6 Drug metabolism and adaptations Flashcards by Cordelia Kuti

4 main stages of drug metabolism?

absorption

distribution

metabolism

elimination

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phase I metabolism

mainly occurs in liver

Oxidation, reduction and hydrolysis

Expose/add a reactive group

cytochrome P450 dependent oxidation
NADPH and NADPH - P450 reductase important factors

diff isoforms (CYP3A4 & CYP2D6)

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phase 2 metabolism

occurs in liver
conjugation w/ polar molecules makes more water soluble
glutathione, glucuronic acid or sulphate enzymes
specific enzymes required + UDPGA

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first pass effect and drug example

substance absorbed from ileum lumen extensively metabolised

enter venous blood which drains into HEPATIC PORTAL VEIN moved to liver

eg) 1g paracetamol

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how is gout formed from excessive alcohol consumption?

reduced NAD+/NADH
increase lactate, kidneys ability to excrete urine decrease, so uric acid levels which increases crystal formation

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alcohol metabolism

90% metabolised
10% excreted

small amount metabolised in liver alcohol oxidised by CYP2E, the rest by alcohol dehydrogenase

then aldehyde dehydrogenase to acetate

alchol>acetaldehyde>acetate

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metabolism of paracetamol

therapeutic level 2 tablets 1g, metabolised in phase II

toxic level goes through phase I and II due to saturation

toxic metabolite formed - NAPQI (oxidising agent depletes glutathione)

N-acetyl cysteine - will replenish glutathione

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treatment for alcohol dependance

disulfram

cause build up acetaldehyde

causes nausea, vomiting - sickness should deter

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what causes fatty liver?

reduced levels of NAD+

increase acetyl CoA, increase in FA and ketone synthesis

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effects of increased acetaldehyde

liver enzymes escape into blood (high levels AST/ALT/GGT)

reduced uptake and conjugation of bilirubin causes hyperbilirubinaemia

reduced synthesis of protein

reduced production of urea - hyperammonaemia

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what is gestational diabetes?

IN SOME WOMEN, the endocrine pancreas is UNABLE to respond to the increased demand of pregnancy AND is unable to respond to the metabolic demands!

fails to release the increased amounts of insulin required

loss of control of metabolism of blood glucose increase -> diabetes

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what changes occurred to meet foetal nutrient demand during pregnancy?

Reducing the maternal utilisation of glucose by switching tissues to fatty acids

delaying disposal of nutrients after meals

releases FAs form storage - first stage of pregnancy

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what is metabolic response to exercise?

energy demands of skeletal & cardiac muscle are met by mobilisation of fuel molecules from energy stores

minimal disturbances to homeostasis to keeping the rate of mobilisation equal to the rate of utilisation

glucose supply to brain maintained

end products are removed

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Metabolic response to short duration of HIGH intensity exercise (100m
sprint!)

muscle ATP and creatine phosphate used ˜5secs

muscle glycogen mobilised to form G6P

G6P metabolised via glycolysis to form ATP from ADP

under anaerobic conditions - forms lactate and H+ causes fatigue

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what does drug metabolism convert

inactive drugs to active form

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How are energy demands of skeletal and cardiac muscle met during metabolic response

Mobilise energy stores

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How can ketogenic-acidosis occur with alcoholics

High acetyl CoA
Low NAD+
ketone body synthesis

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How does damage occur to liver due to acetaldehyde

Acetaldehyde dehydrogenase has a low km and removes acetylaldehyde as it is formed but with excessive drinking acetylaldehyde can accumulate

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How does disulfiram work

Aldehyde dehydrogenase inhibitor
If patient drinks alcohol then acetylaldehyde accumulate leading to symptoms of hangover

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How does N-acetyl cysteine work

replenish glutathione allowing liver to metabolise the NAPQI

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How is acetyl CoA formed during alcohol metabolism

Acetic acid and CoA join to form Acetyl CoA

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How is glucose transported to fetus

Active transport GLUT1

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How is metformin excreted

Not metabolised and excreted as parent drug

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How is the concentration of nutrients in maternal circulation kept high(3)

Reduce maternal use of glucose, mother uses fatty acids and ketones
Delayed disposal of nutrients after meals
Release fatty acids from stores build during 1st half of pregnancy

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How much energy can muscle glycogen provide

2 minutes during intensive 60 minutes during low intensity

How much energy does creatine phosphate provide

5 seconds worth during sprint

What activates glycogen phosphorylase

Adrenaline glucagon AMP

What are the 2 divisions of pharmacology

Pharmacokinetics Pharmacodynamics

What are anti-insulin hormones

Hormones that oppose insulin action.

What are issues with metformin

No hypoglycaemia Lactic acidosis Weight loss

What are risk factors for gestational diabetes (3)

Maternal age greater than 25 BMI>25 Personal/family history of diabetes

What are some drawbacks of using fatty acids as fuel in exercise

Used only in aerobic conditions Slow release from adipose Limited carrying capacity in blood Limited by carnitine shuttle

What are some examples of enzymes deficiencies affecting drug metabolism

Plasma cholinesterase enzymes

What are some examples of phase 2 reaction in drug metabolism

Glucuronidation Sulphate conjugation Glutathione conjugation

What are the 2 functions of drug metabolism

Deactivate drug Elimination of drug

What are the 2 important placental steroid hormones

Oestrogen Progesterone

What are the 2 phases of metabolic adaptation during pregnancy

Anabolic Catabolic

What are the 3 underlying causes of gestational diabetes

Autoantibodies similar to type 1 diabetes Genetic susceptibility to onset diabetes Obesity and chronic insulin resistance

What are the 4 general processes in pharmacokinetics

Absorption Distribution Metabolism Elimination

What are the benefits of exercise

Decreased adipose and increased muscle Increased muscle glycogenesis Blood pressure falls

What are the clinical implications of gestation diabetes (4)

Increased incidence of miscarriage Fetal macrosomia (Large body) Shoulder dystocia Gestational hypertension and preeclampsia

What are the effects of adrenaline and growth hormone rise in marathon

Adrenaline stimulate glycogenolysis and lipolysis Growth hormone mobilise fatty acids

What are the energy sources in 100m sprint

Creatine phosphate Anaerobic production of ATP

What are the energy sources used in 1500m race(3)

Creatine phosphate Anaerobic glycogen Aerobic muscle glycogen

What can be used to treat alcoholism

Disulfiram

What can genetic variability cause in P450 activity

Increase or decrease activity of the CYP

What carrier molecule used to alcohol conversion to acetaldehyde

NAD+ converted to NADH+ and H+

What component of alcohol metabolism causes liver damage

Acetaldehyde

What do anti-insulin hormones do

Reduce glucose uptake in adipose/muscle

What do oestrogen and progesterone do the pancreatic Beta cells in pregnancy

Hyperplasia(more cells) Hypertrophy (bigger cells)

What does drug metabolism do the parent drug molecule

Convert parent drug to polar, lipid Insoluble water soluble derivative

What does increased levels of insulin in mother promote

Anabolic state leading to increased nutrient storage

What does the absorption of a drug depend on

pH of drug Drug has to non ionised

What effect occurs from glucagon levels rising in a marathon

Stimulate glycogenolysis Stimulate glucogenogenesis Stimulate lipolysis

What energy sources are used in a marathon

Muscle glycogen Liver glycogen Fatty acids

What enzyme used to convert acetaldehyde to acetic acid

Aldehyde dehydrogenase

What enzyme used to convert alcohol to acetaldehyde

Alcohol dehydrogenase

What factors affect magnitude and nature of metabolic response to exercise(5)

Type of exercise Intensity Duration Physical condition Nutrition state of individual

What genetic factors can affect drug metabolism

Gene deletions leading to enzyme deficiencies

What goes wrong in paracetamol overdose

High NAPQI Glutathione depleted Glutathione used as anti-oxidant NAPQI covalent bind to hepatic proteins leading to oxidative stress

What hormones changes occur in a marathon (4)

Insulin fall Glucagon rises Adrenaline and growth hormone rise Cortisol rise slowly

What is cytochrome P450

Family of enzymes

What is management for gestational diabetes(3)

Dietary modification Insulin injection Regular ultrasound

What is pharmacodynamics

What the drug does to the body

What is pharmacokinetics

What the body does to the drug

What is the abnormal function of pseudocholinesterase enzyme

Drug metabolised in a few hours

What is the co-factor used in glucuronidation

UDPGA

What is the effect of cortisol rising slowly in a marathon

Stimulation of gluconeogenesis and lipolysis

What is the effect of induction of P450 enzymes

Increase metabolism of other drugs Decrease plasma concentration

What is the effect of inhibition of P450 enzyme

Decrease metabolism Increase plasma concentration

What is the main site of action for phase 2 drug metabolism

Liver-cystolic enzymes

What is the metabolic response to starvation

Tissue switch from glucose to fatty acid/ketones Brain uses ketones

What is the most common anti-insulin hormones

Corticotropin releasing hormone

What is the normal metabolism of paracetamol

NAPQI made in phase 1 NAPQI conjugated with glutathione

What is the pathway for alcohol metabolism

Alcohol to acetaldehyde using alcohol dehydrogenase Acetaldehyde to acetic acid using aldehyde dehydrogenase

What is the polarity of a parent drug

Lipid soluble

What is treatment of Paracetamol overdose

N-acetyl cysteine

What occurs in catabolic phase in pregnancy

Maternal metabolism adapts to accommodate growing foetus

What occurs in anabolic phase in pregnancy

Increase maternal fat stores Small increase insulin sensitivity

What occurs in body due to anti-insulin after meal

Transient hyperglycaemia

What occurs in phase 1 of drug metabolism (3)

Convert lipophilic drug to polar molecule Oxidation, reduction, hydrolysis Add or expose reactive groups on drugs

Where is the main site of action for phase 1 drug metabolism

Liver Microsomes on endoplasmic reticulum of hepatocytes

Why cannot most drugs be excreted by kidney

Most drugs lipid soluble instead of water soluble

Why do lipids accumulate in liver due to liver damage

Reduced Protein synthesis Less lipoprotein synthesis Lipids produced in liver cannot be transported from the liver hence accumulate

Why is NAPQI bad

Depletes Glutathione which acts as a anti-oxidant

Why may alcoholics have fatty liver

High acetyl CoA Low NAD+ Fatty acid synthesis Fatty acids converted to Triacylglycerol Triacylglycerol cannot be transported to liver hence contribute to fatty liver

Why may alcoholics have gout

NAD+ decreased due to alcohol to acetaldehyde NAD+ needed for metabolism of lactate to pyruvate Increased lactate means kidney cannot excrete uric acid hence urate accumulates and forms uric acid crystals

Why might alcoholics have hypoglycaemia

NAD+ needed for fatty acid oxidation and metabolism of glycerol Liver cells cannot use lactate and glycerol hence gluconeogenesis not activated

Why must ATP be rapidly resythesised in exercise

ATP stores are limited in muscle Only last 2 seconds during sprint