Lecture 10 and 11 Flashcards
1
Q
What are the 4 main compartments that water exits in the body?
A
- Extracellular (blood plasma, interstitial fluid, lymph)
- Intracellular
- Transcellular
2
Q
What is Volume of distribution (Vd)?
A
Volume that would contain the total body content of the drug at a concentration equal to that is present in the plasma
3
Q
What is the equation for Volume of distribution (Vd)?
A
Vd = Q/Cp
Cp - Plasma
Q - Drug
4
Q
What is the purpose of Volume of distribution?
A
Relative affinity of the compound for plasma/blood constituents and tissue constituents
5
Q
What affects Volume of distribution?
A
Lipid solubility due to cell peentration
- Plasma protein binding reduces Vd
- Tissue binding increases Vd
6
Q
What influences a drug distribution?
A
Albumin, acid glycoprotein and beta-globulin
7
Q
What form does drugs exist in therapeutic concentrations within plasma?
A
Bound form
8
Q
What are the functions of plasma protein binding?
A
- Binding is rapidly reversible and non specific
- Forms a reservoir of drug
9
Q
What are unexpected effects in plasma protein binding/
A
- Surge or drop in cocnentration leading to side effects or OD
10
Q
How isthe treatments to Parkinson’s disease handled?
A
- To increase dopaminergic activity
11
Q
Dopa is a drug. How is it adminstered and what its effect?
A
Adminstered with Carbidopa
- Increases plasma levels and half life
12
Q
What are the side effects of Dopa on non targeted delivery?
A
Hypotension, caridac arrythmias
13
Q
What is the side effect of Dopa on the CNS?
A
- Depression, anxiety, insomnia, hallucinations
14
Q
What is drug elimination
A
Irreversible loss of drug from the body
15
Q
What is Metabolism?
A
Enzymatic converison of one chemical entity to another within the body
16
Q
What is Excretion?
A
Elimination from the body
17
Q
What are the main excetory routes?
A
- Kidney
- The hepatobiliary system
- Lungs
18
Q
What drugs are elimintated efficiently by the kidneys?
A
Lipophilic drugs
19
Q
What are Xenobiotics?
A
Foreign chemical agent that comes into the bdoy
20
Q
What are examples of Xenobiotics?
A
- Drugs
- Toxins
- Emissions (e.g motor vehicle, CO2 fuels)
- Lifestyle (e.g vaping, alcohol)
21
Q
What are molcecules that are not well metabolised?
A
Heterocyclic aromatic amines
22
Q
What are the two main classes of Heterocyclic aromatic amines?
A
Prolysis of amino acids and sugars
Cancer
23
Q
What are Polycyclic Aromatic Hydrocarbons?
A
Chemicals that occur naturally in coal, crude oil and gasoline
- Found in Cigarettes
24
Q
Example of an inorganic xenobiotic
A
Asbestos
25
Reduced reabsoprtion by the kidney, ehanced billary and renal excretion is caused by?
Transforming a lipophililic drug to polar metabolites
26
5 fluourouracil is activated by metabolism. What drug is it?
Prodrug
27
What are the sites of metabolism?
- Liver
- Plasma
28
How does metabolism occur in the liver?
Drugs absorbed via the Gl tract pass through the liver before entering cirulation
29
Example of drug that is absorbed in the plasma?
Suxamethonium
30
What is the function of Suxamethonium ?
Depolarising neuromuscular blocker
31
How does Suxamethonium have effect in the body?
Persistently over stimulate the receptor Metabolised by plasma cholinesterases
32
What drug has an effect on the metabolism in the lungs?
Epoprostenol
33
What drug has an affect on the metabolism in the intestines?
Monoamine oxidases metabolise Tyramie (amino acid), MAOI inhibits the enzyme
34
What are drugs that undergo substantial first pass eliminaiton?
Salbutamol, Lidocaine, Aspirin. Morphine
35
What does the first pass effect refer to?
Combined effect of metabolism by the liver and in the gut
36
Significant inter-individual variation can occur due to first pass effect. What are the effects?
• Unpredictable efficacy
• Chance of toxic side effects / adverse reactions
37
What are the results of metabolism?
Duration of exposure and biological activity is reduced
• Biological activity of a drug may be changed (prodrugs)
• Biological half life is reduced
• Accumulation in the body is avoided
38
Where can CYP enzymes be found?
Membrane of the smooth endoplasmic reiculum
39
Where are polar drugs excreted?
Urine
40
What are the differences within the P450 enyzmes?
- Amino acid sequence
- Sensitivity to inhibitors and inducing agents
- Specificity of the reactions that they catalyse
41
What does CYP450 enyzms work parallel with?
Electron donors
42
How many CYP enzymes account for 93% of known drug metabolising reactions?
12
43
Where DH is a drug, what is the name for NADH or NAPH?
Reduced nicotinamide adenine dinucleotide cofactor
44
Where DH is a drug, what type of cofactor is NAD or NADP?
Oxidised
45
What is the final electron acceptor?
Oxygen
46
Role of metabolsim?
Abolish drugs/potentially harmful substances from the body
47
What are the phase one reactions?
Catabolic, Oxidation, Reduction or Hydrolysis
48
What is Rate of reaction in Michaelis-Menten kinetics proportional to?
Concentration of enzymes
49
What factors can effect phase 1 metabolism?
Inhibition of CYP450
- Competitive inhibitor - quinidine - CP2D6
- Noncompetitive injibitor - Ketoconazole - Complexes with Fe3+
50
What effect does Phenobarbitol and 3,4 bezo[α]pyrene have on the rate of oxidative metabolism of zoxazolamine?
Increase the rate
51
What drug is coverted into morphine by CYP2D6?
Codeine
52
What does poort metabolisers face when coverting codeine to morphine?
Inadequate pain relief
53
What does rapid metabolisers face when coverting codeine to morphine?
Morphine OD
54
Example of drug interaction in affecting enzyme effectiveness?
Seizures – Anticonvulsant
• Pregnancy – Oral contraceptive
• Graft / organ rejection - Immunosuppressants
55
What are phase II reactions?
Conjugation/ anabolic reactions
56
How does Conjugation reaction occur?
Attachment of a substituent group - causing inactive product
57
Phase II reactions require insertion of glucuronyl, sulphate, methyl or acetyl group. Why?
Reaction sequence requires activation of the groups being coupled through energy transfer from high-energy phosphate compounds
58
What is the purpose of Glucoronic acid in Phase II reactions?
Reacts with high energy UTP forming UDP
59
What is Transferases??
Transfer small polar molecules onto the drug
60
How does Paracetamol OD occur?
- Glucuronide and sulphate pathways become saturated
- More NADPQI is produced by Phase I reactions
- Glutathione becomes depleted, NADPQI remains cytotoxic – hepatocyte damage and death
61
What are the four stages of Paracetamol OD?
• Stage 1 – asymptomatic – GI upset
• Stage 2 – Nausea and vomiting
• Stage 3 Hepatic failure – jaundice, encephalopathy
• Stage 4 – Death from liver failure
62
What are the routes of excretion?
- Kidney - Urine
- Bile - Faces
- Expelled air
- Sweat/Saliva
63
What are the roles of the Kidney?
- Maintaining internal environment
- Regulate volume of water in the body
-Excreting metabolic waste
- Producing erythropoietin and renin
- Coverting Vitamin D
64
Where does Glomerular filtration occur?
Renal corpuscle
65
What type of process is used in Glomerular filtration between the Glomercular capsule and the Peritubular capillary?
Passive diffusion
66
What are not filtered in Glomerular filtration?
Plasma proteins and drug protein complexes
67
How small does a molecular need to be to pass throught he glomeruli?
20 kDA
68
What is Creatinine?
A waste product of creatine phosphate
69
What factors affect glomercular filtration?
- Protein binding
- Size
- Renal disease, renal blood flow, age
70
What is the Glomercular filtration rate?
A test used to check how well the kidneys are working (how much blood pass throught he glomeruli)
71
What does high creatinine levels show?
Low glomerular filtration
72
What are Peritubular absorption?
Substances move fromt he subule into the tubular capillaries
73
What is Peritubular secretion?
Substance moves from the capillaries into the tubule
74
What is Renal Clearance?
Volume of plasma containing the amount of substance that is removed from the body by the kidneys in unit time
75
What is the equation for Renal Clearance?
CLren = Cu x Vu / Cp
Cp - plasma concentration
Cu - the urinary concentration
Vu - the rate of flow of urine
CLren - varies greatly for different drugs
76
What is Ion trapping?
Basic drugs more readily excreted in acidic urine
77
What drug is used in the treatment of recurrent urinar tract infections?
Hiprex
78
What effect does Diuretics have on the kidney?
- Increase the excretion of Na+ and water
- Decreas the reabsorption of Na+ and CL- from the filtrate
79
What sites does Diuretics affect?
- Loop of Henle
- Distal tubule
- Collecting tubule and ducts
80
What is Enteropepatic recycling?
Feedback mechanism involving the intestine and the liver
81
How is drug absorption occur in Enterohepatic recycling?
Intestine into the portal circulation
82
What happens to drugs when they enter the Enterohepatic recycling?
• Uptake of drug by hepatocytes
• Remaining drug and conjugated metabolites are secreted into the bile and back into the intestine
• Drug and conjugates can be reabsorbed into the systemic and hepatic circulation
83
What is the Enterohepatic cycle of bile acids?
Cholic acid and chenodeoxycholic acid – formed in the liver from cholesterol
• Conjugated with taurine or glycine – enhances detergent properties – stored in gall bladder until after a meal
• Bile acids facilitate digestion and absorption of nutrients, lipid-soluble vitamins, lipids
• Metabolised by intestinal microbiota, actively reabsorbed in the distal ilium and recycled by transport back to the liver
84
What prevents overgorwing of interstinal bacteria and cause antimicrobial peptide secretion?
Bile acids
85
What is Glucurondiation?
Excretion into the bile
86
What durgs undergo glucuronidaion during metabolism?
- Morphine
- Propofol
- Sex hormones
- Cardiac glycosides
87
How can Glucurondiated chemicals be de-conjugated by intestinal bacteria?
Via hydrolysis
88
What is Digoxin?
Cardiac glycoside, slows down the heart rate making it easier for the heart to pump blood around the body
89
What happens when small variations to Digoxin is made?
Toxic side effects
90
What is Digoxin is excreted as into the bile?
O-glucuronide
91
What metabolises O-glucuronide back into active digoxin?
GIT bacteria
92
What happens if the blood concentration of digoxin is high?
Enterohepatic recirulation can be blocked
93
What is Cholestyamine?
– binds digoxin stopping high enterohaptic recirulation and reducing blood concentrations
94
What is the Hepatic and biliary clearance equation?
CLbiliary = Bile flow x Cbile / Cp
95
How is Triethylaminuria involved in excretion?
Excreted through sweat to cause a unpleasant odour
96
What happens in Phase 1 to CYP450 enzymes?
Making them more polar
97
What is the purpose of Phase II enyzmes?
Adding another subtitiuent (conjugation)
98
Where does the loop diuettics affect?
Loop of Henle
99
What must happen in MEC?
minimum concentration of drug must be reached in the plasma before the desired therapeutic effect is achieved
