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JMP Semester 2 > Week 21 > Flashcards

Week 21 Flashcards

1
Q

What is first pass metabolism?

A

A drugs metabolism either by the intestines or liver after it is ingested before it has access to the circulatory system.

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2
Q

What is xenobiotics?

A

Foreign substances (not natural to the body)

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3
Q

What are 4 ways biotransformation/metabolism can alter drugs?

A
  1. Active drug –> inactive drug
    1. Active drug –> active or toxic metabolite
    2. Inactive prodrug –> active drug
    3. Un-excretable drug –> excretable metabolite (to enhance renal or biliary clearance)
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4
Q

Where are drugs metabolised?

A
  1. Mostly in the liver
    1. Decent amount In the small intestine
    2. Can also occur in the lungs, nasal passages, kidneys
    3. As well as all cells in the body (smaller scale)
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5
Q

What is bioavailability?

A

Fraction of administered drug that reaches the systemic circulation
Eg IV injection = 100% bioavailability

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6
Q

What is phase one metabolism?

A

Trying to prime - usually reduces water solubility
Add functional group
Reveal functional group
Exchange functional group

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7
Q

What are the main Phase 1 enzymes?

A
  1. Cytochrome P450 haeme protein mono-oxygenases (CYP) (huge 75% of all drug metabolism)
    1. Flavin-containing monooxygenase (FMO)
    2. Epoxide hydrolases (EH)
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8
Q

What is the most important Phase 1 enzyme?

A

Cytochrome P450 enzymes (75% of all drug metabolism)

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9
Q

What is a phase two metabolism?

A

Tagging something onto it - to drive excretion

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10
Q

What is phase two metabolism?

A

Conjugation reactions

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11
Q

What does phase two metabolism usually result in?

A

Inactive hydrophilic products - ready for excretion

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12
Q

Is phase 1 or phase 2 faster?

A

Phase 2 is usually faster than phase 1

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13
Q

What are some potential changes in liver metabolism and that can affect drug interactions?

A
  1. Fast metabolism- lose therapeutic efficacy

2. Slow metabolism- increased therapeutic effect or adverse drug reactions or toxicity

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14
Q

What are some effects drugs may have on metabolism to cause altered effects?

A
  1. Drugs may inhibit metabolism enzymes- which would cause plasma levels on other drugs in the system to rise.
    1. Drug competition - is A and B are metabolised by the same enzyme –> plasma levels will depend on the affinity of each drug and their concentration.
    2. Drugs inhibiting enzymes which catalyze the conversion of prodrugs.
    3. Drug inducers- enzyme induction - some drugs activate transcription and induce expression of drug metabolizing enzymes (can impact other drugs and cause the inducer drugs own metabolism)
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15
Q

What are some potential effects of pharmacogenomics on metabolism of drugs?

A
  1. Enhance enzyme activity

2. Reduce/eliminate enzyme activity

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16
Q

How is alcohol is metabolised by the liver?

A
  1. Alcohol dehydrogenase –> converts to acetaldehyde

2. Acetaldehyde –> acetic acid (by aldehyde dehydrogenase (ALDH)

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17
Q

What is the issues with acetaldehyde?

A 
Reactive and toxic compound
Can cause:
	1. Flushing
	2. Tachycardia
	3. Hyperventilation
	4. Panic and distress
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18
Q

How is paracetamol metabolised?

A

Predominately phase 2 metabolism –> nontoxic glucuronide and sulfate conjugates –> finally excreted in urine

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19
Q

How might alcohol and paracetamol interact?

A
  1. Alcohol metabolism may cause glutathione depletion

2. Alcohol can cause hepatotoxicity –> same with paracetamol is there is conjugation saturation (NAPQI build up)

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20
Q

What happens in paracetamol overdose?

A
  1. There is a saturation of the conjugation
    1. NAPQI produced which binds glutathione –> to be excreted in urine
    2. Glutathione is eventually depleted
    3. NAPQI increases (highly reactive metabolite)
    4. Cell death
    5. Hepatic necrosis
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21
Q

What is the treatment for paracetamol overdose?

A

N-acetylcysteine (NAC) –> hydrolyzed to cysteine
This is the rate limiting factor in glutathione synthesis –> increased glutathione –> increased conjugation to NAPQI and then urine excretion

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22
Q

How does overuse of opioids normally kill people?

A

Respiratory depression

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23
Q

How can metabolism effect opioid analgesic effect?

A

In the example of codeine:

1. Codeine is a weak opioid by itself
2. Is converted into morphine for increased relief 
2. Most people metabolise 10% of codeine to morphine.
3. Hence changes in this metabolism ability can have massive impacts of the analgesic effect of codeine.
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24
Q

What is st John’s Wort and what is it used for?

A

depression

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25
Q

What mechanisms does the liver employ to detoxify drugs and metabolic byproducts?

A

There is Phase I and Phase II mechanisms:
Phase I = oxidation/reduction/ hydrolysis of a drug (CYP enzymes)
Phase II = conjugation of drug or phase I product with another molecule to inactivate the drug etc.

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26
Q

What is biological oxidation?

A

It is the loss of electrons (/loss of energy)

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27
Q

What is biological reduction?

A

The gain of electrons (/gain energy)

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28
Q

What is a feature of Oxidation and reduction reactions?

A

They are always coupled - when one substance is Oxidised another must be Reduced.

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29
Q

What is a free radical?

A

Unstable species - due to an unpaired electron in their outer shell.

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30
Q

What is the risk of free radicals?

A
  1. They are highly reactive- react with other compounds to capture their missing electron to regain stability.
    1. In doing so generates another free radical though (chain reaction)
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31
Q

What is superoxide free radicals?

A

Reactive oxygen species - any oxygen containing molecules including oxides and peroxides.

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32
Q

How are reactive oxygen species derived?

A

Metabolism of oxygen –> within the mitochondria (aerobic metabolism)

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33
Q

Apart from metabolism what are other sources of free radicals?

A

Environmental source - smoking, air pollution etc.

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34
Q

What can excessive ROS (reactive oxygen species) have on a cell?

A
  1. Oxidize- protein, lipids and DNA

2. Mitochondrial damage –> lead to energy failure –> cell death

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35
Q

What is an antioxidant?

A

A substance that inhibits oxidation or reactions promoted by oxygen, peroxides or free radicals.

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36
Q

How do antioxidants function and ultimately prevent damage by free radicals?

A

They donate the missing electrons to ROS to terminate potentially damaging chain reactions.
- Stabilize free radicals before they cause damage.

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37
Q

What are two types of antioxidants?

A

Natural or synthetic

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38
Q

What are the major dietary antioxidants?

A

Flavonoids and carotenoids

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39
Q

What vitamins are major antioxidants?

A

Vitamins (A, C, E)

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40
Q

What is the role of glutathione?

A

It is a major antioxidant in the body produced by enzymes (glutathione peroxidase, catalase and superoxide dismutase) and is involved in the clearance of ROS.

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41
Q

What is oxidative stress?

A

An imbalance of levels of reactive oxygen species (ROS) and antioxidants (AOX)

42
Q

What can lead to oxidative stress?

A

Excess levels of ROS and/or antioxidant depletion

43
Q

What diseases can oxidative stress lead to?

A 
Cancer
Cardiovascular disease
Diabetes
Alzheimer's
Parkinson's
Eye diseases
44
Q

What is potential issues of free biological Iron (Fe)?

A

Can catalyze ROS formation in an oxygen rich environment.
- To the point where excess iron and ROS = important initiators and mediators of cell death in a variety of organisms and pathological situations

45
Q

What does Iron catalyze the conversion of to a ROS?

A

Hydrogen peroxide

46
Q

What is the structure of ammonia?

A

NH3

47
Q

What is the structure of an amino group?

A

NH2

48
Q

What is the structure of an ammonium ion?

A

NH4+

49
Q

What is the role of ammonia in the body?

A

Mostly waste but can be used to synthesise glutamine (an AA)

50
Q

Where does ammonia come from?

A

Protein processing and Gut bacteria

51
Q

How is amino acids metabolised? (what process)

A

Transamination

52
Q

What is transamination?

A

Transfer of an amino group from an amino acid to a keto acid.

53
Q

How are amino acids catabolized? (process)

A

Deamination

54
Q

What is deamination?

A

Removal of the amino group as ammonia

55
Q

What happens if you have excess ammonia?

A
  1. Condition known as hyperammonemia

2. Can be caused by liver damage/disease preventing conversion of ammonia to urea.

56
Q

What are some symptoms of hyperammonemia?

A 
Growth retardation
Hypothermia
Seizures
Tremors
Hepatomegaly
Fatigue 
Coma
Poor coordination
57
Q

What are the proteins synthesised in the liver?

A
  1. Albumin (25% of all liver produced proteins)
    1. Factors involved in haemostasis (blood coagulation/clotting)
    2. Carrier proteins
    3. Hormones
    4. Pro-hormones
    5. Apolipoproteins
    6. Enzymes
    7. Bile proteins
    8. Collagen (produced by stellate cells in liver)
58
Q

What class of drug is alcohol?

A

Sedative hypnotic drug

59
Q

What is the effects of alcohol on the nervous system?

A

Low doses- can act as a stimulant

High doses- depression of the central nervous system

60
Q

What organs does alcohol enter the bloodstream?

A
  1. Stomach (20%)

2. Small intestines (80%)

61
Q

What are some factors effecting BAC?

A
  1. Livers ability to metabolise alcohol (genetic)
    1. Presence or absence of food in stomach
    2. Time to consume alcohol
    3. Body composition (size and muscle/fat mass)
    4. Age
    5. Sex
    6. Frequency of alcohol consumption
62
Q

What are the body systems alcohol can have an effect on?

A
  1. Nervous system- black out, insomnia, impaired judgement and coordination etc
    1. Gastrointestinal system- inflammation of oesophagus and stomach, bleeding, vomiting, Acute pancreatitis, hepatitis.
    2. Cardiovascular system- decreased contractility, 6x increase of coronary artery disease
    3. Genitourinary system- sexual development, foetal development
    4. Immune system
    5. Respiratory system
    6. Other
63
Q

What are the most common pathological processes in the liver?

A
  1. Viral hepatitis
    1. Alcoholic liver disease
    2. Gall stones
    3. Cancer
64
Q

What is a hepatic lobule?

A

Functional unit of the liver

65
Q

What is the shape of a hepatic lobule?

A

Hexagonal (image below of pig) much more obvious

66
Q

What is at the border of a lobule?

A

Connective tissue septum

67
Q

What is at the centre of a lobule?

A

Central vein

68
Q

What does a bile duct look like histologically?

A
  1. Clear hole
    1. blue ring may be around the edge
    2. Might be near a portal tract
    3. Will be cuboidal cells
69
Q

What does a portal tract look like histologically?

A

Larger mass can encompass the Bile duct etc.

70
Q

What does the liver capsule look like histologically?

A

Fibrous layer covering the outside of the entire liver

71
Q

What does a hepatic venule look like?

A
  1. Circle not clear inside

2. Might be solo

72
Q

Where is the triads?

A

Usually away from the hepatic venule (big chunks with a bile duct)

73
Q

What does a hepatic artery branch look like histologically?

A
  1. Potentially circular mass
    1. Probably near a terminal portal venule
    2. Can be white inside circle with other stained cells inside
74
Q

What does a hepatocyte plate look like histologically?

A
  1. Areas of hepatocyte cells
75
Q

What does a lymphatic look like histologically?

A
  1. Small white circles commonly next to hepatic artery branches
76
Q

What does a terminal portal venule look like histologically?

A
  1. Very large circle/oval
    1. white
    2. Surrounded by artery and bile ducts etc.
77
Q

What does a sinusoid look like histologically?

A
  1. Increased redness cells compared to surrounds.

2 .Near hepatic plates

78
Q

What does a Binucleate cell look like histologically?

A
  1. Cells with 2 nucleus

2. Reasonably large cells

79
Q

What does a sinusoid lining cell look like histologically?

A
  1. Clearish cells in between other more obvious cells

2. Quite large in size

80
Q

What do adipocytes look like histologically?

A

White irregular circles

81
Q

What do islets of Langerhans look like histologically?

A
  1. Larger clusters of cells that appear different from the cells around them
    1. Clusters may be circular/ovular in shape and slightly lighter than cells around
82
Q

What do interlobular ducts look like histologically?

A
  1. Largish irregular circle mainly white with a smear of colour centrally.
    1. Obvious dark stain on border
83
Q

What does the septum look like histologically?

A
  1. Next to an interlobular duct
    1. The Pink colouring around the ducts dark outer edge.
    2. Around the septum will be standard cell colouring.
84
Q

What is the name for standard histological illumination?

A

Kohler illumination

85
Q

What is encephalopathy?

A

Encephalopathy is a term that means brain disease, damage, or malfunction.

86
Q

Symptoms of encephalopathy?

A
  1. Memory loss
    1. Personality change
    2. Impaired cognition
    3. Impaired attention
    4. Headaches
    5. Epileptic seizures
      Flapping tremors
87
Q

Is there benefits of alcohol?

A

Not medically- 10-40% of chronic heart disease - but study was terribly designed
Social benefits perhaps

88
Q

What is the guidelines to maintain ‘low risk’?

A
  1. No more than 2 on any particular day

2. Any more than 4 standards in a session is considered harmful

89
Q

What is the pattern of a liver function test for an alcoholic liver?

A

Abnormal serum transaminases, particularly if the level of aspartate aminotransferase (AST) is greater than that of alanine aminotransferase (ALT)

90
Q

When is induction of emesis used for overdose or poisoning?

A

Only really helps if contents still in the stomach/duodenum

91
Q

How do binders like charcoal work?

A

Bind to the toxins. Prevent them being absorbed.

Can be used to decontaminate the stomach mainly to prevent absorption in the small intestine.

92
Q

What is the difference between total and direct bilirubin?

A

Total is total

Direct is conjugated

93
Q

What is best to do after a needle stick injury?

A

Wash with soap and water

94
Q

Can hepatitis cause an increase in conjugated bilirubin?

A

Yes

95
Q

How does Atazanavir work?

A

Atazanavir is a competitive inhibitor of the bilirubin-specific UDP glucuronyltransferase.

96
Q

What is the role of pancreatic lipase?

A

To access and breakdown (by hydrolysis) the triglycerides into free fatty acids and monoglycerides.

97
Q

Where are chylomicrons assembled?

A

Golgi apparatus of the enterocytes

98
Q

What is an enterocyte?

A

Intestinal lining cell

99
Q

Where does phase 1 metabolism normally occur?

A

Endoplasmic reticulum

100
Q

What is the main mechanism and also resulting function of phase 1 metabolism?

A

Adding/revealing a functional group- this reduces the activity of the xenobiotics.

101
Q

What is the main mechanism and also resulting function of phase 2 metabolism?

A

Conjugation- main function is to make water soluble for excretion

102
Q

What age group drinks the most frequently?

A

Goes up with age. 70+ most frequent

JMP Semester 2 (8 decks)

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