PHARM Flashcards
Gastrointestinal absorption of drugs in newborn is implicated as:
they have less gastric acid which is ph~7..
give 3 other reasons
- peristalisis is reduced in first 6months
- reduced production of bile
- GI disorders e.g. gastroschisis, NEC that reduce absorption so need to deliver via TPN
How will absorption of acid labile medicines e.g. penicilin be affected by the gastric acid in a newborn?
As the gastric acid is more alkaline (ph 7) you will get more absorption
IV for drugs in babies is commonly used as it has 100% bioavailability, give 2 disadv of this method of administration:
- difficult line access
- drug compatibility
- infection risk
- longer hospital stay, $$$
Why is intramuscular administration of drugs in babies discouraged?
- absorption form injection site is erratic/variable
- depends on vascular perfusion there, muscle mass and contraction
- too painful
In what 2 pathologies is intramuscular administration of drugs in babies esp. discouraged due to the variable blood flow?
Hypotension
Sepsis
Caution should be taken with percutaneous administration of drugs into the skin of neonates in terms of absorption. Why?
- thinner s.corneum
- increased skin hydration
- larger SA so enhanced absorption
What are the risks associated with the following drugs admisistered percutaneously in neonates?
- topical corticosteroids
- topical aminoglycosides
- Corticosteroids may reach high systemic levels –> Cushingoid symptoms
- Aminoglycosides can lead to hearing loss
Rectal administration of drugs to babies/children is useful in 2 instances in particular…when? What can lead to erratic absorption here?
- vomiting/nil by mouth patients
- children reluctant to take orally
- variation in rectal venous drainage
Vd is the degree to which a drug is distributed in….. rather than…..
distributed in…..body tissue rather than…..plasma
Suggest 3 `things that affect the degree of drug distribution (once within circulation) out of plasma.
- size of body water compartments
- how much drug binds to p.proteins
- degree of development of BBB
- metabolic disturbances e.g acidosis
- specificity of drug to receptor sites
How does total body water and adipose % in neonates compare to adults? Hence water-soluble drug distribution…?
- higher body water (92 vs 60%) and less adipose in neonates
- higher loading doses of water-soluble drug needed to reach steady state
How does the fact that neonates have less plasma protein with lower binding affinities affect Vd?
-less bound drug so more free fraction so more distribution out from plasma
The drug phenytoin is 98% protein bound, how does it cause kernicterus + long-term neuro damage in neonates?
- phenytoin can displace bilirubin
- more free bilirubin which can cross BBB –> kernicterus
Hypoalbuminea can affect protein binding. Suggest 2 conditions this can occur with.
- malnutrition
- sepsis
- nephrotic syndrome
- hepatic disease
What is different about the BBB in neonates? What 2 factors determine the rate of drug transfer to the CNS?
- BBB is functionally incomplete so more enters CNS
- lipid solubility and ionisation of drug affect it
How is hepatic metabolism of drugs in neonates?
Phase I hydroxylation
Phase II Sulfation/Methylation/Glucoronidation
Immature as enzyme functioning esp CYP has delayed maturity (phase I)
Phase II Sulfation/Methylation = normla
Glucoronidation = immature until ~1yr
What syndrome can the antibiotic chloramphenicol or idomethacin cause in a baby due to immature hepatic metabolism?
Grey Baby Syndrome
Nephrogenesis is from wk9-34 gestation but renal function is still immature at birth. In children what can further compromise function, give 2 e.g.s.
- sepsis
- dehydration
- nephrotoxic drugs
Suggest why ADRs are more common in neonates.
- lack of clinical trial data
- immature liver function–>lack of detoxification and excretion so drug accumulates
What is dosage in paedatric units based on?
-weight/SA
The myometrium has 3 smooth muscle layers, what are the fibre orientations?
- outer: longitudinal fibres
- middle: figure of 8 fibres
- inner: circular fibres
How does the myometrrium sm organisation act like a ligature preventing blood loss in birth?
- contraction of the fibres increases the uterine pressure
- forces the contents towards the cervix
The myometrium is spontaneously active/myogenic. What modulates contractions? (increases/decreases?)
- NTs influence
- Oestrogen increases contractions
- Progesterone inhibits activity
-In the non-pregnant uterus why do they experience weak contractions early in the MC and strong contractions during menstruation? (horomones..)
- progesterone starts high then decreases (inhibitory)
- prostoglandins increases at menstuation
The myometrium is myogenic but has ANS innervation, symp/para? Receptors? Effects?
Sympathetic
Alpha receptor stimulation causes contraction
B receptor -> relaxation
What pacemaker cells set the myogenic activity of the mypometrium?
ICC-Interstitial Cells of Cajal, initiate and coordinate contractions
ICCs generate electrical activity. Via what do they pass to SM cells?, what proteins make this pathway?
- via gap junctions made of connexin proteins
- makes low resistance pathways
How does oestrogen increases the contractions of the myometrium?…think GJs
-increases the expression of gap junctions so more activity from ICCs pass to SMs promoting contraction
ICCs generate “slow wave” depolarisations that generate APs. APs to SM via gap junctions..what is the Ca2+ mechanism of contraction?
AP causes Ca2+ influx via VGCC opening
the increases intracellular [Ca2+] causes contraction
What are type of GPCRs does the myometrium have for oxytocin? What happens when oxytocin binds?
- Gaq so stimulates PLC which hydrolyses PIP2 to IP3 and DAG
- Ca2+ release from SR and more depolarisation, VGCC open more, Ca2+ influx
- Ca2+ & calmodulin activates MLCK -> cross bridge
At low conc, of ICC stimulants e.g. oxytocin, there is little slow wave activity and SM contraction. High conc –> sustained contractions, what about [v. high]?
Hypertonus (incomplete relaxation) as Ca2+ extrusion process cant keep up
What is the benefit of hypertonus in birth vs. danger if baby still inside?
stops haemorage if baby out. If baby in, cuts blood supply -> foetal distress
Oxytocin is a nonapeptide released in response to suckling and cervical dilation. Where is it made? Where is it released from?
Made in hypothalamus
Released from post. pituitary
Syntocinon and Pitocin are synthetic versions of which hormone?
Oxytocin
How is oxytocin action dependent on oestrogen release(in late stages of birth)?
- oestogen produces a rise in oxytocin release
- oestrogen increases oxytocin receptors and GJs
Give 2 uses of oxytocin clinically:
- induce labour at TERM to increase contractions (but wont soften cervix)
- used with ergot to prevent post. p. haemorrage by acting like ligature on vessels, less bleeding
Syntometrtine is the name of the drug with which 2 hormones? What are their effects?
Oestrogen-rapid acting
Ergot-prolonged action
Prevent post.partum haem.
Oestrogen promotes the synthesis of what?
Clue: made in endometrium, have role in dys/menorrahgia and partruition
-prostoglandins
Name 3 functions of protoglandins in birth
- coordinate and increase frequency/force of contractions
- increases GJs present
- increases oxytocin synthesis
- SOFTENS CERVIX
Dinoprostone and Carboprost are analougues of what?
Dinoprostone = PGE2 (v.dilates)
Carboprost - PGF2a (v.constricts)
prostoglandins
Give 2 uses of prostoglandin analogues clinically:
- induce labour BEFORE TERM (receptors always present)
- induce abortion
- prevent p.p.haem
- soften the cervix
What is the risk of using prostoglandin analogues in labour clinically if it enters circulation?
- Dinoprostone will cause systemic v.dilation and huge BP drop -> CV collapse
- Carboprost can cause too much contraction -> hypertonus ->f oetal distress
How are prostoglandin analogues in labour clinically administered to reduce systemic effects?
-as a cervical gel/vaginal insert to act locally
The fungus ergot can produce powerful uterine contractions only if myometrium starts relaxed. What is it used for clinically?
-prevent post partum haemorrhage
Why may myometrial relaxants be admistered? What can be done in the time?
In premature labour to delay deliver 48hrs
-transfer to specialist, give corticosteroids for lung maturation, improve survival
Give 3 examples of c;lasses of myometrial relaxants
- Ca2+ channel antagonists (eg. nifedipine)
- Oxytocin receptor antagonists (eg. Retosiban)
- COX inhibitors (eg. NSAIDS)
How may the absorption of drugs in older adults be affected?
- influenced by food/lack of food
- gastric transit time longer
- pH increases a bit (further alkaline if taking PPIs)
What changes to the body of older adults affect distribution of drugs?
- sarcopaenia
- less body water, less mean body mass,
- increase body fat
How does less body water and more body fat affect the Vd of hydrophilic and lipophlic drugs?
(less lean body mass..and digoxin VD..?)
-hydrophilic drugs e.g. lithium have reduced Vd
-lipophilic drugs e.g. bezos have increased VD
(digoxin binds to muscle so Vd decreases with age)
What changes in the liver cause metabolism of drugs in older adults to change?
- liver mass decreases and hepatic b.flow decreases
- (enzyme activity unchanged)
What age-related changes affect pharmacodynamics of e.g. opiates, digoxin..
- more sensitive to sedation & psychomotor impairment as BBB leaky (e.g. benzo, opiates)
- more intensity and longer duration of opiates
- more cardiac sensitivity to digoxin
What changes in the kidney cause elimination chof drugs in older adults to change?
- smaller kidneys as basement membrane changes
- less renal BF as artery resistance increased
- poorer nephron functioning (sclerosis)
- reduced GFR
What is optimal pharmacotherapy for older adults?
- balance of over/under prescribing
- correct drug and dose for condition
- specific to that patient
What 2 criteria are in place to screen for inappropriate prescriptions in older adults?
- STOPP START criteria
- Beers criteria
10% of over 75yrs patients have an ADR…what are some risk factors in older adults?
- multiple medications
- multi-morbidity
- previous ADRs
- lower BMI (sarcopaenia)
- renal/liver impairment
- compliance
Drug interactions can cause confustion, cognitive impairment, hypotension, acute renal faliure…what 2 classes of drugs most commonly interact?
-cardiovascular and psychotropic drugs
What 3 factors/impairments affect compliance of taking medications in older adults?
- impaired cognition
- impaired vision
- impaired manual dexterity
Suggest 4 ways we can improve compliance in older adults:
- communication, simplify regimes
- readable labels, specific instructions
- easy openable containers
- blister packs/Dosset boxes
- involve carers/family
- recognise side effects
