1
Q
Pharmacokinetics
A
what the body does to the drug
2
Q
Pharmacodynamics
A
what the drug does to the body
3
Q
Why is it important to understand the differences between routes and formulations for drug administration?
A
- can affect how quickly and how much drug enters the systemic circulation
- not all routes are suitable for all drugs
4
Q
Excipients
A
non-medicinal ingredients such as fillers, antioxidants, disintegrants, colorants and coatings, flavourants and sweeteners
5
Q
Enteral administration
A
entry of drug through the GI tract
6
Q
Parenteral administration
A
entry of drug not by the GI tract
7
Q
Oral (enteral administration)
A
- usually results in drug absorption through the stomach or small intestine
- absorption is often <100% and depends on: disintegration/solubility, acidity of the GI tract, stability of the drug (destroyed by acid or digestive enzymes?), gastric emptying and motility and GI blood flow
8
Q
Benefits of oral administration
A
- easiest, safest and cheapest
- no need for drug to be sterile or pure
9
Q
Drawbacks of oral administration
A
- acid-sensitive and protein drugs are unstable
- patient must be conscious and cooperative
- variable absorption and bioavailability
- possible upper GI tract irritation
10
Q
First pass metabolism (Effect)
A
- most drugs given orally first pass through the liver before entering the systemic circulation
- liver is the major site of drug metabolism
- drug concentration can drop dramatically
- the extent of drug metabolism is drug-to-drug dependent (some drugs are extensively metabolized, some are not)
11
Q
Rectal (enteral administration)
A
absorption is through the rectal mucosa
12
Q
Benefits of rectal administration
A
- rapid absorption
- cheap and easy
- useful when patients cannot or will not swallow
- less first pass effect (fewer rectal veins enter liver)
13
Q
Drawbacks of rectal administration
A
- absorption often incomplete
- many drugs cause irritation of mucosal lining
14
Q
Enteral administration formulations
A
- tablets
- capsules (powder in a gelatin coating)- allows faster absorption
- caplets (capsule-shaped tablets)- more easily swallowed
- liquids (even faster absorption)- aqueous, suspensions or emulsions
15
Q
Sublingual (enteral administration)
A
drug placed under tongue
16
Q
Advantages of sublingual administration
A
- relatively rapid absorption
- no first-pass effect (direct entry into systemic circulation)
- suitable for acid-sensitive drugs (mouth pH ~7)
- fast, easy and cheap
17
Q
Disadvantages of sublingual administration
A
many drugs taste bad
18
Q
Subcutaneous injection (parenteral administration)
A
drug is injected under skin
19
Q
Advantages to subcutaneous injection administration
A
- rapid effect
- useful for local drug delivery (e.g. local anesthetics)
- drug absorption into circulation may be controlled (e.g. vasoconstricting agents can slow absorption)
20
Q
Disadvantages to subcutaneous injection administration
A
- requires sterile drug
- some patients do not like injections
- absorption greatly affected by blood flow and injection volume
21
Q
Intramuscular injection (parenteral)
A
drug injected into skeletal muscle
22
Q
Advantages to intramuscular injection
A
- can be into a large muscle mass
- easy self administration
- absorption into systemic circulation can be controlled
23
Q
Disadvantages to intramuscular injection
A
can be painful
24
Q
Intravenous injection (parenteral)
A
drug injected directly into vein (either as a rapid bolus i.v. push or as a continuous infusion i.v. drip)
25
Advantages to intravenous injection (parenteral)
- rapid distribution and onset of action
- very close to 100% bioavailability
- large drug volumes
26
Disadvantages to intravenous injection
- requires skilled administration and close monitoring
- drug must be sterile
- greater cost
27
Inhalation (parenteral)
drug inhaled into airways
28
Advantages to inhalation administration
- useful for local action (e.g. bronchodilators) but can also be absorbed into pulmonary circulation
- no first-pass effect
- useful for gasses
29
Disadvantages to inhalation administration
- limited absorption of large proteins
- possible irritation of lung lining
30
Inhalation formulations
- gasses or gas mixtures
- inhalers for pulmonary use (particular powders, nebulized/mist)
- pressurized aerosol containers allow unused product to remain uncontaminated for later use
31
Topical routes (transdermal)
- absorption through skin
- for local effects and systemic effects
32
Topical benefits
- cheap and easy
- simple local administration
- no first pass effect
33
Topical drawbacks
- not suitable for many drugs (i.e. fat insoluble)
- absorption affected by skin hydration
34
Topical formulations
- creams, gels, ointments
- absorption can be enhanced by suspension in an oily vehicle
- controlled release patches (e.g. nicotine)
- topical aerosol spray
35
Absorption
entry of drug into circulatory system
36
Absorption of a drug from the GI tract may be..
- active
- passive: movement of a drug across the GI wall down its concentration gradient, most drugs are absorbed this way
37
Chemical factors affecting drug absorption
- drug size
- lipid solubility
- drug charge
38
Physical factors affecting drug absorption
- blood flow to the site of absorption: blood flow to the intestine is much higher than the stomach so absorption from the intestine is favoured; in shock, blood flow to the extremities is reduced so subcutaneous administration is less effective
- total surface area for absorption: very high surface area in intestine
- contact time: time in which drug is in contact with the absorbing surface, greatly affected by diarrhea or drugs that delay gastric emptying
- drug formulation: particle size, disintegrants, emulsifying agents, capsules or gel coatings
39
Bioavailability
the proportion of drug the passes into the systemic circulation after administration, taking into account both absorption and local metabolic degradation
40
Bioavailability is affected by..
- first pass effect
- drug absorption: solubility of the drug, stability of the drug, formulation of the drug
41
Drug distribution
- after absorption, the drug is distributed throughout the body
- drug is mixed throughout the blood very quickly (~1 minute)
- initial rapid (within a couple of minutes) distribution of a drug depends almost entirely on the rate of blood flow to a given tissue
- i.e. tissues with a high blood flow will be exposed to more drug, more quickly, than those with low blood flow
- rapid distribution: heart, liver, kidneys, brain
- slow distribution: muscle, skin, fat
- second slower phase of distribution that depends on where a drug 'likes' to be
42
Drug distribution is determined by these 3 factors..
- blood flow to tissues
- exiting the vascular system
- entering cells
43
Factors that affect drug distribution
- lean mass (watery environment e.g. muscle)
- fat solubility of the drug- drug accumulation
- plasma protein binding
44
Plasma protein binding
- the majority of drugs to not simply float around, entirely free, within blood
- drug are often bound to plasma protein
- albumin- major carrier of drugs
- only free drug can have effects
45
How does our body get rid of drugs?
- metabolism: modification (change) of drug molecule by cell enzymes
- excretion: removal from body
46
Drug metabolism
- most occurs in the liver, but also in the gut, kidney, lungs, plasma and placenta
- drugs are largely metabolized by cytochrome P450 family of enzymes
- variation between individuals
- inhibition of CYPs can be dangerous e.g. grapefruit juice
- enzyme induction- cells stimulated to make more enzymes
47
Drug excretion
- occurs mostly through the kidney
- drug excretion depends on: plasma protein binding, drug fat solubility/charge
- some drugs may be excreted in an unaltered form e.g. some antibiotics
- most drugs however, must be metabolized first- this usually renders the drug 'inactive', makes drug less fat soluble
48
Steady state
- When there is a consistent level of drug in the body that corresponds to maximum therapeutic benefits
- time to reach a steady state is dependent on the drug’s half-life (T1/2)- reached in 4-5 T 1/2
49
Half-life (T 1/2)
- the time required for the amount of drug in the body to decrease by 50%
- a measure of the rate at which drugs are removed from the body
50
___ drugs are metabolized/excreted according to principles of percentage loss of drug over time (i.e. not a fixed amount), __ drugs leave the body at a constant rate e.g. ethanol/alcohol, phenytoin (drug for epilepsy)
most drugs are metabolized/excreted according to principles of percentage loss of drug over time (i.e. not a fixed amount), few drugs leave the body at a constant rate e.g. ethanol/alcohol, phenytoin (drug for epilepsy)
51
Pharmacodynamics
what the drug does to the body
52
Drug receptors
- To elicit an effect on the body drugs must interact directly with cells (usually)
- Drugs usually bind to specific targets- mostly proteins although some drugs act on DNA or cell membranes
- Drugs should exhibit ‘selectivity’ for their receptor
53
Agonist
elicits a response
54
Antagonist
prevents a response to endogenous agonist
55
Dose-response relationships
Relationship between the size of an administered dose and the intensity of the response produced
56
Dose-response relationships determine...
- the minimum amount of drug to be used
- the maximum response a drug can elicit
- how much to increase the dosage to produce the desired increase in response
57
Therapeutic Index
- measure of a drug's safety
- Ratio of the drug’s toxic:effective blood concentration
- The larger/higher the therapeutic index, the safer the drug
-The smaller/lower the therapeutic index, the less safe the drug
58
Teratogen
drugs and other agents that can disrupt development of the fetus or halt pregnancy
59
Pregnancy and teratogens
- 1st trimester: period of greatest danger for drug-induced developmental defects- congenital gross malformations because of enormous cell multiplication & differentiation
- 2nd and 3rd trimester: disruption of function (not gross anatomy)
60
Breastfeeding and teratogens
- Breastfed infants are at risk for exposure to drugs consumed by the mother
- Consider risk-to-benefit ratio
61
Pediatric Considerations: Absorption
- gastric environment is less acidic
- gastric emptying is slowed- slow peristalsis
- first pass effect is reduced (neonates)- immature liver
- topical absorption faster through the skin
- intramuscular absorption faster and irregular
62
Pediatric Considerations: Distribution
- high total body water= low fat content
- protein binding decreased because of decreased protein made in immature liver
- immature blood-brain barrier allows more drugs to cross into their brain
63
Pediatric Considerations: Metabolism
- immature liver does not produce enough microsomal enzymes (CYP enzymes) so drug metabolism is reduced- newborns are most affected
- older children may have increased drug metabolism, requiring higher doses
64
Pediatric considerations: Excretion
- kidney immaturity (up to ~ 1 year)- affects perfusion, glomerular filtration rate and tubular secretion
- = reduced excretion of drugs
65
Other pediatric considerations
- skin is thin and permeable
- stomach lacks acid to kill bacteria
- lungs lack mucus barriers
- body temperatures poorly regulated and dehydration occurs easily
- liver and kidneys are immature, impairing drug metabolism and excretion
66
Older adult (geriatric) considerations
- geriatric: older than age 65
- use of medications is common
- polypharmacy: concurrent multiple medications- increase risk of drug interactions, adverse effects
- more sensitive to drugs compared to young adults- pharmacokinetic changes, complex health conditions, polypharmacy, drug regime adherence
67
Physiological changes in geriatric populations
- decreased cardiac output, decreased blood flow to organs= decreased absorption and distribution
- increased pH= altered absorption
- decreased peristalsis= delayed gastric emptying, slower lower GI tract
- decreased cytochrome P450= decreased metabolism
- reduced kidney function= decreased excretion of water-soluble drugs and metabolites
68
Adverse drug events (ADEs)
harm associated with any dose of a drug
69
Adverse drug reactions (ADRs)
- any noxious, unintended, and undesired effect that occurs at normal drug doses
- excludes excessive dosages
- can range from annoying to life-threatening
70
Medication errors
- preventable
- common cause of adverse health care outcomes
- Effects can range from no significant effect to disability or death
71
Types of medication errors
- Direct e.g. dose is too high
- Indirect e.g. dose is too low
- Fatal medication errors- overdose, wrong drug, wrong route
72
Causes of medication errors
- 90% of all errors are due to: human factors, communication mistakes, drug name confusion
- human factors= performance deficits e.g. wrong route, knowledge deficits, miscalculation of dosage
73
Who makes medication errors?
- Risk for error in hospitals is high because each medication order is processed by several people
- nurse is the last person in this sequence
- Thus, the nurse is the last line of defense against mistakes
- This places a responsibility on the nurse to ensure patient safety
74
Preventing medication errors
- Minimize verbal or telephone orders: repeat order to prescriber, spell drug name aloud, speak slowly and clearly
- List indications next to each order
- Be aware of dangerous abbreviations, symbols, and dose designations
- Never assume anything about items not specified in a drug order (eg., route)
- Do not hesitate to question a medication order for any reason when in doubt
- Do not try to decipher illegibly written orders
- Carefully read all labels for accuracy, expiration dates, and dilution requirements
- Encourage the use of both trade names and generic names in drug orders and prescriptions
- Always listen to and honour any concerns expressed by patients regarding medications
- Check patient’s allergies and identification
- Advocate for suitable working conditions
- Always double-check a medication’s product labeling
- Safeguard medications on admission or transfer
- Verify medication administration records that have been rewritten or re-entered
- Compare the pharmacy label against the initial medication administration record before giving the first dose
- Use integrated computerized prescriber order entry and pharmacy systems
- Provide for mandatory entry of patient’s weight
- Institute mandatory recalculation of every drug dosage for high-risk drugs or populations
- Always suspect an error whenever an adult dosage form is dispensed for a child
- Provide a translator for patients who do not speak English
- Ensure readability of labels
- Use “tall-man lettering” to differentiate look-alike drug names (use of CAPS for the name e.g. EPINEPHrine)
75
The rule for 0s in medication orders
always lead e.g. never use .25 mg but use 0.25 mg, never follow e.g. do not use 1.0 mg use 1 mg
76
10 rights of medication use
1. right patient
2. right drug
3. right time
4. right route
5. right dose
6. right documentation
7. right reason
8. right patient education
9. right to refuse
10. right evaluation
77
AHS: Independent double-check
- All medication administration
- Preferable 2 professionals
- Independently check all aspects of drug administration
78
Psychosocial factors contributing to drug errors
disruptive behaviour among nurses and among physicians
79
Reporting and responding to errors
- shared professional responsibility
- follow facility-based error reporting systems
- encourage the reporting of “near-misses”
- complete documentation- medication error reporting form
- notify patients of errors
80
Necrotizing fasciitis
- “Flesh-eating disease”
- Caused by variety of bacteria
81
Infections
- Invasion and multiplication of organisms
- may be caused by foreign bacteria or normal flora (e.g. in immunocompromized patients)
82
Gram-positive cell wall
- Thick peptidoglycan layer – up to 40 layers, 50% of wall
- Gram stain (crystal violet) is trapped in peptidoglycan layer -stains cells purple
83
Gram-negative cell wall
- Cell wall contains a thin peptidoglycan layer (5% of wall)
- An outer membrane
- Less Gram stain is trapped
- LPS barrier to some antibiotics to penetrate
84
Antibacterial drugs
- Medications used to treat bacterial infections
- exploit differences between human cells and bacteria
- Ideally, identify causative organism before beginning antibacterial therapy
85
Narrow-spectrum antibacterials
selective against one class of bacteria
86
Broad-spectrum antibacterials
effective against both gram-positive and gram-negative bacteria
87
Bactericidal
drugs are directly lethal to bacteria at clinically achievable concentrations
88
Bacteriostatic
drugs can slow bacterial growth but do not cause cell death
89
Superinfection (suprainfection)
- new microbes take over when antibacterials kill normal flora
- microbe resistant to drug action = difficult to treat
90
Opportunistic infections
- Infections that would not normally harm an immunocompetent person
- occur in immunocompromised patients
- existing colonization become infections
91
Selection of mutant bacteria is enhanced by..
- Improper choice of antibacterials
- Dose of antibacterial is too low
- Dosing not continued for long enough
- Improper use of antibacterial, e.g. to treat a viral infection
- Prophylactic use of antibacterials, e.g. in animal feed
92
4 antibacterials mechanisms of action
1. disruption of critical metabolic reactions
2. interference with cell wall synthesis
3. interference with protein synthesis
4. interference with DNA replication
93
Metabolite inhibitors: sulfonamides
- broad spectrum
- bacteriostatic
- prevents synthesis of folic acid
94
Indications: Sulfonamides
- combined with trimethoprim
- Reaches effective concentrations in the urinary tract
95
Other clinical uses of sulfonamides
- Upper respiratory tract infections
- Others eg malaria, chlamydia (sexually transmitted)
96
Contraindicated conditions of sulfonamides
- known allergy: applies to other derivatives of the sulfa-like drugs
- pregnant women: linked to birth defects (1st trimester), close to end of pregnancy may increase fetal bilirubin --> kernicterus (brain damage)
- not advised during breastfeeding
- infants less than 2 months of age
97
Sulfonamides: Adverse effects
- Integumentary (skin) allergies (hypersensitivity reactions)- Stevens-Johnson syndrome, Photosensitivity
- Blood (by bone marrow depression)- agranulocytosis, thrombocytopenia, aplastic anemia
- GI- nausea and vomiting
98
Beta-lactam antibacterials
- Inhibit cell wall enzyme responsible for peptidoglycan synthesis
- bactericidal
- characterized by the common beta-lactam ring in their structures
99
4 groups of beta-lactam antibacterials
- penicillins
- cephalosporins
- monobactams
- carbapenems
100
Penicillins
- naturally occurring: sensitive to beta-lactamase
- semi-synthetic: beta-lactamase-resistant, broad-spectrum or aminopenicillins, extended-spectrum or anti-pseudomonal penicillins
- active against most gram-positive bacteria and some gram-negative
101
Penicillins: mechanism of action
- penicillins enter the bacteria
- inside the cell they bind to penicillin-binding proteins
- Normal cell wall synthesis is disrupted
- Bacteria cells rupture
- Penicillins do not kill other cells in the body
102
Drug resistance to penicillins
- Some bacteria produce enzymes capable of destroying penicillins
- Bacteria make beta-lactamases --> split the beta-lactam ring
103
Is there a drug to inhibit beta-lactamases?
- Clavulanic acid
- tazobactam
104
Beta-lactamases
enzymes produced by bacteria that provide multi-resistance to beta-lactam antibiotics
105
Penicillins: Indications
- Gram-positive bacteria (streptococcus, enterococcus, staphylococcus)
- broad/extended-spectrum types kill Gram-negative
- Administration: PO, IM, IV- Penicillin G is IV or IM, Penicillin V is PO
106
Penicillins: Adverse effects
- generally well tolerated
- GI problems: disturb normal gut flora
- allergic reactions- skin rashes, subcutaneous edema (lips)
- can be fatal
107
Cephalosporins
- most widely used antibacterial drugs
- semisynthetic derivatives from a Cephalosporium fungus
- Structurally and pharmacologically related to penicillins
- bactericidal action
- Divided into groups according to their introduction to clinical use- increased permeability to Gram-negative cell wall, increased stability against β-lactamases
108
Cephalosporins: First generation
- Examples: Cefazolin (Ancef), cefadroxil, cephalexin (Keflex)
- Good gram-positive coverage
- poor gram-negative coverage
- Used for surgical prophylaxis, URIs, otitis media
109
First generation Cephalosporins: Cefazolin (Ancef)
- very commonly used
- IV administration
- prototype for 1st generation - excellent on gram positive
110
Cephalosporins: Second generation
- Good gram-positive coverage
- Better gram-negative coverage than first generation
- example: Cefuroxime
111
Second generation cephalosporins: Cefuroxime
- PO
- surgical prophylaxis
- does not kill anaerobes
112
Second generation cephalosporins: Cefoxitin
- IV and IM
- used prophylactically for abdominal or colorectal surgeries
- also kills anaerobes
113
Cephalosporins: Third generation
- more broad spectrum
- better against gram-negative than previous generations
- examples: cefotaxime, ceftriaxone, cefixime
114
Third generation cephalosporins: Cefotaxime
- IV and IM
- easily passes meninges and diffused into CSF to treat CNS infections e.g. meningitis
115
Cephalosporins: Fourth generation
- broader spectrum of antibacterial activity than third generation- especially against gram-positive bacteria
- example: cefepime
116
Cephalosporins: Fifth generation
Example= Ceftaroline- MRSA infections
117
Cephalosporins: Adverse effects
- similar to penicillins
- patients with a history of allergy to penicillins- cross-reactivity, but does not exclude its use
118
Carbapenems
- broad-spectrum antibacterial action
- all parenterally given- not orally active
- example: imipenem
- Reserved for severe, complicated body cavity and connective tissue infections- a "last resort" antibiotic
119
Carbapenems: Drug resistance
- Carbapenem-resistant Enterobacteriaceae (CRE)
- KPC (Klebsiella pneumoniae carbapenemase) and NDM (New Delhi Metallo-beta-lactamase)- enzymes that break down carbapenems
- Resistant to most antibacterial drugs
- Opportunistic infections – very difficult to treat
120
Macrolides
- examples= erythromycin (prototypical example), azithromycin, clarithromycin
- azithromycin and clarithromycin- now being used in combination for people with HIV/AIDS for opportunistic infections
- erythromycin and clarithromycin compete for hepatic metabolism with other drugs
- used for infections of: respiratory, skin and soft tissue
- inhibits protein synthesis- binds to ribosomes
- Most Gram-positive, some Gram-negative
- bacteriostatic and bactericidal
- highly protein bound
121
Macrolides: Adverse effects
- GI disturbances- primarily with erythromycin
- Azithromycin and clarithromycin= fewer adverse effects, better tissue penetration
122
Tetracyclines
- broad-spectrum antibiotic
- inhibit protein synthesis
- bacteriostatic
123
Tetracycline: Indications
- Gram-negative and Gram-positive
- Non-bacterial action- Demeclocycline (treat SIADH/syndrome of inappropriate ADH)
- bind to metal ions (calcium, magnesium, iron, aluminum)
- if taken with diary products, antacids, and iron salts = reduce absorption of tetracyclines
124
Tetracycline: Adverse effects
- do not use in: children less than 8 yrs, pregnancy/breastfeeding
- strong affinity for calcium- discoloration of permanent teeth and tooth enamel in fetuses and children
- GI disturbances
- alteration in intestinal flora may result in: superinfection, diarrhea, C.diff
- Potentiate warfarin effect (oral anticoagulant)
- Photosensitivity
- Antagonistic to bacteriocidal antibiotics so must be timed for use usually at least an hour apart
125
Aminoglycosides
- natural and semisynthetic- produced from Streptomyces
- first antibacterial effective against gram-negative bacteria
- bactericidal
- prevents/abnormal protein synthesis
- Against mostly Gram-negative and some Gram-positive
- example= Gentamicin
- poorly absorbed through the GI tract = given parenterally (IV or IM)
126
Aminoglycosides: Indications
- Active against gram-negative bacteria (Pseudomonas spp., E.coli, Proteus spp., Klebsiella spp., Serratia spp.)
- Often used in combination with other antibacterials for synergistic effect
127
Aminoglycosides: Adverse effects
- serious toxicities
- ototoxicity (ear) -irreversible, auditory impairment e.g. ringing (tinnitus), deafness, vestibular e.g. balance problems, dizziness, vertigo
- nephrotoxicity (kidney)- reversible, extreme in neonates and pre-existing renal conditions, must monitor plasma drug levels to prevent toxicities
- rarely, neuromuscular blockade
128
Aminoglycosides: Interactions
Increased risk for nephrotoxicity (additive effect) if used with:
- Vancomycin (antiinfective)
- Cyclosporine (immunosuppressant)
- Amphotericin B (antifungal)
129
Quinolones
- alters DNA of bacteria- prevents proper supercoiling
- do not affect human DNA
- Broad spectrum
- bactericidal
- Example= ciprofloxacin (very effective, common)
130
Quinolones: Indications
- UTI
- lower respiratory tract infections
- bone and joint infections
- infectious diarrhea
- skin infections
- sexually transmitted diseases
- anthrax
131
Quinolones: Adverse effects
- GI: nausea, vomiting, diarrhea
- Skin: rashes
- CNS: headache, dizziness
132
Quinolones: Interactions
- drug-drug (CYP inhibition)
- oral absorption reduced by: antacids, iron, zinc, and calcium-containing preparations
133
Viruses
- tiny microorganisms that infect and replicate inside host cells
- uses host cell machinery to synthesize protein, DNA, and RNA
- virus cannot replicate on its own
- must attach to and enter a host cell
134
Problems of viral treatments
- Viruses are difficult to kill because they live inside host cells
- any drug that kills a virus may also kill cells
- Viral infections are often initially asymptomatic
- delay of treatment until infection is well established (extensive replication)
135
Antiviral medications
- Most antiviral drugs work by inhibiting replication of virus inside host cell
- Not directly destroying mature virions
- AntiRETROviral drugs- used to treat infections caused by HIV, the virus that causes AIDS
- Antiviral drugs- used to treat infections caused by viruses
136
HIV
- Virus that leads to acquired immunodeficiency syndrome (AIDS)
- member of the retrovirus family
- transmitted:
by sexual activity, by intravenous drug use, or from mother to fetus
- Pre-Exposure Prophylaxis (PrEP)- to prevent acquisition of HIV infection by uninfected persons
- Post-Exposure Prophylaxis (PEP)- drugs taken very soon after possible exposure to HIV
137
Anti-virals for HIV
- reverse transcriptase inhibitors
- protease inhibitors
- integrase inhibitors
138
Reverse transcriptase inhibitors (RTIs)
- Block activity of the enzyme reverse transcriptase- preventing production of new DNA from viral RNA
- Subclasses: Nucleoside RTIs (NRTIs), Non-nucleoside RTIs (NNRTIs)
- adverse effect= bone marrow suppression --> anemia and neutropenia
139
Protease inhibitors
- Inhibit the retroviral protease enzyme, preventing viral protein preparation
- Viral enzyme = good drug target
- adverse effect= hyperglycemia, new/exacerbate diabetes
- example= ritonavir
140
Integrase inhibitors
- HIV integrase strand transfer inhibitors (INSTIs)
- inhibits insertion of HIV DNA into CD4 (T-helper) cell DNA
141
Anti-virals for Influenza virus
- Neuraminidase inhibitors
- Inhibitor of viral coat disassembly
142
Neuraminidase Inhibitors
- Prevents release of virus from host cell
- Treatment should begin within 2 days of influenza symptom onset
- Can be used prophylactically when vaccination is not possible or in early stages of infection
- Can reduce recovery time when used therapeutically
- example= oseltamivir- active against influenza A and B virus, GI adverse effects
143
Inhibitor of viral coat assembly
Example= Amantadine- moderate activity against influenza A, none against influenza B, 99% of viruses now resistant
144
Antivirals for herpesvirus (VZV and HSV)
DNA polymerase inhibitors
145
DNA polymerase inhibitors (for herpes VZV and HSV)
- synthetic nucleoside analogues- nucleosides are building blocks of DNA, stops viral DNA synthesis
- example= acyclovir
146
Antivirals for herpesvirus (CMV)
DNA polymerase inhibitors
147
DNA polymerase inhibitors (for herpes CMV)
- example= Ganciclovir- synthetic nucleoside analogue, available in oral or parenteral forms
148
Antiviral: Ribavirin
- synthetic nucleoside (mechanism unclear)
- given orally or nasal inhalation
- used to treat RSV
- inhalation form (Virazole) used for hospitalized infants with RSV
149
Fungi
- large and diverse group of microorganisms
- broken down into yeasts and moulds
- fungal infections= mycoses
150
types of antifungal drugs
- naturally occurring e.g. polyenes
- synthetic e.g. azoles
151
Examples of polygenes
- amphotericin B
- nystatin
152
Example of azoles
ketoconazole
153
Mechanism of action: polyenes
- bind to sterols in cell membrane lining
- makes holes in fungi cell membranes
- fungal cell death (mostly)
- Higher concentrations bind to cholesterol of human cells to cause toxicities
154
Mechanism of action: Azoles
- inhibit sterol-altering enzyme
- Lead to altered cell membrane
- Inhibits growth/kills cells
155
Adverse effects: Amphotericin B
- many adverse effects
- main concerns: renal toxicity and impairs hepatic functions
- Asses kidney and liver functions before systemic administration
156
Other adverse effects: Amphotericin B
- fever
- headache
- malaise
- hypotension
- muscle and joint pain
- chills
- dysrhythmias
- nausea and vomiting
- anorexia
157
To reduce the severity of the infusion-related reactions from Amphotericin B, pretreat with..
- antipyretic (acetaminophen)
- antihistamines (diphenhydramine)
- anti-emetics
158
Diuresis
increased water loss
159
Diuretic drugs
- increase urine output
- remove excess fluid
- first line drugs for heart failure and hypertension
160
Sodium movement in renal tubule
- 20-25% of all sodium is reabsorbed in loop of Henle
- 7% in the distal tubules
- 1-2% in collecting tubes
- REMEMBER: where sodium goes, water follows
161
Diuretic drugs can produce...
- excessive fluid loss (dehydration)
- acid base imbalances
- alter electrolyte levels
162
Diuretic drugs that block NaCl reabsorption
- loop diuretics
- thiazide and thiazide-like diuretics
- potassium-sparing diuretics
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Loop diuretics
- 'high ceiling' diuretics
- example= furosemide (lasix)
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Furosemide
- act in ascending limb of the loop of Henle
- inhibits sodium and chloride transporter
- secreted into nephron fluid
- significant diuresis- significant loss of fluid
- decreased fluid volume causes: reduced edema, reduced venous return (reduced CO)
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Furosemide: Indications
- edema associated with heart failure or hepatic (liver) or renal disease
- Control of hypertension
- Increase renal excretion of calcium in clients with hypercalcemia
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Furosemide: Adverse effects
- excessive fluid loss- low Na, Cl, water (dehydration) --> hypotension, thrombosis/embolism
- potassium depletion/hypokalemia --> irregular heartbeat (potentially fatal dysrhythmias), muscle weakness/lethargy, leg cramps, GI disturbances (constipation)
- hyperuricemia (may lead to gout- arthritis)
- hyperglycemia
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Furosemide: Interactions
- Patients using digoxin need to be monitored for hypokalemia
- can increase digoxin toxicity
- increased hypokalemia with other diuretics, glucocorticoids
- Ototoxicity esp with aminoglycosides
- Increases levels of lithium (bipolar disorder)
- May decrease hypoglycemic effect of antidiabetic drugs = hyperglycemia
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Example of thiazide and thiazide-like diuretics
hydrochlorothiazide
168
Thiazide diuretics: Mechanism of action
- Inhibit reabsorption of sodium and chloride ions
- action primarily in the distal convoluted tubule
- Results in excretion of water, sodium, and chloride= reduced blood volume
- Less powerful than loop diuretics -‘low ceiling’
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Thiazide diuretics: Indications
- Hypertension- first line treatment, single or combination therapy
- Edematous states- adjunct agents in treatment of HF, hepatic cirrhosis
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Thiazide diuretics: adverse effects
- Hypokalemia
- Hyperuricemia
- Hyperglycemia (inhibits insulin secretion)
- Genitourinary System- impotence (inability to have erection)
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Thiazide diuretics: Interactions
- Digoxin- increased risk of toxicity due to hypokalemia
- Antidiabetic drugs- reduces effect from diabetic drugs so may lead to hyperglycemia
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Potassium-sparing diuretics
- Act on collecting tubules of nephron (only 1-2% of Na reabsorption)
- therefore, limited effectiveness used on their own
- example= Spironolactone (Aldactone)- aldosterone receptor blocker, Na Channel Blockers
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Spironolactone (Aldactone) onset and peak
- onset: 24-48 hours
- peak: 2-3 days
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Spironolactone: Mechanism of Action
- Antagonist at aldosterone receptors
- blocks the reabsorption of sodium and water usually induced by aldosterone
- Reduces sodium-potassium exchange
- body retains K+ – ‘K-sparing’
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Spironolactone: Indications
- Edema associated with heart failure
- Hypertension
- Reversing the potassium loss caused by potassium-losing drugs (combination therapy)
- Hyperaldosteronism
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Spironolactone: Contraindications
Hyperkalemia- withhold if above upper level
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Spironolactone: adverse effect
- Hyperkalemia --> Cardiac dysrhythmias eg tachycardia, muscle weakness, GI - Cramps, nausea, vomiting, diarrhea
- Sex hormone-like effects: Amenorrhea (absence of period), Irregular menses, Postmenopausal bleeding, Gynecomastia (overdevelopment of breast tissue in men)
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Potassium-sparing diuretics: interactions
- Significant drug interactions with: Other heart failure drugs that also increase plasma K+, RAAS drugs e.g. ACE inhibitors
- Potassium supplements – do not give
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Foods high in potassium
Bananas, oranges, raisins, plums, fresh vegetables, legumes, potatoes
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Diuretics: Nursing implications
- Instruct clients to take in the morning as much as possible to avoid interference with sleep patterns
- Monitor serum potassium levels during therapy
- Teach clients to eat more potassium-rich foods when taking loop or thiazide diuretics
- Patients taking diuretics along with a digoxin should be taught to monitor for digoxin toxicity (fatigue, GI problems, changes in heart rate and rhythm, loss of appetite (anorexia),visual disturbances )
- Diabetic patients who are taking thiazide and/or loop diuretics should monitor blood glucose and watch for elevated glucose levels
- Instruct clients to notify the physician immediately if they experience.. rapid heart rates or syncope (reflects hypotension or fluid loss), rapid weight loss
- Teach clients to change positions slowly, and to rise slowly after sitting or lying to prevent dizziness and possible fainting related to orthostatic hypotension
- Monitor for therapeutic effects- Reduction in edema, fluid volume overload, HF , Reduction of hypertension; ICP
HLSC 220
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