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Year 3 Sem 1 COPY COPY > PA30325 1. Pharmaceutics > Flashcards

PA30325 1. Pharmaceutics Flashcards

1
Q

Name 4 renal functions

A
  • Regulate body fluids
  • Electrolyte balance
  • Remove metabolic waste
  • Drug excretion
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2
Q

What are the common causes of kidney failure?

A

Pyelonephritis
- inflammation, deterioration of pyelonephrons due to infection antigens

Hypertension
- Chronic overloading of kidney with fluid and electrolytes may lead to kidney insufficiency

Diabetes mellitus
- Disturbance of sugar metabolism and acid-base balance may lead to degenerative renal diseases

Nephrotoxic drugs/metals
- Certain drugs taken chronically may cause irreversible kidney damage (aminoglycosides, phenacetin, heavy metals)

Hypovolemia
- Reduction in renal blood flow will lead to renal ischemia and damage

Neophroallergens
- Certain compounds may produce an immune type of sensitivity reaction with nephritic syndrome (quartan malaria nephrotoxic serum)

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3
Q

Describe Renal impairment

A
  • Chronic, acute renal failure
  • Uremia
    : glomerular filtration impaired or reduced (decreased renal drug excretion, accumulation, excessive fluid, blood nitrogenous products) caused by acute diseases, trauma
  • Alterations in PK processes
    : distribution (Vd, protein binding), elimination (biotransformation, renal excretion)
  • Alterations in therapeutic and toxic responses
  • Special dosing considerations
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4
Q

What are the PK considerations in Uremic patients?

A

Oral bioavailability
- may decrease, drugs with high 1st pass effect: increased BA

Apparent Volume of Distribution (Vd)

  • drug protein binding (decrease)
  • accumulation of metabolites (weak acids: decreased & weak bases: less affected), changes in total body water, increase in Vd

Elimination
- increased elimination half-life (t1/2), reduced glomerular filtration

Total body clearance (Cl.t)
- reduced (reduced glomerular filtration and active tubular secretion, or reduced hepatic clearance)

Drug dosage regimen
- estimation of remaining renal function, prediction of Cl.t

Assumptions, limitations

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5
Q

What are the 2 general approaches of dose adjustment in renal diseases?

A
  1. Methods based on drug clearance

2. Methods based on elimination half-life

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6
Q

What is the equation for dose adjustment based on Clearance for uremic patients?

A 
N = normal
U = uremic

D u.0 = (D. N.0 x Cl u.T) / Cl N.T

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7
Q

Describe dose adjustment based on elimination rate constant in uremic patients

A

Overall elimination rate constance reduced in uremic patients

    1. Reduced dose, constant dosage interval
    1. Constant dose, reduce dosage interval

D u.0 = (D N.0 x k.u) / k.N

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8
Q

Describe Glomerulrar filtration rate regarding markers

A

Markers need to be…

  • freely filtered at the glomerulus
  • not be reabsorbed not actively secreted by renal tubules
  • not be metabolised
  • not bind significantly to plasma proteins
  • not have an effect on filtration rate nor alter renal function
  • be nontoxic
  • may be infused in sufficient dose (simple, accurate quantitation)

Markers = inulin, creatine, blood urea nitrogen

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9
Q

Describe estimated Cl.cr in renal impairment

A
  1. Normal renal function
    : >80 ml/min
  2. Mild renal impairment
    : 50-80 ml/min
  3. Moderate renal impairment
    : 30-50 ml/min
  4. Severe renal impairment
    : <30 ml/min
  5. End stage renal disease (ESRD)
    : requires dialysis
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10
Q

Define the following terms

  • Hemoperfusion

- Hemofiltration

A

Hemoperfusion
- by passing blood through an adsorbent material and back to the patient (accidental poisoning, drug overdosage)

Hemofiltration
- Fluids, electrolytes and small molecular weight substances removed from the body by means of low pressure flow through hollow artificial fibres or flat membranes (replacement fluid)

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11
Q

When and why is IV fluids needed?

A
  • IV fluids include water, glucose and major electrolytes potassium and sodium
  • When the oral route is either not available or cannot supply adequate quantities of these substances
    : to maintain hydration, metabolic activity and organ function
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12
Q

What are the problems encountered with IV fluids?

A
  • IV fluids cannot provide sufficient calories
  • Increasing the volumes of fluid to reach adequate calories
    = fluid overload (hyponatraemia: low sodium in blood)
  • Increasing glucose concentration to reach adequate calories
    = infusion of hypertonic glucose solutions >10% by peripheral route will damage the blood vessels used
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13
Q

Fluid regimens even with sufficient calories infusion through a peripheral vein, do not provide the other essential requirements

IV fluids can be replaced with enteral route (EN) for patients needing a healthy diet. Why is this route a good alternative?

A
  • Good balance of carbohydrates, protein, fat, vitamins electrolytes and trace elements
  • EN is generally indicated for patients that are unable to obtain adequate nutrition by mouth but who have a functioning gut
  • EN routes include through nasogastric, nasojejunal, gastrostomy or jejunostomy tubes
  • EN routes are cheaper than PN and carry less risks of patient harm or medical error than PN
  • EN routes also maintain healthy gut function until normal feeding is resumed
  • Enteral access is usually decided by estimating if a tube will be required short-term or long-term
  • Nasoenteric feeding is commonly used, and nasogastric tubes have the additional advantage of being able to quantify gastric residuals
  • Nasoenteric tubes are also less likely to become clogged, but are less comfortable than smaller size tubes intended for small bowel feeding
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14
Q

What are the common conditional reasons for Enteral Nutrition?

A
  • Functional Gastrointestinal Tract
  • Anoxic Encephalopathy
  • Neurological Disorder (stroke, Amyotrophic Lateral Sclerosis)
  • Oropharyngeal-Esophageal Disease
  • Tumours
  • Trauma
  • Patients with altered oral intake for whatever reason
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15
Q

When and why is Parenteral Nutrition needed?

A

PN (Parenteral Nutrition) generally indicated for patients requiring long-term (>7days) supplemental nutrition when they

  • are unable to receive daily requirements through oral or enteral feedings
  • have severe gut dysfunction
  • are unable to tolerate enteral feedings
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16
Q

Define Parenteral nutrition (PN)

A
  • aims to provide sufficient nutrient supplementation in patient groups such as cancer patients, critically ill and elderly patients or pre-term infants
  • Must provide patients with adequate calories and to prevent malnutrition and its associated complications
  • As for normal diet, it needs to provide proteins(amino acids), carbohydrates(glucose, dextrose), lipids (emulsion), vitamins, electrolytes, water and trace elements in variable proportions to meet the required clinical demand
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17
Q

How is Parenteral Nutrition (PN) delivered?

A
  • All nutrition is provided intravenously, bypassing the normal GI tract processes of eating and digesting

Depending on the type of parenteral nutrition solution used

  1. Total Parenteral Nutrition (TPN)
    - given centrally
  2. Partial Parenteral Nutrition (PPN)
    - given peripherally(IV) or centrally

Mechanical pump delivers nutrition intravenously, may be utilised as an inpatient or at home

Specific volumes.amounts and composition vary based on patient’s age, status, comorbid conditions and should be calculated for each patient

Monitoring is required to regularly evaluate

  • body weight, Complete Blood Count (CBC), electrolytes, blood urea nitrogen
  • Glucose, intake/output, liver function test
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18
Q

Who decides Parenteral Nutrition in hospital and what are the considerations?

A
  • Decision for PN is made in hospitals by a nutrition team (doctor, specialist nurse, pharmacist and dietitian)
  1. Fluid volume of regimen
  2. Energy requirement
  3. Nitrogen requirement proportion of fat, protein and carbohydrate
  4. Type of IV access available (peripheral, central)
  5. Whether or not a standard regimen is suitable as a basis for therapy
  6. Electrolyte and trace elements requirements
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19
Q

What is the aim of Amino Acids (AA) supplement in PN?

A
  • to achieve a positive nitrogen balance
  • provide the body with all essential AAs for metabolic functions and tissue building

Targeted supplementation or complete substitution of AAs via PN for patients with

  • Metabolic dysfunction
  • Insufficient reabsorption
  • Increased nutritional demands after severe surgical trauma
  • Medical care of preterm and neonates
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20
Q

What are the possible reactions to infusion bag of All-in-One mixtures in TPN

A
  • creaming and coalescence of a fat emulsion
  • sugars and AAs may react to yellow or brown substances
  • occurence of precipitates of electrolytes
  • a non-preferred change in pH
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21
Q

What is Maillards reaction?

A
  • Glucose has reducing properties.

- Presence of reducing sugar can react with free AAs in solution forming imines

22
Q

What are the physiological changes during pregnancy?

A
  • changes in total BW and body fat composition
  • delayed gastric emptying and prolonged GI transit time
  • increase in extra cellular fluid and total body water
  • increased cardiac output, increased stroke volume, and elevated maternal heart rate
  • decreased albumin concentration with reduced protein binding
  • increased blood flow
  • increased glomerular filtration rate
  • changed hepatic enzyme activity
23
Q

Describe the changes in following areas in pregnancy

  • Absorption
  • Distribution
  • Protein binding
  • Metabolism
  • Renal excretion
A

Absorption

  • physiological changes could alter drug absorption
  • limited studies: F not altered during pregnancy

Distribution

  • increase in Vd (increased plasma volume, changes in protein binding) could result in a decrease in Co (after loading dose), and decrease in Cmax (after multiple-dose adjustment)
  • if Cl decreased or unchanged = increase in Vd result in increased terminal elimination half-life
  • if Vd and Cl are increased = increase, decrease or no change in terminal elimination half life

Protein binding
- Albumin conc decrease 2nd trimester, decline throughout pregnancy reaching conc 70-80% of normal values at time of delivery
- protein binding effects clinically significant
A. low extraction ratio drugs, doses monitored using total Cp
: total Cp will underestimate unbound or active Cp phenytoin and valproic acid
B. High extraction ratio drugs, narrow therapeutic window, non-oral routes
: AUC unbound drug significantly increased when albumin is decreased, increased pharmacological effect

Metabolism

  • Hepatic clearance (Cl.h): protein binding, metabolic enzymes and liver blood flow
  • CYP450, uridine dipohsphate glucuronosyltransferase (UGT) and N-acetyltransferase (NAT)
  • Increased activity of CYP3A4, CYP2D6, CYP2C9, CYP2A6, UGT1A4
  • decrease activity of CYP1A2 and CYP2C19

Renal excretion

  • GFR, active tubular secretion, reabsorption
  • renal excretion unchanged drugs: increased
  • GFR increased approx 50% by the 1st trimester, continued increase throughout pregnancy
  • tubular secretion, reabsorption = saturable membrane transport proteins
24
Q

Describe PK in Obesity and factors affecting the PK

A
  • Excess of fat tissue
  • increased mortality (hypertension, atherosclerosis, coronary artery disease, diabetes, breast, colon, prostate, endometrium
  • IBW: height, gender
  • BMI >30kg/m2 (obesity)

Factors affecting PK
- no significant difference in absorption between obese and lean subjects

  • affect drug distribution
    : higher percentage of body fat
    : lower percentage of lean tissue and body water
  • affect metabolism
    : higher cardiac output and liver blood flow
    : enlarged liver with altered histologic status
  • affect drug elimination
    : higher renal blood flow
    : higher glomerular filtration rate
25
Q

Describe Distribution in Obesity

A
  • distribution between fat and lean tissues: influence PK
  • Obesity: lipophilic compounds > hydrophillic compounds
  • weak or moderate lipophilicity (lithium): limited distribution in excess body fat
  • lipophilic compounds: increase in Vd in obesity
26
Q

Describe plasma protein binding in Obesity

A
  • albumin (acidic drugs), R1-acid glycoprotein (AAG)
  • binding to albumin: no significant changes
  • binding to AAG: increase and decrease
    : increase in AAG = decrease in free fraction of propanolol
    : decrease in AAG = no change in free fraction of triazolam
  • plasma protein binding affinity may change in obesity without changes in protein concentration
27
Q

Describe metabolism in Obesity

A
  • liver: fatty infiltration, influence metabolic activity of liver
  • markers to assess enzyme activities
  • CYP450 isoforms altered, no clear overview of drug hepatic metabolism
  • increased glucuronidation
  • changes in antioxidant systems
28
Q

Why are excipients used?

A
  • to optimise the formulation of the medicine
    : improve palatability, shelf-life and/or manufacturing processes
  • certain excipients not to be used in children’s medicines
    : e.g ehtanol, propylene glycol, benzyl alcohol and parabens can retard development
  • need to be safe & acceptable for use in children
29
Q

Advantage of using oral liquids?

A
  • provides maximal dosing flexibility

- possible to use for a wide range of age range including neonates

30
Q

Describe the use of Solids for reconstitution

A

Dispersible tablets, powders, granules, pellets and sprinkles

  • better stability compared to a formulated liquid
  • reconstitution either at the point of dispensing or at the point of administration
  • instructions can be complicated for untrained individuals
31
Q

Describe GI tract development in neonatal

A
  • Near neutral gastric pH (pH 6-8) at birth related to the presence of amniotic fluid in the stomach
  • The resting pH of neonatal stomach shortly after the initiation of feeding is similar to that in adults (pH 2)
  • HCl secretion in neonates is lower than in adults, resulting in a lower buffering capacity of the stomach, which in turn leads to protracted high pH following feeding
  • This lower buffer capacity has been linked to increased bioavailability of acid-labile drug, penicillin G, in premature and term neonates
  • Since non-ionised drug is better absorbed, higher pH is expected to decrease the rate and/or extent of absorption of weak acids, while weak bases such as astropine may be absorbed more readily from stoamch
32
Q

Describe Gastric Emptying Time in neonates

A
  • Time taken for stomach to empty its contents into small intestine is prolonged in neonates and infants in comparison to children and adults
  • volume of a meal, its osmotic pressure and its composition of macronutrients all has a major effect on rate of gastric emptying
  • because of the differences in the type of food and gastric contractions in neonates and infants, GET is prolonged in neonates and infants compared to children and adults
33
Q

Describe Paediatric populations

A

Neonate
- birth to 1 month

Infant
- 1 month to 2 years

Children
- 2 to 12 years

Adolescent
- 12 years to <16 years

34
Q

Describe Newborn-infants regarding their PK

A
  • differences in therapeutic efficacy and toxicant susceptibility at a given dose
  • immature PK processes
  • significant growth and maturational changes of physiological and biochemical processes with postnatal development
  • genetic and environmental factors influence maturation
  • tremendous interindividual variability: changes at different rates and pattern
  • premature birth: more pronounced anatomical and functional immaturity of the organs involved in PK processes
35
Q

Why is there a variation in average weight with age?

A
  • Weight increases rapidly particularly during the first year of life
  • Rapid changes in body size and composition, organ size and function
36
Q

What are the developmental changes that induce PK implications?

A
  • gastric acidity
  • rates of gastric and intestinal emptying
  • surface area of the absorption site
  • GI enzyme systems
  • gastrointestinal permeability
  • biliary function
  • I.M, SC, percutaneous absorption: skin, muscle, fat, water, content, degree of vascularisation
37
Q

Describe gastric secretions (PK implication) in paediatric patients

A

High gastric pH

  • enhanced BA of basic compounds
  • reduced BA of acidic compounds

Deficiency of bile salts and pancreatic enzymes
- reduced BA of drugs that require solubilisation or intraluminal hydrolysis for adequate absorption (pro-drug esters)

38
Q

Describe gastrointestinal motility (PK implication) in paediatric patients

A

Effect on drug BA

  • physico-chemical properties
  • interaction with anatomical and physiological factors of the GI tract
39
Q

Describe GI metabolism and transport (PK implication) in paediatric patients

A

Bacterial flora

  • extent of drug absorption: GI motility, ability to metabolise compounds
  • approaches adult populations by 4 years of age
40
Q

Describe GI first-pass effect (PK implication) in paediatric patients

A

Improved oral BA
- immature GI metabolic reactions; transporters and other active efflux processes

Reduced oral BA
- drugs dependent upon carrier-mediated uptake systems

41
Q

Describe Distribution (PK implication) in paediatric patients

A

High relative proportion of total body water and low proportion of fat

  • increase in Vd for water-soluble compounds
  • lower Vd for fat-soluble drugs

Enhancements in cardiac output, organ blood flows and tissue perfusion

Changes in membrane permeabilities and maturation of carrier-mediated transport systems

Changes in tissue binding affinities

42
Q

Describe Plasma protein binding (PK implication) in paediatric patients

A
  • Distribution and elimination of compounds
  • Larger unbound fractions
  • Lower total plasma protein levels
  • Lower binding affinities to albumin and a1-acid glycoprotein
43
Q

Describe metabolism and elimination (PK implication) in paediatric patients

A
  • same metabolites as adults; rates of metabolite formation can be different
  • underdeveloped and inefficient hepatic and/or renal elimination pathways
  • hepatic blood flow, plasma protein binding and intrinsic clearance
  • phase 1 reactions
    : CYP450 enzymes
44
Q

What is the change in body composition in elderly patients?

A
  • reduction in total body water and lean body mass, resulting in a relative increase in body fat
45
Q

What is the change in Cardiac structure and function in elderly patients?

A

Anatomical changes

  • increase pigmentation
  • endocardial thickening
  • increase in collagen
  • increase in elastic fibres

Physiological parameter changes

  • decreased cardiac output
  • decreased stroke volume
  • lengthening of recovery time after exercise
  • increase in BP
  • increased peripheral vascular resistance
  • greater rise in systolic than diastolic blood pressure
  • increased circulation transit time
46
Q

What is the change in GI system in elderly patients?

  • stomach and duodenum
  • small intestine
A

Stomach and duodenum

  • decreased secretion of HCl and pepsin (basal conditions)
  • atrophy of gastric mucosa
  • gastric emptying similar to that of young subjects

Small intestine

  • reduced absorption of several substances (e.g sugar, Ca, Fe)
  • digestion and motility remain relatively unchanged
  • atrophy of intestinal macro- and micro-villi
  • possible bacterial overgrowth in intestine
47
Q

What is the change in Pancreas and Liver in elderly patients?

A

Pancreas

  • amylase remain constant
  • lipase, trypsin decreased dramatically
  • secretin-stimulated pancreatic juice and bicarbonate concentration remain unchanged

Liver

  • progressive reduction in liver volume and liver blood flow
  • moderate alteration of hepatic structure an enzymatic functions
  • increase in the size of hepatocytes
48
Q

What is the change in Renal system in elderly patients?

A
  • decreased renal blood flow, glomerular filtration rate and tubular secretion
  • decreased renal mass (reduction in nephrons)
  • plasma creatinine
    : no concomitant increase
  • Acid-base balance maintained
  • reduced response to stress
    : inability to deal with acid loads
49
Q

What is the change in First-pass metabolism and Bioavailability in elderly patients?

A
  • reduction in first-pass metabolism
  • BA of drugs undergoing extensive first-pass metabolism increased
  • BA of prodrugs that need to be activated in the liver decreased
50
Q

What is the change in Distribution of polar and nonpolar compounds in elderly patients?

A 
Polar compounds (water soluble)
- smaller Vd, little net effect on the elimination half life
Nonpolar compounds (lipid soluble)
- increased Vd, prolongation of half-life

Year 3 Sem 1 COPY COPY (7 decks)

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