eLFH - Pharmacological changes during Pregnancy Flashcards
Four pharmacokinetic phases of drug handling
Absorption
Distribution
Elimination
Metabolism
Definition of tmax
Time to maximum plasma plasma drug concentration
Definition of Cmax
Maximum plasma drug concentration
Effect of pregnancy on oral drug absorption
Decreased gut motility
Oral bioavailability is the same but more slowly absorbed over longer period of time
Increased tmax
Reduced Cmax
Effect of pregnancy on IM drug absorption
Increased blood flow through muscle
Speeds up absorption of IM drugs
Reduced tmax
Increased Cmax
Hormone responsible for decrease in gut motility
Progesterone - peaks in third trimester
Factors in pregnancy responsible for increasing volume of distribution of drugs
Increased extracellular fluid
Increased adipose tissue
Decreased serum alpha1 acid glycoprotein
Decreased serum albumin
Volume of increase in extracellular fluid by third trimester
6-8L
Effect of extracellular fluid in drug distribution
Increased fluid leads to increased dilution of hydrophilic drugs
Thus increases volume of distribution
Effect of adipose tissue in drug distribution
Average 4kg increase will sequester lipophilic drugs
Thus increases volume of distribution
Effect of alpha1 acid glycoprotein in drug distribution
Drug binding protein
High affinity low capacity binding sites for basic drugs
For highly protein bound drugs, lower protein concentrations leads to decreased total serum concentrations and increased volume of distribution as free drug equilibrates across compartments
Effect of albumin in drug distribution
Drug binding protein
Various low affinity high capacity binding sites for variety of drugs
For highly protein bound drugs, lower protein concentrations leads to decreased total serum concentrations and increased volume of distribution as free drug equilibrates across compartments
Effect of pregnancy on elimination of drugs
Pregnancy increases renal and pulmonary elimination (increased renal blood flow / GFR and minute ventilation)
Pregnancy decreases biliary elimination (cholestatic effects of oestrogens)
Drug examples which have pulmonary elimination
Sevoflurane
Nitrous oxide
When will anaesthetic agents have higher elimination in pregnancy
When women are spontaneously ventilation
Elimination will not be increased in mechanically ventilated women
Drug examples which have renal elimination
Atenolol
Digoxin
Lithium
Ampicillin
Drug examples which have biliary elimination
Rocuronium
Rifampicin
Aspects of drug metabolism to consider in pregnancy
Hepatic blood flow
Phase 1 (oxidative metabolism)
Phase 2 (conjugation)
Extra hepatic metabolism
Pharmacogenetics
Effect of pregnancy on hepatic blood flow
Increased hepatic blood flow
Effect of increased hepatic blood flow on drug metabolism
Most drugs metabolised by hepatic enzyme systems working far below their maximum rate
Therefore clearance depends on rate of delivery of drug to liver
Therefore clearance increases with increasing hepatic blood flow
Effect of pregnancy on Phase 1 - oxidative metabolism
Varied changes in hepatic cytochrome P450 activity
Eg:
Increased CYP3A4 and CYP2D6 activity
Decreased CYP1A2 activity
Role of CYP3A4 and CYP2D6
Responsible for metabolism of around half of all pharmacological agents
Role of CYP1A2
Metabolises caffeine
Effect of pregnancy on Phase 2 - conjugation
Increased
Eg increased activity of UGT2B7 and UGT1A4
Role of UGT2B7
Glucuronidation of morphine
Increased in pregnancy
Role of UGT1A4
Glucuronidation of lamotrigine
Increased in pregnancy
Effect of pregnancy on extra hepatic metabolism
Plasma cholinesterase activity decreases by 25% in pregnancy, and by 33% immediately post partum
Effect of pregnancy on metabolism of suxamethonium
Little clinical effect on duration of action of suxamethonium in patients with normal underlying enzyme activity, despite the decrease in plasma cholinesterase activity
Five mechanisms of placental transfer
Simple diffusion
Facilitated diffusion
Active transport
Receptor mediated endocytosis
General pinocytosis
Most common mechanism of drug transfer across placenta
Simple diffusion
Equation for rate of diffusion from mother to foetus (Q/t)
Factors which increase simple diffusion
Higher concentration gradients
Increased diffusion surface area
Permeability to drug
Shorter diffusion distance
Placental binding
Factors which increase permeability of drug
Small molecular weight
High lipid solubility
Increased drug in unionised form
Molecular weight at which molecules freely diffuse through placenta
< 400-500 daltons
Molecular weight at which placenta becomes impermeable
> 1000 daltons
Example of large highly ionised drugs which don’t cross placenta
Heparin
Protamine
Pathologies which decrease area of villous structure of placenta available for diffusion
Abruption
HTN
Infarction
Intrauterine infection
Diabetes
Diffusion layers in the placenta
Maternal blood in intervillous space
Foetal trophoblast
Foetal capillary endothelium
Foetal blood
What makes up foetal trophoblast
Cytotrophoblast
Syncytiotrophoblast
Pathologies which increase diffusion distance in the placenta
Abruption
HTN
Infarction
Intrauterine infection
Diabetes
(Same as pathologies which reduce surface area)
Factors which affect foetal distribution of drug which crosses placenta
Foetal circulation
Foetal cerebral blood flow
Highest proportion of cardiac output
Cerebral blood flow increased by foetal hypoxia
Foetal pulmonary blood flow
Very low - especially compared to adults where 100% blood passes through lungs
Foetal hepatic blood flow
From umbilical vein:
- 60-80% blood flows through liver with potential for 1st pass metabolism before entering IVC
- 20-40% bypasses liver via ductus venosus directly to IVC
Foetal placental shunt
50-60% of foetal blood returns to the placenta without perfusing foetal tissues due to placental shunt
In context of drug passing across the placenta, this increases foetal blood concentration of drug so decreases further diffusions from maternal circulation
Factors affecting teratogenicity of a drug
If a drug has teratogenic potential, its effect on foetus depends on gestational age and the organogenesis that is in progress at that point
Effect of plasma protein binding on drug transfer across placenta
Plasma protein binding is low for albumin and alpha1 acid glycoprotein, therefore free plasma proportion of drug is higher
It is free drug that equilibrates across placenta and through foetal compartments
Foetal drug metabolism
Oxidative metabolism develops in first trimester
Sulphation is well developed
Glucuronidation poorly developed even at birth
Greater proportion of metabolism is extra hepatic
Relevance of metabolic products in foetal circulation
Metabolic products of drug may have crossed placenta from mother so does not demonstrate organ function
Total body water percentage by gestation of foetus
94% by mass at 16 weeks
76% at term
Higher TBW increases volume of distribution of hydrophilic drugs and lowers serum concentration
Body fat of the foetus by gestation
Adipose tissue only laid down in 3rd trimester
Foetuses <1 kg have essentially no fat
CNS myelination of foetus and relevance for drug metabolism
CNS myelination is low so there is reduced binding of lipophilic drugs
Eg phenytoin
Foetal elimination of drugs
Primarily via placenta
Secondary organs are:
Renal
Intestinal
Skin (permeable to water in foetus)
Recirculation of drugs from foetal elimination
All secondary organs excrete into amniotic fluid
Some amniotic fluid is swallowed by foetus
If any previously excreted drug compounds can be absorbed by gut then it will recirculate in the foetus
M:F ratio
Materno:Foetal ratio
Ratio of uterine vein concentration to umbilical vein concentration
Used to describe degree of placental transfer of drugs
Factors which impact M:F ratio
Time since drug dose given to mother
Elimination rate in mother
Transfer rate to foetus
Elimination rate in foetus
