Pharmacology and Therapeutics

Question 1

What are some of the risk factors for CKD progression?

Answer 1

CVD

Hypertension

Diabetes

Smoking

AKIs

African origin

Chronic use of NSAIDs

Urinary tract outflow obstruction

Question 2

What are the indications for starting RRT?

Answer 2

Uremia starting to effect daily life

Biochemical measures (hyperkalemia/acidosis)

Fluid overload

eGFR of 5-7ml/min/1.73m2

Question 3

What are the 2 different types of dialysis?

Answer 3

Haemodialysis –> Transfer of uraemic solutes from the blood by diffusion via a semi-permeable membrane

Requires a fistula, or a line/graft (which has an increased risk of infections)

LMWHs are added to prevent clots, and bicarbonate is added to the blood

Peritoneal –> Access to the peritoneal cavity allows continuous dialysis whilst at home, with only the bags needing to be changed 4 times per day

Question 4

What 3 vaccines are compulsory before starting dialysis?

Answer 4

Hep B

Influenza

Pneumonia

Question 5

What is the effect of volume of distribution on the removal of drugs by dialysis?

Answer 5

Over 2L/Kg –> Not removed

Under 1L/Kg –> Removed significanlty by dialysis

Question 6

What is the effect of protein binding in dialysis?

Answer 6

Only the unbound (free) drug can be removed in dialysis

Over 80% bound means that no drug will be dialysed

Question 7

What is the “Triad of General Anasthesia”?

Answer 7

Unconsiousness

Analgesia

Muscle Relaxation

Question 8

Name some of the key characteristics of the ideal general anaesthetic

Answer 8

Stable and potent

Controllable –> So it can be turned off if needed

Minimal cardio/resipiratory depressent

Non-irritant

Question 9

What are the 4 stages of anasthesia?

Answer 9

Stage 1 (Analgesia) –> Consiousness and drowsiness

Stage 2 (Excitement) –> Loss of consiouness, but delirium occurs, spaciticity, gagging and vomiting

This stage needs to be minimised!

Stage 3 (Anasthesia) –> Regular respiration, loss of reflex and muscle tone

Stage 4 (Medulllary Paralysis) –> Cardiorespiration depression and so death

Dont want to push it this far!!

Question 10

What are the 2 types of general anasthetic?

Answer 10

Inhalation –> Controllable with rapid blood-gas exchange

Stable and potent

Usually halogenated ethers or hydrocarbons

Used to maintain unconsiousness

Intravenous –> Rapid and short acting. Normally used for the induction of anasthesia

Question 11

Explain the difference between the lipid and protein theory of anasthesia

Answer 11

Lipid –> Anasthetic potency is proportional to lipid solubility

The drug binds to lipid membranes and causes the shape of Na+ channels to change, meaning they’re less effective

Protein –> States that anasthetics bind to membrane proteins and receptors

Eg, potency correlates with luciferase inhibition

Question 12

How does halothane affect K+ channels?

Answer 12

Cause them to open, meaning that APs are less likely to occur

Question 13

In what stage of anaesthesia are muscle spasms most likely?

Answer 13

Stage 2

‘Excitement stage’

Question 14

What is a motor unit?

Answer 14

The motor neuron and the muscle fibre that it innervates

Question 15

What is the make up of nicotinic receptors in skeletal muscle?

Answer 15

2 alpha

1 beta

1 delta

1 gamma

2 moleucles of ACh must bind to activate it (with Na+ going in and K+ going out….cause end plate depolarisation)

Question 16

What is the mechanism of muscle contraction?

Answer 16

ACh binds to Na+ channels, causing depolarisation at the end plate. This causes VG Na+ channels to open, causing APs to fire further into the muscle

This depolarisation causes VG Ca2+ to open, causing calcium-dependent calcium release from the SR. This calcium then binds to troponin which causes muscular contraction

Question 17

What are the 2 types of Neuromuscular Junction blocking drugs?

Answer 17

Non-Depolarising (competitive antagonists) –> Acts by blocking ACh

Reversible by increase ACh levels (neostigmine)

Depolarising –> Weak nicotinic agonists

Question 18

What % of ACh receptors needs to be blocked to prevent synaptic transmission at NMJs?

Answer 18

90% of receptors

Question 19

What determins the rate of recovery, in terms of non-depolarising NMJ blockers?

Answer 19

Susceptibility to cholinesterases and clearance

Question 20

What are the 3 main side effects of non-depolarising NMJ blockers?

Answer 20

Hypotension –> Due to the blockade

Histamine release from mast cells

Respiratory faliure

Question 21

What type of molecules are depolarising NMJ blockers?

Answer 21

Symmetrical bisquarternary ammonium compounds

Question 22

How do depolarising NMJ blockers work?

Answer 22

Bind and activate the nicotinic receptor, opening Na+ channels and causing depolarisation

They are slowly hydrolysed by cholinesterases, but the depolrisation is kept at the end plate

The Na+ channels become refractory, and so further binding of nictonic agonists has no effect, causing Ca2+ to build up….making the muscles flacid

The persistant stimulation that also occurs causes the receptors to desensitise. Therefore when the muscle does partially repolarise it has no effect (transmission is still blocked)

Question 23

What are the main problems with depolarising NMBs?

Answer 23

Initial Muscle Twitching –> Due to initial depolarisation

Bradycardia

Post-op pain

Prolonged paralysis –> ONLY in cholinesterase deficinet patients

Hyperkalemia

Question 24

What is the train of 4?

Answer 24

A way of assessing anasthetic depth

Usually 4 stimulatons would cause 4 APs, but when done with NMBs the response is reduced

Non Depolarising produces a greater first reponse due to the higher ACh levels (due to ACh block)

Question 25

What is **Suxamethonium**?

Answer 25

**A depolarising NMB** Doesn't cross the placenta as ionized Has a rapid onset and short duration of action

Question 26

What's **Neostigmine**?

Answer 26

An acetylcholinesterase inhibitor **Reverse non-depolarising NMBs**... but potentiates depolarising NMBs!!

Question 27

What's **Sugammadex**?

Answer 27

**Chelates aminosteroids, such as rocurnium** (a non-depolarising NMB) Will NOT bind to atracurium

Question 28

What is **Phenylketonuria**?

Answer 28

An inherited **deficinecy of Phenylalanine Hydroxylase (PAH)** (an allosteric liver enzyme) which converts S-Phe to S-Tyr **Causes an increase in S-Phe**, and deficinecy in S-Tyr This causes neurological defects such as smaller brains and mental retardation (in children)

Question 29

What is the normal **metabolic pathway for phenylalanine**? And where does it occur?

Answer 29

Occurs in the **liver**

Question 30

What are the **consequences of Phenylketonuria**?

Answer 30

**Mental retardation** **Prone to fractures due to poor bone metabolism** --\> due to strict diet that needs to be adhered to **Increases inflammation** --\> Due to ROS stimulation **Less NO levels**

Question 31

How can we **treat Phenylketonuria via dietary means**?

Answer 31

Restrict S-Phe intake, such as meats (high AA content) and aspartate! Must also take S-Tyr and other supplements Very expensive foods!

Question 32

How can **Large Neutral Amino Acids (LNAAs)** and **Sapropterin (BH4)** help treat **Phenylketonuria**?

Answer 32

**LNNAs** --\> Decrease the absorbance of S-Phe and competes for amino acid transporters (increasing AA levels in the brain) Glycomacropeptdies are often a source of LNNAs **Sapropterin** --\> Acts as a co-substrate to PAH, creating more S-Tyr Need some PAH to be avaliable to work, so milder PKU has the better outcomes Often means diet can go back to normal (which is tempting for patients!) Very expensive (over £100k per annum!)

Question 33

How can we treat **PKU with gene, enzyme and probiotic therapy**?

Answer 33

**Gene** --\> Using an adenovirus to replace the genes in the tissue This vector is only effective for a few weeks before the immune response renders it useless Female mice needed 3x more of the vector, due to androgen signalling **Enzyme** --\> Directly replace PAH, or use enzymes (such as Phenylalanine Ammonia Lyase (PAL)) to degrade S-Phe Must be given IV to prevent side effects in the HI **Probiotics** --\> Contain recombinant enzymes that are released in the small intestines (due to the bacteria being lysed). The enzmye breaks down S-Phe Given IV and very expensive

Question 34

Define **Safeguarding**

Answer 34

Protecting peoples health, wellbeing and human rights, and enabling them to live free from harm, abuse and neglect. It's fundemental to high-quality health and social care

Question 35

When does a **child become an adult**, in terms of safeguarding?

Answer 35

18 years old

Question 36

What could cause somebody to be a **vunerable adult**?

Answer 36

Elderly or frail Has learning diabilities Mental illnesses (dementia etc) Physical disability Substance misuser Homeless

Question 37

What are the 1**0 different types of possible abuse**?

Answer 37

Physical Domestic Sexual Psychological Finanical/Material Modern Slavery Discriminatory Organisational Neglect and Acts of Omission Self-Neglect

Question 38

When abouts do the **3 trimesters occur in pregnancy**?

Answer 38

**1st** --\> Up to 13 weeks....the embryo is forming **2nd** --\> 13-28 weeks.....bodily systems are being refined **3rd** --\> After 28 weeks.....The body is growing

Question 39

What are some of the **changes in absorption and distribution that occur in pregnancy**?

Answer 39

**Absorption** --\> Morning sickness can cause tablets not to be absorbed! Progesterone slows gastric empyting, causing slower and less absorption **Distribution** --\> Total body water volume increases to 8L, which means drug concs are reduced due to dilation Serum albumin decreases, so there is more free drug for highly bound drugs

Question 40

What do we **measure in pregnancy to check thyroid function**?

Answer 40

**TSH** due to protein binding changes

Question 41

What are some of the **metabolism and excretion changes that occur during pregnancy**?

Answer 41

**Metabolism** --\> Quicker breakdown of pro-drugs and active drugs due to liver CYP450 changes Eg, lamotrigene needs an increased dose in the 3rd trimester **Excretion** --\> Cardiac output and GFR increases, so renally excreted drugs are removed quicker

Question 42

In reference to **pregnancy**, why do we get **less side effects of B-blockers** and why are **CCBs less effective**?

Answer 42

**B-Blockers** --\> Tachycardia occurs naturally in pregnancy, so the side effect of bradycardia is less likely to occur **CCBs** --\> The total peripheral resistance is already reduced, so CCBs are unlikely to futher decrease this

Question 43

How do most **drugs pass through the placenta**?

Answer 43

**Simple diffusion** So dependent on MW and concentration gradient

Question 44

How is **diabetes dealt with in pregnancy**?

Answer 44

**Glucose levels go all over the place** during pregnancy due to glucose tolerence arising from anti-insulin effects Lots of finger pricking is needed to check glucose levels Insulin often needs to be administered

Question 45

What type of **antihypertensives can be used in pregnancy**?

Answer 45

Alpha-Methyl Dopa Nifedipine Labetalol Hydralazine

Question 46

When is a baby known as a **pre-term new born**?

Answer 46

**\<37 weeks gestation**

Question 47

What is the use of the **IM**, **percutanous** and **rectal routes in neonates**?

Answer 47

**IM** --\> Not often used due to low muscle mass and blood flow, as well as distress to the patient **Percutaneous** --\> High absorption occurs due to the thin SC **Rectal** --\> Useful when other routes are inavaliable. However there is varaible blood supply to the rectum, and so absorption can be slow/incomplete

Question 48

What are the 2 different **metabolic pathways for paracetamol in neonates and children/adults**?

Answer 48

**Neonates** --\> Sulphonation **Children/Adults** --\> Glucuronidation

Question 49

Why does a l**ower dose of Theophylline need to be given to neonates**?

Answer 49

Because it is **broken down to caffiene** (which is active) is neonates, whereas in children/adults it is broken down to inactive metabolites

Question 50

What are the **3 different types of licence of drugs**?

Answer 50

**Licenced** --\> Shown to be safe and effective Has suitable quality control **Unlicenced** --\> Not licenced for any age group or condition (eg, imports, specials or extemp) Expensive but only some quality control **Off-Label** --\> Used outside of the drugs licence Most common in the paediatric community

Question 51

What is a **PUMA**? And what was the first drug to get one?

Answer 51

**Paediatric Use Marketing Authorisation** (PUMA) Buccolam (Buccal Midazolam) --\> 3 months to 18 years

Question 52

What type of **IV formulations are contraindicated in pre-term neonates**?

Answer 52

Benzyl Alcohol Polyoxyl Castor Oil Propylene Glycol (unless properly diluted)

Question 53

What type of antibody is given to babies via colostrum breastmilk?

Answer 53

IgA

Question 54

What **type of drugs will pass into breastmilk**?

Answer 54

Weak Bases Low protein bound drugs Drugs with high lipid solubility MW of less than 300 Those with much longer half lives --\> accumulation more likely

Question 55

How long does **WHO recommend that women should breastfeed for**?

Answer 55

First 6 months of the babies life

Question 56

What **percentage of men and women are predicted to be obese by 2020**?

Answer 56

**80% of men** **70% of women**

Question 57

When can people be allowed to have **bariatric surgery**?

Answer 57

BMI of 40 or over.....or 35-40 and a co-morbitidity like T2DM All non-surgical methods have been tried Generally fit for anasthesia and the surgery Commits to long term follow up

Question 58

Name **2 types of reversible and 2 types of non-reversible baratric surgeries**

Answer 58

**Reversible** --\> Intra-gastric balloon and Gastric band **Irreversible** --\> Gastric sleeve and Gastric bypass

Question 59

What is the **peri-operative diet** that patients must do when having **bariatric surgery**?

Answer 59

**Liquid diet --\> Pureed foods --\> Soft foods --\> Solid foods** Normal foods return after around 4-6 weeks Often needed to reduce the size of the patients liver, which normally is very large...making surgery difficult

Question 60

What are the **main physiological changes that occur after bariatric surgery**?

Answer 60

**Reduction in the surface area of the stomach** --\> Means disintergration takes longer **Reduced gastric volume** --\> Means many liquid preperations cant be taken, and solids may get stuck **Bypass of main areas of absorption** --\> sites of absorption for many drugs (like the duodenum) can be totally bypassed **pH changes** --\> Decreased HCl secretion means different salts for drugs (eg, calcium citrate instead of carbonate) that are not pH effected need to be used **Potentially rapid weight loss** --\> Alters volume of distribution

Question 61

What are the main **post-op considerations that need to be made for bariatric surgery**?

Answer 61

Review drugs with GI side effects (eg, NSAIDs and bisphosphonates) Ensure monthly Vit B12 injections Calcium and iron supplements (due to deficiency in bypass patients)