance does occur
if used as a single agent
– Exhibits synergy with other antifungals
• With Amp B for cryptococcus meningitis
• With itraconazole for chromoblastomycosis
192. Flucytosine
• Adverse Effects
– Metabolized to toxic agent 5-fluorouracil (possibly
by intestinal flora) – antineoplastic
• Leads to bone marrow toxicity – anemia, leukopenia,
thrombocytopenia
• Affects liver enzymes occasionally
• Toxic enterocolitis
– Narrow therapeutic window – increased risk of
toxicity with higher drug levels
193. Azoles
• Mechanism of Action
– Reduction of ergosterol synthesis by inhibition of
fungal P450 enzymes – specific for fungal P450s
• Imidazoles are less specific – higher incidence of drug
interactions and side effects
– Resistance to azoles are increasing
194. Echinocandins
• Newest class of antifungal agents
– Caspofungin, micofungin, anidulafungin
– Only available in IV form
• Mechanism of Action
– Inhibit synthesis of fungal cell wall component β
(1-3) glucan
195. Mucocutaneous Infections
• Griseofulvin
– Fungistatic
– Absorption is improved when given with fatty foods
– Only use is dermatophytosis
– Mechanism of action unknown
• Binds to keratin to protect skin from new infection
– Adverse effects – allergic syndrome similar to serum
sickness, hepatitis, drug interactions with warfarin and
phenobarb
– Replaced by itraconazole and terbinafine
196. Topical Drugs
• Nystatin
– Structurally similar to Amp B
– Too toxic for systemic administration, so used only
topically
– Available in creams, ointments, suppositories, etc.
– Not absorbed through epithelium, so little toxicity
– Active against most Candida species
– Thrush, vaginal candidiasis
197. Topical Drugs
• Topical Azoles
– Clotrimazole and miconazole
– Available over-the-counter
– Often used for vulvovaginal candidiasis
– Oral clotrimazole troches are available for oral thrush
– Both are useful for tinea corporis, tinea pedis, tinea cruris
– Adverse effects are rare
– Also available are econazole, terconazole, butoconazole,
tioconazole, oxiconazole, sulconazole, sertaconazole,
ciclopirox olamine, haloprogin, tolnaftate, terbinafine,
naftifine, and butenafine
199. www.sfu.ca/.../Physiology/HPA_model.html
• Negative feedback regulation occurs at multiple levels of the
HPA axis and is the major mechanism that maintains normal
circulating levels of glucocorticoids.
• Stress (injury, hemorrhage, pain, cold, severe infection) can
override the normal negative feedback control mechanisms
leading to markedly increased plasma glucocorticoid levels.
200. Adrenocorticotropic hormone (ACTH)
• A 39-amino acid protein, synthesized from a
precursor protein = pro-opiomelanocortin
(POMC)
– The first 13 amino acids of ACTH may be
cleaved to form α-melanocyte-stimulating
hormone (α-MSH)
• Secreted from the anterior pituitary in
response to CRH, which is released by the
hypothalamus
– Diurnal rhythm of ACTH release
• highest plasma levels early in the morning
201. Glucocorticoids (GCs)
• All GCs are
synthesized
from
cholesterol and
are highly
lipophilic
• Cortisol is the
main
glucocorticoid
in humans
• Circulating
cortisol is either
bound to
corticosteroid-
binding protein
CBG (~85%) or
free (<10%)
- Cortisol plasma levels
are regulated by ACTH
and negative feedback
- Circadian rhythm
202. Mechanism of action of GCs
• The mechanism of GC
action is the regulation
of gene expression
• GR (GC receptor) belongs
to the nuclear receptor
family of transcription
factors
• Free GCs are lipophilic –
diffuse across the cell
membrane and bind to
cytosolic and nuclear GRs
• GC-GR complex dimerizes
and binds to the
glucocorticoid response
element (GRE)
• This interaction initiates
transcription and
translation of target genes.www.people.vcu.edu/~urdesai/estr.htm
204. Sudden withdrawal from glucocorticoid
therapy leads to adrenal suppression
• Synthetic GCs suppress
ACTH secretion
through a negative
feedback mechanism
• Without ACTH adrenal
glands are not able to
produce cortisol
• Adrenal suppression
may occur when GCs
are administered for
longer than 2 weeks
Synthetic GCs
Natural
205. Synthetic mineralocorticoids
• Fludrocortisone
• Used in treatment of adrenocortical
insufficiency (Addison’s disease)
• Most adverse reactions are caused by the
drug's mineralocorticoid activity (retention
of sodium and water) and include
hypertension, edema, potassium loss, and
hypokalemic alkalosis
206. Mineralocorticoid antagonist
• Spironolactone
• Binds MR (but also Androgen Receptor, AR)
• Used in treatment of hyperaldosteronism
and as a potassium-sparing diuretic
• Side effects: hyperkalemia and
antiandrogen effects
207. Hypothalamic-Releasing Hormones
• Include:
– Corticotropin-releasing
hormone (CRH)
– Gonadotropin-releasing
hormone (GnRH)
– Growth-hormone-releasing
hormone (GHRH)
– Thyrotropin-releasing
hormone (TRH)
– Somatostatin
• Travel from hypothalamus to
pituitary via portal
hypophysial blood vessels.
• Control the synthesis and
release of tropic hormones
from the anterior pituitary
208. Hypothalamic Neurohormones
• Oxytocin and
vasopressin (ADH)
• Travel to the pituitary
via the hypothalamo-
hypophysial tract
(neural)
– Synthesized in the
supraoptic and
paraventricular nuclei
of the hypothalamus
– Travel along the axons
to the pituitary
– Released from the
posterior lobe into
systemic circulation
209. Oxytocin
• Physiologic roles:
– PG stimulation in uterine smooth muscle:
• Uterine contractions in the last trimester of pregnancy
– PG stimulation in mammary myoepithelial cells:
• Milk ejection in lactating women
• Clinical application (uterine):
– Induction of labor (administered IV via an infusion
pump with appropriate fetal and maternal
monitoring)
– Postpartum hemorrhage (administered IM or IV)
210. Vasopressin & Desmopressin
• Desmopressin
– Synthetic analog of vasopressin
• Contains a D-arginine at position 8 and 1st
aa is deaminated.
• Relatively selective V2 agonist
• Longer acting because less readily degraded than ADH
• Vasopressin and desmopressin are treatments for
central (neurogenic) diabetes insipidus
– Vasopressin:
• administered IM or IV; half-life 15 min
• Nonselective for V1 and V2
– Desmopressin:
• administered IV, SC, intranasally or orally; half-life ~ 2 hours
• More selective for V2 (less V1 side effects)
• Side effects of vasopressin and desmopressin:
– peripheral vasoconstriction, arrhythmias, GI cramps,
headache, water intoxication (hyponatremia, seizures,
death)
211. Prolactin
• 198-amino-acid protein
• It is the principal hormone responsible for
lactation.
• Milk production is stimulated by prolactin
when appropriate circulating levels of
estrogen, progesterone, corticosteroids and
insulin are present.
• Note: oxytocin also stimulates lactation by
stimulating milk let-down, in preparation for
release.
212. GH replacement
• 2 types of recombinant human GH (rhGH):
– Somatropin (191-amino acid protein)
– Somatrem – Use in pituitary dwarfism [Note the
difference between drugs and endogenous hormone somatotropin.]
• rhGH is administered SC 3-6 times per week
• rhGH is used in:
– Treatment of GH deficiency in children
– Treatment of idiopathic short stature (controversial)
– GH replacement therapy in GH-deficient adults
– For its anabolic effects, used in conditions associated
with severe catabolic state (AIDS)
• Also used by athletes (although banned by the Olympic
Committee)
213. Hypersecretion of GH
• Gigantism
– Hypersecretion of GH in children and adolescents
(before closure of the growth plates)
– Long bone growth
• Acromegaly- DON’T USE SOMATREM
– Hypersecretion of GH during adulthood
– Connective tissue, cartilage and periostal growth
– Gradual coarsening of facial features; enlargement
of hands, feet, and lower jaw
– Enlarged heart, kidneys, liver and spleen
– Type 2 diabetes
214. GH receptor antagonist:
Pegvisomant
• GH analogue that blocks GH receptors
• Prevents GH receptor dimers from
forming, which is required for receptor
activation
• Leads to reduced IGF-1 level
• Given SC
215. Lecture Outline
• Hormones secreted at different levels of the
hypothalamic-pituitary-gonadal (HPG) axis
and their derivatives
– Hypothalamic hormones: GnRH
– Pituitary hormones: LH, FSH
– Ovarian hormones:
• Estrogens and progestins
– Testicular hormones:
• Androgens
– Gonadal pathophysiology
– Synthetic gonadal hormones
• Estrogens & Progestins: contraceptives & HRT, cancer
treatments
• Androgens: prostate cancer treatments, HRT, others
216. professionals.epilepsy.com/page/specpop_men.html
• The HPG axis plays a
critical role in the
development and
regulation of the
reproductive system
• Hypothalamus:
gonadotropin releasing
hormone (GnRH)
• Anterior pituitary:
luteinizing hormone (LH)
and follicle stimulating
hormone (FSH)
• Gonads: ovarian and
testicular hormones
217. Gonadotropin-releasing hormone
(GnRH)
• Secretion is pulsatile – required to stimulate LH
and FSH production and secretion.
– Males: secreted in pulses at a constant frequency
– Females: the frequency of the pulses varies during the
menstrual cycle and there is a large surge of GnRH
just before ovulation
• Nonpulsatile, sustained administration of GnRH
or its analogs inhibits the release of LH and FSH
(stimulates negative feedback)
• Clinical use: used for diagnostic tests (to
distinguish hypogonadism of pituitary origin from
hypogonadism of hypothalamic origin)
218. GnRH analogs
• Agonists: Leuprolide
– U.S. Brand Names: Eligard®; Lupron Depot-Ped®; Lupron Depot®; Lupron
Depot®-3 Month; Lupron Depot®-4 Month; Lupron®
– Also a 10-amino acid protein, but longer-acting than
GnRH
– Nonpulsatile, sustained administration inhibits the
release of LH and FSH
– suppression of gonadotropin (LH and FSH) release by
activating GnRH negative feedback receptors, which
suppresses gonadal hormone production
– Important in treating hormone-dependent cancers
• Use - Labeled Indications: Palliative treatment of advanced
prostate cancer; management of endometriosis; treatment of
anemia caused by uterine leiomyomata (fibroids); central
precocious puberty
• Use - Unlabeled/Investigational: Treatment of breast cancer;
infertility; prostatic hyperplasia
219. Gonadotropin hormones: LH, FSH, hCG
• All 3 hormones consist of two peptide chains:
–α and β
– α chain: identical in all 3 hormones
– β chain: distinct; provides specificity for
receptor interactions
• Receptors:
– All are G-protein coupled receptors
– FSH receptors bind FSH
– LH receptor binds both LH and hCG
220. Mechanism of action of estrogens
• Estrogens bind to
estrogen
receptors
• 2 estrogen
receptors:
• ERα and ERβ
• Both belong to
the nuclear
receptor family
of transcription
factors.
http://www.people.vcu.edu/~urdesai/estr.h2.gif
221. Mechanism of action of testosterone
and DHT
• Similar to the
mechanism of action
of estrogens and
progesterone
• Testosterone and DHT
bind to androgen
receptor (AR)
– DHT binds AR with
higher affinity than
testosterone
• Results in increased
protein synthesis
http://www.people.vcu.edu/~urdesai/estr.h2.gif
222. Misc.
• Progestin- doesn’t affect anticoagulation factors
• Dexamethasone- affect negative feedback on
normal PITUITARY release
• MSH- actually made in the middle lobe
• V2- aquaporin
• Estrogen- causes positive feedback on day 12-14
• PTH- doesn’t help with intestinal absorption
223. Hormonal control of Ca2+
• Three principal hormones regulate Ca++
and
three organs that function in Ca++
homeostasis.
• Parathyroid hormone (PTH), 1,25-dihydroxy
Vitamin D3 (Vitamin D3), and Calcitonin,
regulate Ca++
resorption, reabsorption,
absorption and excretion from the bone,
kidney and intestine.
225. Calcimimetics
• Cinacalcet – activates the calcium sensing
receptor. Target organ is the parathoroid
although many tissues express the receptor.
– Don’t use for peroxisome proliferator receptor
• Useful for the treatment of secondary
hyperparathyroidism and parathyroid
carcimomas that hypersecrete PTH
226. 4. Secretion of T4. Secretion of T44 and Tand T33
• Proteolysis releases T4 and T3 stored within
thyroglobulin (TG)
• Endocytosis of TG/colloid from follicular lumen
• Fusion with lysosomal granules containing
proteolytic enzymes
• Breakdown of TG and release of T4 and T3
• MIT and DIT deiodinated; iodine reutilized
• T4 and T3 reversibly bind to specific serum proteins
thyroxine binding globulin and transthyretin;
protect against metabolism
228. Thionamides
• Therapeutic Use
– Hyperthyroidism
• Untoward Effects
– Relatively low incidence (3 – 12%)
– Most occur early
– Agranulocytosis (<1%)
229. ThyroidThyroid HypofunctionHypofunction
Thyroid hormone deficiency
(Gull’s Disease)
Hypothyroidism: mild
Myxedema: more severe symptoms
Degeneration or atrophy thyroid gland may be
associated with goiter
Hashimoto’s Thyroiditis: autoimmune destruction
of thyroid gland; most common in US
230. Diagnosis and Treatment ofDiagnosis and Treatment of
HypothyroidismHypothyroidism
Diagnosis: decreased T4 production;
presence of anti-thyroid antibody (autoimmune)
Treatment:
Replacement therapy with levothyroxine (T4);
Stable, long half-life (7 d), converted to T3; used to
treat hypothyroidism, myxedemia, coma, cretinism,
simple goiter, nodular goiter
234. Sulfonylurea and Meglitinides
Both drugs block the KATP channel and cause
membrane depolarization leading to….
Opening of the Ca2+
and influx of Ca2+
Important - Ca2+
needed for the secretion of
most cellular products….including insulin!
Thus increased insulin secretion occurs in
response to sulfonylurea or meglitinides
235. DPP-4 inhibitors
• Also known generically as
– Gliptins
• Linapgliptin
• Sitagliptin
• Saxagliptin
• WORKS WHEN BLOOD SUGAR INCREASES DURING A
MEAL
238. Therapeutic uses of PG analogues
Dinoprostone : vaginal gel or vaginal insert
Indication : for the initiation or continuation of cervical ripening
in patients at or near term in whom there is a medical or
obstetrical indication for the induction of labor.
MOA: mimics the action of PGE 2
• PGE 2is released during natural labor and plays a role in
cervical ripening (softening, thinning, and dilation) which
allows the fetus to pass through the birth canal
239. Therapeutic uses of PG analogues
Epoprostenol, Iloprost, treprostenil: PGI2 (prostacyclin)
analogues
Indication
Treatment of severe Pulmonary Arterial Hypertension (PAH)
– Improves symptoms
– Prolong survival
– Delays or prevent the need for lung or lung-heart transplantation
MOA: Epoprostenol (PGI2) causes direct vasodilation of
pulmonary and systemic arterial vascular beds and inhibition
of platelet aggregation.
240. Therapeutic uses of PG analogues
• Latanoprost, bimatoprost, travoprost: PGF2α analogues
Drug Trade name Administration
Latanoprost Xalatan® Eye drop
Bimatoprost Lumigan® Eye drop
Travoprost Travatan Z® Eye drop
Bimatoprost Latisse™ Topical
242. Therapeutic uses of PG analogues
• Latanoprost, bimatoprost, travoprost: PGF2α analogues
Indication
For the reduction of elevated intraocular pressure in patients with
open-angle glaucoma and ocular hypertension
243. Therapeutic uses of PG analogues
• Bimatoprost: PGF2α analogues
Indication#2
Bimatoprost (Latisse™): Hypotrichosis treatment of the eyelashes
MOA: Bimatoprost may increase the percent and duration of hairs in the
growth phase, resulting in eyelash growth
244. Therapeutic uses of PG analogues
Latanoprost, bimatoprost, travoprost: PGF2α analogues
Adverse effects:
Ocular
– Blurred vision, burning, foreign body sensation
– Redness, dryness of the eyes ,itching
– Irreversible brown pigmentation of the iris
246. Nonsteroidal anti-inflammatory drugs (NSAIDs)
Specific mechanism of action
• Nonselective NSAIDS: Reversibly (except for aspirin)
inhibits cyclooxygenase-1 and 2 (COX-1 and 2) enzymes,
which results in decreased formation of prostaglandins
• Aspirin: Irreversible inhibitor of COXs
• COX-2 selective inhibitors: Selectively inhibiting
cyclooxygenase-2 (COX-2), which results in decreased
formation of prostaglandins- LESS RISK OF STOMACH
PROBLEMS, INCREASED RISK OF CV EVENT
247. Nonsteroidal anti-inflammatory drugs (NSAIDs)
• TXA2 generated by COX-1
increases platelet adhesion
• This is balanced by PGI2
generated by COX-2 in
endothelium which decreases
platelet adhesion
COX-1
TXA2 in platelets
Platelet aggregation
248. Nonsteroidal anti-inflammatory drugs (NSAIDs)
Other issues
– NSAIDs delay bone healing after fractures
(PGE 2 stimulate bone resorption and formation)
– Highly COX-1 selective NSAIDs increase the risk of
surgical bleeding
– Aspirin: exacerbation of asthma
– NSAIDs have increased toxicity in the elderly
249. Nonsteroidal anti-inflammatory drugs (NSAIDs)
Black Box Warnings
• Cardiovascular events: NSAIDs are associated with an
increased risk of adverse cardiovascular thrombotic events,
including MI and stroke. (celebrex AND naproxen)
• Gastrointestinal events: NSAIDs may increase risk of
gastrointestinal irritation, ulceration, bleeding, and
perforation.
250. Acetaminophen toxicity is the is the most
common cause of acute liver failure in the US
• Toxic dose
– Vary (10g, or 200mg/kg body wt)
• Symptoms
– Phase I (<24hrs): GI symptoms
– Phase II (24-72 hrs): Signs of liver damage
– Phase III (3-5 days): Massive hepatic necrosis,
encephalopathy
• Risk factors
– Excessive chronic alcohol intake
• Treatment
– Activated charcoal (adsorbs APAP in the GI)
– N-acetylcysteine (replenishing body stores of
glutathione)
251. Gout
Colchicine
Adverse effects
• Gastrointestinal: Gastrointestinal disorders including
abdominal pain, cramping, nausea, vomiting, diarrhea (can
be severe enough to warrant discontinuation of therapy)
• Bone marrow toxicity
• Hepatic necrosis
• Renal failure
252. Gout
• Uricosuric agents
Probenecid- can cause gouty attack because it reduces excretion
at subtherapeutic levels
Sulfinpyrazone
Adverse effects
• Gastrointestinal irritation: Take with food or antacids or alkaline
ash foods (milk, nuts, beets)
• Renal: Uric acid stones, nephrotic syndrome
– To minimize the possibility of stone formation maintain adequate
hydration, titrate dose upward slowly, maintain an alkaline urine
• Bone marrow suppression (with sulfinpyrazone)
253. Gout
Drug therapy
• Xanthine Oxidaze inhibitors
– Allopurinol
– Febuxostat
Mechanism of action
• Inhibits xanthine oxidase (the enzyme responsible for the
conversion of hypoxanthine to xanthine to uric acid) thereby
decreasing uric acid formation
254. Histamine antagonism
• Histamine has no clinical application in the treatment of disease, but
drugs that inhibit the actions of histamine are useful
Histamine can be antagonized by the followings:
1. Functional or physiological antagonist
e.g. Adrenaline, by acting on β2-ARs can oppose histamine-induced
bronchoconstriction (important clinically because injection of
adrenaline can be lifesaving in systemic anaphylaxis, where massive
release of histamine occurs)- FALSE
2. Release inhibitors
Cromolyn and nedochromil reduce the degranulation of mast cells
3. Histamine Receptors Antagonists
Competitive antagonists at histamine receptors
• H1-receptor antagonists
• H2-receptor antagonists
255. H1 receptor antagonists
First Generation Antihistamines
• Older H1-receptor blockers
• Small, lipophilic molecules that can cross the BBB (Marked sedative activity)
• Not highly selective to histamine receptor (Also blocks cholinergic, α-
adrenergic, & 5-HT receptors)
• Different chemical groups:
– Ethylenediamines
– Ethanolamines
– Alkylamines
– Piperazines
– Tricyclics
• Common structural features of classical (1st
generation) antihistamines
X = N, C, CO
R1 = R2 = small alkyl groups
256. Other clinical uses of 1st generation
H1-receptor antagonists
… not primarily due to H1 receptor blockade
Sedation
e.g Diphenhydramine
Prevention of motion sickness
e.g cyclizine, meclizine
Treatment of nausea & vomiting
e.g promethazine
Hinweis der Redaktion
- In numerous studies ciprofloxacin decreased theophylline clearance by 25-30%, and increased theophylline plasma concentrations by up to 308%.
