Pharmacology Flashcards
1
Q
What is the definition of drug absorption?
A
The movement of the drug from its site of administration into the bloodstream
2
Q
When do medicines not need to be absorbed?
A
When they are administered directly to the circulation
3
Q
What do different routes of administration result in?
A
Different bioavailability and onset
4
Q
What makes the choice of delivery route of a drug a compromise?
A
- speed of onset
- convenience: IV vs oral
- bioavailability: proportion of administered drug reaching the systemic circulation - 100% for drugs given via IV
- side effects/specificity of action
5
Q
Where does most drug absorption occur?
A
Most occurs through cells, some occurs between cells.
6
Q
How can absorption occur by?
A
- active transport through cells (very few medicines)
- facilitated diffusion through cells (few medicines)
- passive diffusion ( most medicines)
7
Q
What are most drugs ionisable?
A
Because they are weak acids (proton donor) or bases (proton acceptor)
8
Q
What does the extent of drug ionisation occur on?
A
- pH of the environment
- acid-base dissociation constant of the drug
9
Q
What sort of drugs are absorbed most effectively?
A
To diffuse across cell membranes, medicines must be unchanged. Non-ionisable, lipophilic drugs are absorbed most effectively. Ionised (charged) drugs are absorbed least effectively.
10
Q
What do the Henderson-Haselcalch equations predict?
A
The more unionised the drug will be as the pH becomes work acidic/alkaline
11
Q
What is ion trapping?
A
- acidic drugs are absorbed efficiently from the stomach
- basic drugs are absorbed less efficiently
- note that the same principles apply to the renal excretion of drugs (alkaline urine traps and enhances excretion of acidic drugs)
12
Q
Can basic drugs be given orally?
A
Yes, unless very basic or permanent ionised.
- basic drugs absorbed poorly from the stomach (pH 1-2, 1m^2)
- but are absorbed better from the intestine (pH 6.6-7.5)
- surface area of intestine (200m^2) compensates for low absorption efficiency
- many drugs are absorbed in the intestine
13
Q
What are the lipinski rules?
A
An orally-active drug has no more than one violation of the following:
- molecular weight
14
Q
What is the definition of a drug?
A
a medicine or other substance which has a physiological effect when ingested or otherwise introduced into the body
15
Q
What is the definition of drug abuse?
A
the habitual taking of illegal drugs
16
Q
What is the definition of drug dependency?
A
the body’s physical need, or addiction, to a specific agent
17
Q
What is the definition of drug addiction?
A
compulsive, out of control drug use, despite negative consequences.
18
Q
What is ICD dependence?
A
- a craving or compulsion to use
- impairment of the ability to control use
- withdrawal state
- tolerance
- neglect of pleasures
- persistent use despite harmful consequences
19
Q
What are examples of Class A drugs?
A
ecstacy, LSD, heroin, cocaine, crack, magic mushrooms, amphetamines (if prepared for injection)
20
Q
What are examples of Class B drugs?
A
amphetamines, cannabis, methylphenidate (Ritalin), Pholcodine
21
Q
What are examples of Class C drugs?
A
tranquillisers, some pain killers, gamma hydroxybutyrate (GHB), ketamine
22
Q
What other conditions is drug abuse/dependence often found alongside?
A
- depression
- anxiety
- schizophrenia (smoking might help symptoms of SZ)
- PTSD
23
Q
What are two variations of addiction?
A
Psychological addiction: activate same brain systems as natural rewards - are ‘rewarding’
Physical addictions: to self-medicate withdrawal symptoms (e.g. dysphoria, cramping, agitation)
24
Q
What is self-stimulation?
A
Animals will work (e.g. press a lever) in order to receive electrical stimulation of certain brain areas.
Best areas: median forebrain bundle, ventral segmental area
Less effective: prefrontal cortex, nucleus accumbens
25
How can amphetamines get into the cell?
they can get into the cell via the dopamine transporter and displace dopamine from synaptic vesicles, so called 'reverse transport'. They are also lipophilic and cationic so can get into cells and intracellular organelles quite easily, e.g. mitochondria.
26
What different behavioural effects can addictive drugs have?
- CNS stimulants - amphetamine, cocaine, nicotine, caffeine
- CNS depressants - alcohol, opioids, barbiturates, benzodiazepines, volatile, solvents
- Hallucinogens - LSD, ecstasy, ketamine, cannabis
27
How do amphetamines interact with dopamine?
increases dopamine release, decreases uptake
28
How does cocaine interact with dopamine?
decreases dopamine uptake
29
How does nicotine interact with dopamine?
stimulates dopamine neurones, by activating nicotinic Ach receptors on VTA cell bodies (heteroceptors)
30
How does alcohol interact with dopamine?
has effects on opioid, GABA and glutamate systems. Stimulation of dopamine neurones may be direct or may be through one of these.
31
How do opioids interact with dopamine?
stimulates dopamine neurones, by inhibiting GABAergic neurones in VTA, which inhibit VTA dopamine neurones (disinhibition)
32
How do barbiturates and benzodiazepines interact with dopamine?
stimulates dopamine neurones, by enhancing GABAergic inhibition son inhibitory neurones in VTA (i.e. disinhibition)
33
How does LSD interact with dopamine?
stimulates dopamine neurones, via 5HT receptors, probably in VTD (heteroceptors)
34
How does ecstasy interact with dopamine?
stimulates dopamine neurones, possible by a direct amphetamine-like effect or via 5HT mechanisms
35
How does ketamine interact with dopamine?
stimulates dopamine neurones, by activating glutamatergic input to VTA (heteroceptors)
36
How does cannabis interact with dopamine?
acts through cannabinoid receptors. May interact with opioid systems to increase mesolimbic dopamine release
37
What are possible effects of drugs on the body?
- cardiovascular (eg alcohol, cocaine, solvents, glues, ketamine)
- liver disease (alcohol, ecstasy)
- neurotoxicity (amphetamine, ecstasy?)
- behaviour e.g. depression, dementia (e.g. alcohol), psychosis, anxiety (e.g. opioids, PCP, amphetamines), memory loss (cannabis)
- anorectic effects (cocaine, amphetamines)
Loss of dopamine transporter in human methamphetamine abuser - neurotoxic - can lead to early onset of Parkinson's disease.
Drug effects on the brain take a long time to recover - probably underlies the long-term issues with relapse.
38
What is the 5-HT2A receptor responsible for?
- platelet aggregation
- smooth muscle contraction
- adrenaline release
- tachycardia
39
What is the 5-HT2B receptor responsible for?
- smooth muscle contraction
| - cardiac valve cell proliferation (MDMA can lead to heart valve problems)
40
What are the treatments for abuse of medicines? e.g. methylphenidate
- mainly psychological - CBT/groups
- disulfiram for alcohol, detox
- methadone replacement therapy and opioid antagonists for heroin
41
What are treatments for heroin dependence?
Activity at mu opioid receptor. Agonists treatments can work, but the antagonist would cause terrible withdrawal symptoms - use only for heroin overdose
42
Why would you feel sick if you take alcohol whilst on disulfiram?
Disulfiram (antabuse) blocks the ALDH enzyme, leading to build up of acetaldehyde which is toxic.
43
Why do we have new drugs of dependence?
- decreased purity
- increased cost
- decreased availability
- variety
44
What are examples of other addictive behaviours?
- gambling
- sex
- exercise
- over-eating
all activate dopamine systems, the same as drugs of abuse.
Recent evidence suggests that pathological gambling affects dopamine systems, or rather dopamine systems are abnormal in pathological gamblers.
Exercise stimulated DA release via actions at the hypothalamus/pituitary axis and endogenous opioid systems.
45
What is the definition of drug distribution?
the dispersion of a drug among fluids and tissues of the body
46
What is the aim of good therapeutics in terms of drug distribution?
To deliver medicines to their site of action at effective concentrations. In multiple-dose therapy, the aim is to keep these levels as stable as possible.
47
Where is a drug going in terms of distribution?
A drug diffuses from inside blood vessels to and from outside the blood vessels (extravascular space) e.g. adipose tissue, skeletal muscle. The drug moves fast into well-perfused areas and then moves into poorly perfused areas.
[drug] in blood [drug] at site of action = proportional
The drug concentration in the blood is what we usually measure
48
What is the time course of drug concentration in the circulation?
The increase in concentration is almost instantaneous because it is being injected into the blood stream so absorption doesn't take time.
It will decline partly because of distribution but partly and mainly because of the elimination process
49
What is first order kinetics?
- a constant fraction of drug is removed
- the time to remove the drug is independent of dose (if you have increased [drug], the same fraction is still removed).
Anything that follows first order kinetics means that the rate of elimination will be proportional to the rate of drug concentration. As the concentration of the drug increases, the capacity of the enzymes or transporters to handle the drug in the body increases also. Because of this it means that in a given time period a constant fraction of it will be removed.
The higher the drug concentration, the higher the rate of elimination, resulting in a constant fraction of it being removed.
50
What is zero order kinetics?
- a constant amount of drug is removed
- the bigger the dose, the longer the time to remove it
- as dose decreases - no saturation so processes return to 1st order
This is rate but it doesn't happen particularly when we talk about overdose. There are some drugs that are more likely to do so than others - alcohol, phenytoin.
the transporters/enzymes become completely saturated, so their capacity to work doesn't increase with the concentration of the drug - it will remove it at the same rate no matter what, hence getting negative effects of alcohol etc.
It promotes accumulation of the drug in the body system. The body can't increase its capacity to remove the drug - it gets more unpredictable as more and more drug accumulates over time, and it takes more time to remove it than first order kinetics.
51
What are other pharmacokinetic parameters?
- volume of distribution
- clearance
- biolavailability
52
What are important points about volume of distribution (Vd)?
- indicates the extent of distribution for a drug
- clinically important for adjusting dosage
- influenced by lipid/water solubility, binding to plasma proteins
total amount of drug/[plasma] = apparent volume of distribution (Vd)
Vascular space: 4L + extravascular space: 6L
the greater the volume the more widely dispersed the drug.
53
What is drug elimination?
Describes the activity of metabolising enzymes/excretion mechanisms
54
What is plasma clearance (CL)?
- volume of plasma cleared of drug per time (ml min-1)
- CL = rate of elimination/[drug plasma]
- a constant for first order reactions
```
CL = dose x F / AUC
CL = Vd x Ke
```
55
In reality what affects the kinetics of drugs?
- most medicines are not given IV
- most are given as multiple doses
- kinetics may be altered by age and diseases
56
What is bioavailability of a drug?
F: fraction of drug in circulation compared to dose
measures extent of absorption
calculated by: equal oral/IV dose, measure AUC oral/AUC IV
Unless it is injected directly into the blood some of it isn't going to be absorbed. In IV dose F = 1 because it is 100% in the circulation. At 10% you need to increase the dose x 10
57
What is low bioavailability caused by?
- poor absorption
- chemical reactions at site of delivery
- first-pass metabolism
58
What guides the choice of administration route?
- bioavailability
- chemical properties of drug
- convenience
- need to control specificity of action
- desired onset/duration/offset of action
59
What are dosing regimens?
- multiple dosing leads to a 'steady state'
- additional doses administered before [drug] falls to zero
- [drug] variation depends on half-life and dose interval
- multiple dose therapy compromises: minimisation of drug level variability, and simplicity
Dosing rate x F = CL x target concentration
Css = steady state concentration
Equilibrium: drugs going in drugs going out
60
What are the general rules of achieving steady state?
- repeated doses of drug eventually produce a steady state (plateau) concentration
- time to plateau is 4-5 x drug half lives
- when does is changed a new plateau is reached in 4-5 half lives
- steady state levels are not actually flat
- fluctuation size is inversely proportional to the number of daily doses
- fluctuations create the potential for sub-therapeutic treatment or toxicity
- for drugs with long half-lives, achievement of steady state can be accelerated by a loading dose
61
About drug in the circulation...
- determined by supply rate, distribution and removal from the body
- for drug at site(s) of action
- for metabolism and excretion from the body
62
About drug metabolism...
- removal of lipid-soluble drug molecules to prevent reabsorption by kidneys
- achieved by converting drugs into water-soluble molecules
- mostly in the liver, but also in plasma, lung and intestinal epithelium
Drug metabolism begins immediately, must undergo metabolism prior to removal to increase excretion. There is a loss of (or reduced) biological activity and an increase in polarity/less receptor binding. Some drugs are 'activated' by metabolism (prodrug), and some are eliminated unchanged - toxic metabolites.
63
About drug excretion...
- removal of drug/metabolites from the body
| - mostly in urine, but also via bile/faeces, sweat, tears, saliva, exhaled air and milk
64
What needs to be taken into consideration regarding dosing issues?
- metabolism/clearance determines the amount of drug available at the site of action
- time taken for a drug to reach steady state levels
65
What needs to be taken into consideration regarding drug safety issues?
- metabolism produces new chemical entities that may have their own effects
- components of racemic molecules (D/L) handled differently
- knowledge can aid design of future drugs
- drug metabolites measured in substance abuse tests
66
What are the two phases of drug metabolism?
PHASE 1: introduces chemically reactive groups
PHASE 2: increases water solubility of drug for excretion
IMPORTANT!: in paracetamol metabolism, phase 2 occurs before phase 1
67
What happens in phase 1 of drug metabolism?
Introduces chemically reactive groups...
- main process is oxidation within the liver
- addition of oxygen molecules to carbon, nitrogen, sulphur molecules in drug structure
- carried out by cytochrome P450 enzymes (huge superfamily of enzymes in liver): bind drug and molecules oxygen, oxidation of drug occurs through one oxygen atom, the other oxygen atom is reduced to water
- other reactions: hydrolysis, hydration, etc
68
What happens in phase 2 of drug metabolism?
Increases water solubility of drug for excretion...
- conjugates the phase 1 product with an endogenous substance through production of stable covalent bonds
- eg glucuronidation (reaction with glucose)
69
What happens in excretion via the kidney?
- glomerulus filtration
- reabsorption
- tubular secretion
70
What is reabsorption in the kidney?
- as molecules pass through tubules they are concentrated, creating large concentration gradient for reabsorption - hence need to make drugs water-soluble
71
What is tubular secretion?
- acid/base molecule carriers transporting molecules into tubular fluid
- lower levels of unbound drug in plasma, pushing reaction for plasma proteins to release more free drug for secretion by carriers
72
What is renal clearance?
- the volume of plasma cleared of rug per unit time in one pass through the kidney
- the drug is cleared from blood and appears in urine
- e.g. the plasma [drug] is 10 micrograms/ml; drug is appearing in urine at 500 micrograms/min, then its renal clearance is 50ml of plasma per min
- decreased renal elimination --> increased plasma half life
73
What factors affect drug metabolism and excretion?
AGE
- cyto P450 activity reduced in neonates/elderly
- GFR reduced greatly in neonates/elderly
- increased % fat content in elderly
GENETICS
- 45% in europe and USA; 80-90% asians fast acetylators
- 1/3000 slow metabolism by pseudocholinesterase
DRUG METABOLISING ENZYMES
- can be induced by other drugs or lifestyle factors
- can be inhibited by some drugs
DISEASE
- liver disease impairs drug metabolism - drug toxicity
- renal disease may alter pharmacokinetics
74
Why do we monitor drug concentration?
- for drugs that have a narrow therapeutic index
- for drug concentrations that relate well to either therapeutic effect or toxic effect, or both
- to individualise therapy
- to confirm adherence of therapy
- to diagnose toxicity
- to determine the presence of other drugs before starting therapy
- as part of post-marketing surveillance to detect drug-drug interactions
75
What is an adverse drug reaction and what is the importance of this?
- all drugs are poisons - correct dose determines a remedy or toxicity
- ADR - undesirable effect of drug beyond its anticipated therapeutic effects
- WHO - noxious and unintentional drug effect
ADRs are either type A or type B
76
What is a type A ADR?
- consequence of drug action - predictable form knowledge of drug pharmacodynamics and pharmacokinetics
- most common type of ADR
- often dose dependent
- not usually life-threatening
- can be resolved by lowering dose or withdrawing treatment
- generally picked up - understood during drug testing
77
What is a type B ADR?
- unrelated to known pharmacology of drug - difficult to predict
- not dose related
- often involves immune system and/or genetic abnormality
- can be fatal
- need to withdraw drug - do not use again
- need longer term and widespread use in the population to identify - hence importance of pharmacovigilance
78
what are examples of Type A ADRs?
NSAIDS: GI bleeds, peptic ulcer, renal impairment, bronchospasm
- due to COX inhibition, reduction of PGs
Diuretics: hypotension, dehydration, electrolyte changes
- due to vasodilation effects, fluid excretion
Opioids: vomiting, confusion, constipation, urinary retention, respiratory depression (overdose)
- due to stimulation of opiate receptors
Insulin/oral hypoglycaemic drugs: hypoglycaemia
- due to poor control of blood glucose, excess glucose uptake, storage
All these ADRs are predictable consequences of drug action
79
What are examples of Type B ADRs?
- hypersensitivity reactions
- can lead to anaphylaxis shock - life threatening
- amoxicillin (broad-spectrum penicillin), anti-convulsants
80
What is Steven Johnson Syndrome?
- very severe, very rare, very difficult to predict
- linked to genetics, infections poor liver metabolism or drug metabolites
- flu like symptoms/high fever
- blistering of skin, mucous membranes
- skin falls off
-
81
What are options for reducing and avoiding ADRs?
- minor type A retcons may be tolerable
- continue to treat, and then treat the ADR with another drug
- 'accept' more severe ADRs - risk and reward balance
- be aware of vulnerable groups and drugs likely to cause interactions - know your pharmacology, particularly mechanisms of action of drugs, signalling pathways involved!
- good drug history essential
- keep up to date with drug information (e.g. BNF)
- patients/healthcare professionals should report problems asap
82
What can pharmacovigilance lead to?
- drug withdrawal from market
- contraindication
- warnings given
- dose changes (see BNF)
83
What are the systems in the UK for reporting ADRs?
- yellow card
- black triangle
- green form
84
What are the pros and cons of yellow cards?
PROS
- yellow cards main method of post-marketing surveillance
- any one can make a report
- forms available from BNF, online, MIMS
- serious ADRs reported to Medicines and Healthcare products Regulatory Agency (MHRA)
CONS
- originally relied on reporting by doctors
- gross under-reporting suspected
- numerator data only: nothing to compare it to - how many take the drug? how many similar ADRs per year?
85
What does the black triangle system do?
Highlights possible adverse reactions to new medicines
86
What is the green form system?
- green form reporting is limited to a small number of (usually new) drugs
- involves recording any significant medical event that occurs whilst a patient is taking a drug
- potential to find rare and unusual side effects that may be ignored by individual doctors
- numerator and denominator data are available (good) - all patients taking the drug are monitored
- return of forms can be poor (bad)
87
About pharmacokinetic drug interaction and ADRs...
- Changes in drug absorption, distribution, metabolism and excretion
- profound effects on drug action - onset, duration, magnitude of action
- drugs can be enzyme inducers or inhibitors
