Theme 4: Drug excretion (L18-20) Flashcards
1
Q
What are the features of the filtration barrier?
A
Capillary feeds into the basement membrane with endothelial cells, fenestration slits, fenestration pores and podocytes lining it leading into bowman space
2
Q
Describe the structure of podocytes
A
Cell body leading into podocytes, primary and secondary processes with filtration slits in between
3
Q
What are the only 2 things the filtration barrier cannot filter?
A
Red blood cells and serum albumin
4
Q
What happens to filtration when the filtration barrier swells?
A
There are larger holes therefore there are more molecules filtered out
5
Q
What is creatinine?
A
It is produced by enzyme creatine kinase in muscle (muscle breakdown product)
6
Q
What is uric acid?
A
It is a product of nucleic acid metabolism
7
Q
How is the amount excreted calculated?
A
X = amount filtered - amount reabsorbed + amount secreted
8
Q
How can different patterns of urinary excretion be monitored?
A
Using plasma concentration against urinary excretion
E.g. para amino hippurate, inulin (directly proportional) and glucose
9
Q
How is total renal clearance calculated?
A
Total renal clearance = CL by filtration + Cl by secretion - retention by reabsorption
10
Q
How does drug metabolism impact renal excretion?
A
When drug is metabolised into inactive metabolites renal function does not greatly affect elimination of active compound
Drug and/or active metabolites excreted in the kindest changes in renal function do affect elimination of active compound
11
Q
How does the inability to filter serum albumin impact drug metabolism?
A
Many drugs are bound to plasma proteins (HSA) therefore they cannot be excreted
12
Q
What is plasma?
A
The absence of clotting proteins
13
Q
What size do molecules have to be to be filtered through the glomerulus?
A
MW of <20000
14
Q
How is free unbound drug determined?
A
Using the concentration of the drug in the filtrate (drug filtered in the glomerulus) which is equal to the free unbound drug so clearance is reduced
15
Q
What is filtration proportional to?
A
Glomerular filtration rate and fraction of unbound drug in plasma (fu)
16
Q
How is rate of clearance determined?
A
Using fraction of unbound drug in plasma (fu) * glomerular filtration rate
17
Q
What is used to measure elimination rate?
A
Creatinine
18
Q
What does creatinine suggest about glomerular filtration rate?
A
It is equal to clearance as it is filtered by not reabsorbed or secreted
19
Q
What are the features of passive tubular reabsorption?
A
Drugs have low rate of clearance and is significantly affected by changed in urine flow
20
Q
When is rate of clearance less than drug in plasma and glomerular filtration rate?
A
When renal reabsorption is taking place
21
Q
What is the principle factor for weak acids and bases?
A
The pH of renal tubular fluid
22
Q
What happens to drugs in an ionised and unionised state in passive tubular reabsorption?
A
Ionised at pH of tubular fluid - reabsorption is much lower
Unionised at pH of tubular fluid - reabsorption higher as diffusion can take place through PCT
23
Q
What happens to aspirin (WA) in passive tubular reabsorption?
A
pKa < 7.5 - more highly ionised and not well reabsorbed in alkaline urine
24
Q
What happens to amphetamine (WB) in passive tubular reabsorption?
A
pKa > 7.5 - decreased reabsorption and increased rate of clearance by acidic urine
25
What can be manipulated in times of overdose?
Urine pH
26
What happens to phenobarbitone in different pH?
It is ionised at alkaline pH so tubular reabsorption is inhibited = more clearance
When urine is more acidic more phenobarbitone is unionised so more is reabsorbed = less clearance
27
What happens when clearance rate is more than drug in plasma and glomerular filtration rate?
The drug filtered at the glomerulus is also cleared by active tubular secretion (e.g. penicillin)
28
What are the two independent and relatively non-selective carrier systems?
Acidic drugs and endogenous compounds
Organic bases
29
How do carrier systems transport drugs?
Against an electrochemical gradient
30
What can happen during tubular secretion using carriers?
There can be competition between drugs meaning there can be drug interactions
31
What can happen when there are few transport proteins for drugs actively secreted?
Proteins can be non-specific therefore there is more competition between drugs
When administered together one drug may accumulate
32
Give examples of acidic drugs that are actively secreted into renal tubule?
Aminosalicyclic acid
Glycine conjugates
Penecillins
Salicylic acid
Thazide diuretics
Uric acid
33
Give examples of basic drugs that are actively secreted into renal tubule?
Amiloride
Dopamine
Histamine
Morphine
Serotonin
34
Which drugs cause hyperuircaemia and gout?
Hyperuricaemia - diuretics (compete same transporters uric acid) and low-dose aspirin
Uricosuric (urea in urine) drugs - sulphinpyrazone and probenecid (allows drugs to stay in body)
Allopurinol - 1st line therapy
35
How is gout caused in drug-drug interactions?
As it is not reabsorbed which forms crystallising
36
What happens to lithium when using diuretics?
It can cause lithium retention due to increase in sodium reabsorption
37
What happens to gentamicin when loop diuretics are used?
Causes gentamicin build up therefore nephrotoxicity
38
What happens to acetohexamide and chlorpropamide when phenylbutazone is used?
Causes hypoglycaemia as it displaces drugs from binding to albumin so increases clearance
39
What happens to penicillin when probenecid is used?
Penicillin is retained by blocking OAT1 and 3 transporters in the PCT
40
What happens to digoxin when quinidine is used?
Digoxin toxicity by inhibiting Pgp in PCT
41
What are the main determinants for renal drug excretion?
Active tubular secretion and passive reabsorption
42
What is the main factor in duration in drug action?
Renal elimination rate
43
Which excreted drugs are 100-75% unchanged in urine?
Amiloride
Gentamicin
Ampicillin
Digoxin
44
Which excreted drugs are 75-50% unchanged in urine?
Cabenicillin
Cimetidine
Cephaloridine
45
Which excreted drugs are ~50% unchanged in urine?
Propatheline and tubocurare
46
Which groups have tightly controlled drugs?
Elderly and renal diseases patients
47
What are factors are known when renal function and drug elimination is modified?
Use of a particular drug in a patient
Usually disposed of primarily through real elimination
Patients renal function is inadequate
48
What are type A adverse reactions?
They are predictable reactions known from the pharmacology of the drug
49
What happens to clearance when renal function is inadequate?
There could be inadequate function drug elimination
50
Which drugs can be most toxic when renal elimination is modified?
Digoxin, ACE inhibitors, amino glycoside antibiotics, class I antiarrythmic agents and cytotoxic agents
51
What is essential to alter when patients have modified renal function?
Drug dosing
52
What can be measured to ensure adequate renal clearance?
Creatinine clearance
53
How is creatinine clearance calculated?
Urine collected, pooled then volume is measured and assayed for creatinine
Serum is also assayed
CLcr= rate urinary excretion of creatinine/serum concentration of creatinine
54
Why is creatinine clearance used?
Because it is directly proportional to GFR
any reduction in clearance = reduction in elimination
55
What happens to reabsorption and secretion in renal disease?
Alteration in passive reabsorption indirectly by altering urine flow rate and pH
Active tubular secretion is also impaired
Depends on severity of disease
56
What are the limitations of finding GFR in creatinine clearance?
Early stages show normal clearance
Production can be dependent on muscle bulk - loss/gain
Plasma concentration is affected by hydration state
Different heritage groups can have different GFRs
57
What are the limitations with renal function and younger age?
Neonates have immature renal tubular function and GFR
Takes ~6months to reach adult levels
Drug metabolites can accumulate in the kidneys of neonates and young infants
58
How is drug metabolite accumulation monitored in neonates and young infants?
Using plasma concentration
59
What are the limitations with renal function and older age?
Older people are a larger proportion of the health services expenditure on drugs
Adverse drug reactions are more likely in older patients
Polypharmacy is very common - drug interaction is large
Error rate in taking drugs is also more likely in older patients if taking >3 drugs
60
Why are older people not a homogenous group?
Because there is large variability in the handling and response to drugs
61
What happens to GFR in the elderly?
It decreases
62
What can GFR fall to in the elderly?
60-70ml/min
63
How do drugs have to be adjusted in the elderly?
The dosage has to be reduced and the active metabolites excreted by kidneys
64
How does diet influence renal elimination?
Overall decrease in GFR
Either in a fasted or state of starvation
65
How does starvation impact renal elimination?
It can increase the formation of ketones which competes with the uric acid transporter in the nephron for tubular secretion
66
What other factors of diet impact renal elimination?
Protein loads increase GFR
Parenteral or enteral nutrition can enhance renal elimination of drugs - dosage
67
How does proteins increase GFR?
More amino acids are spare and need to increase elimination therefore more urea and ammonia have to be formed
68
How does pregnancy impact renal elimination?
GFR increase by 70% in pregnancy
Drugs eliminated by renal excretion are cleared quicker
Plasma drug monitoring required
69
How do NSAIDs affect renal function?
Prostaglandins production is inhibited therefore arterioles are unable to dilate
Can cause acute renal failure
Retention of fluid and electrolytes
Can also cause hypertension
70
How does biliary excretion of drugs take place?
Allows drugs to leave the systemic circulation immediately
It is then absorbed into the liver via the hepatic artery and portal vein using the efflux transporters
71
What type of current does blood and bile have?
Counter current
72
What substrates have active transport systems?
Acids
Bases
Unionised molecules (digoxin)
73
What molecular weight are drugs if excreted in the bile?
>300
74
What is the mechanism of biliary excretion?
Drug conjugates concentrated in bile and delivered to intestine
↓
Drug conjugate hydrolysed
↓
Free drug
↓
Drug reabsorbed and enterohepatic recirculation takes place
↓
Can prolong action of drug
75
When does pulmonary elimination take place?
When eliminating and up taking volatile anaesthetics
76
When does pulmonary elimination have a medico-legal significance?
Ethanol concentrations in expired air (auto-brewery syndrome, diabetic ketoacidosis)
77
What are the problems associated with elimination in breast milk?
The drug can appear in breast milk - not significant
Important for suckling child - immature drug metabolism and elimination
78
What drug classes can be found in saliva?
Analgesics (paracetamol and salicylate)
Anticonvulsants (carbamazepine and phenytoin)
Cardiovascular agents (propranolol)
79
What are the benefits of detecting drugs in saliva?
For drug monitoring
80
What factors determine if drugs are found in saliva?
Lipid solubility, pKa and molecular weight
81
What are 3 important factors of drugs passing cell membranes?
Lipid solubility (diffusion)
Degree of ionisation (uncharged pass more efficiently)
pH differences between compartments
82
What is the role of drug transporters in drug disposition?
Absorption - intestine facilitating and preventing entry of drugs
Distribution - allowing entry into target organs (activity and metabolism)
Excretion - renal and biliary excretion (absorption and secretion)
83
What are the different drug transport proteins?
ABC proteins:
MRP
MDR
BSEP
BCRP
SLC family:
OAT - ANION
OATP - ANION
OCT - CATION
MATE - CATION
PEPT - PEPTIDES
84
What is the SLC family?
Solute carrier
85
What are the properties of SLC-encoded proteins?
52 different genes - membrane proteins, movement of endogenous proteins
2 general types of protein:
Facilitate and secondary active
Not ATP dependent
12 transmembrane domains
Membrane of polarised cell
86
What are the properties of the OATP family?
Organic anion-transporting polypeptide
SCLO1-6 genes
1&2 most important (OATP1&2) - drug transport across sinusoidal membrane into liver
OATP1B1, OATP1B3 and OATP2B1 liver
Drug substances normally anionic with high mol wt and plasma bound protein
87
Name examples of OATP1B1 substrates
Statins, rifampicin and benzylpenicilin
88
What are properties of the OAT proteins?
SLC22A subfamily
Renal excretion (also liver and small intestine)
OAT1, 2 and 3 basolateral membrane of PCT (facing bloodstream)
OAT4 apical membrane of PCT (sometimes transport both direction)
89
Which anion transporters are on the apical side of PCT cells?
BCRP, MRP2/4 and OAT4
90
Which anion transporters are on the basolateral side of PCT cells?
OATP4C1, OAT1, OAT3
91
What are OAT1-3 coupled to?
Dicarboxylic acid which is sodium dependent
92
What are the substrates for OAT transporters?
Not entirely clear
Sulphate or glucuronide conjugates
Drugs that don't undergo metabolism
93
What are examples of OAT substrates?
OAT1 Tetracyclines
OAT2 AZT, diclofenac (NSAID)
OAT3 Oestrone sulphate, benzypenicillin
OAT4 oestrogen sulphate, diclofenac glucuronide
94
What are the properties of OCTs?
Organic cation transporters
SLC22A (homology to OAT)
OCT1&2 most important
OCT1: sinusoidal face of liver, substrates metformin and cisplatin
OCT2: basolateral membrane kidney, substrates metformin, cisplatin and cimetidine
95
What are problems with OCT transporters and cisplatin?
High affinity for OCT2 which allow build up of cisplatin in PCT which causes nephrotoxicity
96
Which cation transporters are on the apical side of PCT cells?
MATE1
MATE2K
MDR1
97
Which cation transporters are on the basolateral side of PCT cells?
OCT2 and OCT3
98
What are properties of the PEPT transporters?
PEPT1&2 are members of POT protein family (SLC12A subfamily)
PEPT1 - intestine and kidney
PEPT2 - mainly kidney
Similar substrate specificity (penicillins, ACEIs and valacyclovir)
Proton-dependent
99
What are properties of the MATE transporters?
Multidrug and toxin extrusion family
Identified in bacteria - cationic compounds
SLC47 family:
MATE1 - liver and kidney
MATE2 - kidney only
Export pumps biliary and renal excretion
Proton-Dependent
100
What is the ASBT transporter?
Na-dependent bile salt transporter
101
How are compounds transported through the intestine?
Enter enterocytes through brush border membrane and cross basolateral into hepatic portal vein
102
Which transporters are located on the basolateral side of the enterocyte?
OCT1, OSTα&β(organic solute carrier) and MRP3
103
Which transporters are located on the apical side of the enterocyte?
OATP, PEPT1, ASBT, MCT1 (monocarboxylate transporter), MRP2, BCRP and P-gp
104
What is the role of transport proteins in the liver?
Transported into hepatocyte across sinusoidal membrane for metabolism and reaching targets
Following metabolism transported across canalicular membrane or sinusoidal membrane
105
What is the role of transporters in the kidney?
BL membrane:
Tubular secretion need to enter
Reabsorbed return to circulation
Brush border membrane:
Enter lumen for renal excretion
Reabsorption may occur
106
How is diclofenac excreted?
Metabolism: CYP2C9 and UGT2B7
UGT2B7 - acylglucuronide (DF-AG)
OAT2 & 4 - excrete DF-AG and parent compund
Biliary excretion and may reenter circulation
107
What happens in drug-drug interaction of OAT transporters?
Inhibition
Penicillin and probenecid (prevent uric acid build up)
108
What happens in drug-drug interaction of ABCB1 transporters?
Inhibition
Digoxin can be impacted by different drugs due to competition to saturate receptor
High levels are toxic (small TI)
109
What happens in drug-drug interaction with PXR?
Induction: ABCB1, ABCC2, SLCO1B1
Rifampicin drug-drug interaction
Rapid clearance of other drugs
St. John's wort has similar effect
110
What are the pharmacogenetics of OATP1B1?
Polymorphisms = higher plasma levels of statins (impaired ability to enter hepatocyte)
Toxic statin levels in muscle cells (fatal rhabdomyolysis - muscle dissolves)
111
What are the pharmacogenetics of OCT2?
Nephrotoxicity with cisplatin (involve MATE2)
Drug accumulation
112
What happens to renal cells with cisplatin?
Can cause renal tubular death as it is taken up into PCT cell
Higher exposure destroys mitochondria
Organic solutes lost to urine +Na+ and H2O loss (Fanconi syndrome)
