Clinical Pharmacology and Therapeutics Flashcards
(167 cards)
1
Q
how much do prescriptions cost the NHS a year?
A
around 15 billion/year or 10% of all healthcare needs
2
Q
lifestyle drugs
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to feel better- not for treatment
3
Q
Antibiotics for
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infection
4
Q
Analgesics for
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pain
5
Q
Chemotherapy for
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malignancy
6
Q
Statins for
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hypercholesterolaemia
7
Q
ACE inhibitors for
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heart disease
8
Q
Proton pump inhibitors for
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dyspepsia
9
Q
pharmacodynamics
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what a drug does to the body
10
Q
pharmacokinetics
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what the body does to a drug
11
Q
what are receptors made of?
A
glycoproteins
12
Q
channel linked receptors
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ligand binding opens and closes them
13
Q
kinase linked receptors
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Linked directly to an intracellular protein kinase that triggers a cascade of phosphorylation reactions (eg. insulin receptor)
14
Q
DNA linked receptors
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• Binding of a ligand promotes or inhibits synthesis of new proteins which may take time to promote a biological effect (eg. steroid receptors)
15
Q
agonist
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mostly reversible
• ligand that binds to a receptor protein to produce a conformation change which is signals for the initiation of a biological response
16
Q
as free ligand concentration increases,
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so does the proportion of receptors occupied, hence biological effect
17
Q
partial agonist
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• activated signalling pathway to lesser extent than maximum potential of receptors available (less of an effect than a full agonist)
18
Q
inverse agonist
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- ligand that produces the opposite effect to the full agonist when they bind to a receptor
- Useful on receptors that when not acted upon by a drug would be constitutively active
19
Q
competitive antagonist
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occupies a receptor that would otherwise eb occupied by an endogenous molecule and prevents it from binding
20
Q
noncompetitive antagonist
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binds to allosteric site and brings about conformation change that stops receptor from working
21
Q
irreversible antagonist
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- Non-competitive antagonist whose effect persists even after antagonist has been removed
- Antagonism only disappears when new proteins or enzymes are synthesised
- Ex. Aspirin
22
Q
partial antagonist
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able to activate a receptor after it binds to it but is unable to produce a maximal signalling effect even when all receptors are occupied, when mixed with full antagonists, they can reduce biological response
23
Q
receptor affinity
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how strong the attachment between drug and receptor is and how long it will take to dissociate
24
Q
drugs with high affinity
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low concentrations as they bind well and for a long time, produce effects when concentration falls
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what does the log10 dose response curve look like?
sigmoidal dose-response curve (kinda looks like an S)
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Emax
point where S flattens at the top, dose no longer increases effect of drug, receptors are full
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ED50
dose that produces a response that is half of Emax
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ED
effective dose
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efficacy
extent to which a drug can produce a response when all available receptors or binding sites are occupied
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potency
amount of drug required for a given response (combined with efficacy), relates to affinity for receptor
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how can differences in potency be overcome?
giving the less potent drug in high doses
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therapeutic efficacy
compares two drugs that bind to difference receptors and have different mechanisms but provide same therapeutic effect to see which one has the greater effect
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specificity
drug that is specific to one receptor only acts on that receptor, no matter what the dose
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agonist selectivity
If it has a higher ED50 for one receptor we can see it is more selective for it so to have the same effects at other receptors, it would need a higher dose
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antagonist selectivity
competitive antagonist increase the dose required to reach the Emax- moves the curve to the right
if the competitive antagonist pushes the curve right for one receptor move than another, it is more selective for that receptor
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therapeutic index
ratio between the dose of a drug that causes adverse effects and the dose that achieves therapeutic effects
• Drugs with higher therapeutic index are preferred
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factors that affect pharmacokinetics
age (renal function), sex, body weight, impaired organ function, genetic variation, environmental factors, food, drug interactions
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larger body weight effect on drugs
drugs are more diluted in blood stream so drug dose must be scaled depending on patient body weight
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older age effect on drugs
need lower doses of drugs and experience prolonged effects, aging is also associated with changes in drug metabolism and excretion
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impaired liver function leads to
reduced drug metabolism
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impaired renal function leads to
reduced excretion
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example of genetic variation effect on drugs
prolonged paralysis of those with low or atypical plasma cholinesterase following administration of Suxamethonium
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4 stages of pharmacokinetics
* Absorption
* Distribution
* Metabolism
* Excretion
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enteral routes of absorption
oral, buccal, sublingual, rectal
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parenteral routes of absorption
- intramuscular- simple to administer, unpredictable rate of absorption, painful e. vaccinations
- intravenous (IV)
- subcutaneous- drugs need to be absorbed well by fat and repeated injections can hinder absorption, invasive
- inhaled- must be inhaled into the target airways in the lung
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topical application of drug
delivered directly to the place its needed
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oral route of absorption
* convenient + simple
* can be self-administered
* ideal for long term treatments for less acute illnesses
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IV route of absorption
* No concerns about absorption
* Rapidly achieves high drug absorptions
* No ‘first pass’ effect
* Ideal for v ill patients where rapid, certain outcome is critical to outcome
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drug distribution
movement of drug into and out of the blood to other tissues
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Key factors involved in drug distribution:
protein binding, water/lipid solubility (ionisation)
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where are hydrophilic water-soluble drugs more likely to be?
plasma as blood is highly hydrophilic
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where are hydrophobic fatty drugs likely to be?
fatty compartment
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why dose a drug need to have a degree of lipid solubility?
to diffuse across cell membrane
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drug distribution passive or active?
Majority of drug distribution is passive, some may be active
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volume of distribution
apparent volume of that dose appears to have distributed into shortly after intravenous injection based on plasma drug concentration
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what can increase volume of distribution
Renal failure and liver failure
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what can decrease volume of distribution
dehydration
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site of drug metabolism
liver
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importance of water solubility
excretion
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drug interactions- inducing metabolism enzymes in liver, effect of this and what drugs can do this?
results in faster elimination of a dug, shorter half-life, reduced activity, increase patient’s exposure to toxic metabolites
- Drugs that can do this= phenytoin (anti-seizure), rifampicin (antibiotic) and chronic alcohol
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drug interactions-inhibiting metabolism enzymes in liver, effect of this and what drugs can do this?
result in slower elimination, longer half-life, increased activity, potential drug accumulation and toxic effects so standard dose of second drug will give higher plasma concentration
- Drugs that can do this: ciprofloxacin, erythromycin, cimetidine
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what drugs should drug interactions be considered for?
warfarin, oral contraceptives and morphine which require a stable plasma concentration
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Phase 1 metabolism: oxidation
* Oxidation in microsomal mixed function oxidase system
* Once a drug goes through this, it is usually pharmacologically inactive
* Some drugs can be excreted after this but most require phase II
* Site of drug interactions
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phase 2 metabolism: conjugation
* Conjugation of phase I metabolite with another molecule to increase water solubility
* Examples: acetylation or glucuronidation
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first pass metabolism
- Major determinant of peak plasma drug concentration for oral drugs
Drug molecules absorbed from the stomach or any part of the small intestine must pass through the portal venous system and the liver sinusoids
- Can be metabolised by enzymes in intestinal wall and liver before entering system circulation.
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3 effects of first pass metabolism
- Biotransformation of active drug to inactive metabolite reduce drug response
- Active drug can be changed into an active metabolite no effect on drug response
- Inactive drug (pro-drug) changed into active metabolite increasing drug response
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Drugs that are known to be affected by first pass metabolism:
aspirin, oestrogen, amitriptyline, glyceryl trinitrate
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routes of drug excretion
* Renal excretion
* Biliary excretion
* Faeces
* Breast milk
* sweat
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for what drugs is urinary excretion the usual route?
low molecular weight drugs that are sufficiently water soluble to avoid reabsorption from the tubule
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what happens to lipid soluble drugs that have been filtered in?
diffuse back into body down a concentration gradient as urine becomes more concentrated during passage through renal tubule
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what can urine pH affect?
pH partitioning of drugs between plasma and urine- acids have tendency to accumulate in basic compartments (& vice versa) so urine’s low pH may affect where drugs accumulate
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for what drugs is fecal excretion the usual route?
large molecular weight drugs and ones that undergo conjugation with glucuronide
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where do molecules of drugs that enter bile after liver metabolism go?
carried into the intestinal lumen and are excreted in the faeces
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entero-hepatic circulation
recycling between the liver, bile, gut and portal vein
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effect of entero-hepatic circulation on active drugs
prolongs residence time of drugs in body and effect
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effect of broad spectrum antibiotics and other drugs killing bacterial flora
allows recycling of glucuronide conjugates reduce reabsorption and drug availability
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drug clearance
* volume of plasma which is completely cleared of drug per unit time
* cause by either liver metabolism or renal excretion
* drugs with high rate of clearance= short half life
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bioavailability
* fraction of administered dose of unchanged drug that reaches system circulation
* all of an intravenous dose enters systemic circulation but not true for other routes
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what does oral bioavailability depend on?
* Gastric acid destruction (insulin can’t be given orally)
* Formulation of drug (slow release or enteric coated)
* First pass of metabolism (morphine, glyceryl trinate)
* Solubility, ionisation, food, diarrhoea etc
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first order kinetics
constant fraction of drug is clear in unit time, exponential decrease in drug, most drugs clear like this
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zero order kinetics
constant amount of drug is cleared in unit time, metabolism has limited capacity- becomes saturated, elimination rate has reached a maximum, if drug is administered at a rate faster than its clearance then it will progressively accumulate eg. ethanol, phenytoin
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half life
* Time taken for plasma concentration of drug to halve
* Concept that only related to first order metabolism
* Half-life remains constant throughout period of drug elimination
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steady state
point where elimination rate and absorption rate are equal
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what happens if repeated doses aren't given when previous doses haven't been eliminated?
drug will progressively accumulate
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long half life
```
• Slow to reach steady state
• Loading dose may be needed
• Slow to be eliminated
• Less regular dosing
Eg. atenolol 8h
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short half life
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• Rapid steady state
• Fine control
• Not suitable orally
• More regular dosing required
Eg. dobutamine 2mins
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loading dose
* In order to reach a target steady state plasma concentration with long half life drugs before 5 half lives, you can give an initial dose (loading dose) that is much larger than maintenance dose and equivalent to amount of drug required in body at steady state
* Peak plasma concentration that is close to steady state concentration can be maintained by maintenance doses
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optimal dose interval
trade-off between convenience and constant level of drug exposure
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modified release formulations
tablets that break up slowly so is released progressively over several hours, allow drugs with short half lives to be given less often while having a smooth onset and decline in effect
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drug toxicity
adverse effect that occurs because dose or plasma concentration has risen above therapeutic range, can be unintentional or intentional drug overdose
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type A (augmented) ADR
```
• dose related
• common
• usually detected in drug development
• usually mild
eg. Warfarin can cause subcutaneous haemorrhage
```
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type B ADR
• non predictable
• rare and severe
• usually remain undiscovered until post licensing
eg. Practlol (beta blocker) causes sclerosing peritonitis (fibrous thickening of the peritoneum in the abdomen)
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2 genetic factors that commonly have an effect on ADRs?
* cytochrome P450 enzyme- vital for drug metabolism so polymorphisms are associated with different ADRs
* HLA (human leukocyte antigen)- important for immunity
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drugs that may affect cell division or protein/DNA synthesis- teratogenesis
Thalidomide, warfarin, phenytoin, steroids, alcohol
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drugs that cause altered growth
Smoking, tetracycline
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drugs that interfere with labour
Beta blockers affect uterine muscles
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Respiratory or cardiovascular depressant that can cross the placenta
Opioids
98
drugs that often cause ADRs
aspirin, diuretics, warfarin, NSAIDs and opioid analgesics
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common ADR
GI bleeding
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what do ADR cost the NHS and it's prevalence?
£466 million and prevalence is 6.5% of admissions
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hypersensitivity drug reactions (allergic)
* Type B reactions: not dose related, potentially v serious
* Common targets of allergic drug reactions: skin (rashes), lungs (airway constriction), haematopoiesis
* Penicillin is an example of a Type I reaction (anaphylaxis)
102
what is the autonomic nervous system divided into?
sympathetic and parasympathetic system
103
sympathetic system effect on heart
• Increases heart rate, conduction rate, contractility (force of contraction), stroke volume and cardiac output allows more blood to be pumped
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sympathetic system effect on lungs
bronchodilation by relaxing smooth muscle surrounding bronchi and bronchioles less resistance to airflow and improved transfer of oxygen and carbon dioxide (adequate oxygen supply to muscles that need it)
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sympathetic system effect on kidney
constriction of renal arterioles (reduction of blood flow into kidney and urine production), releases renin from juxtaglomerular apparatus to cause vasoconstriction main target is to increase blood pressure
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sympathetic system effect on GI tract
reduction of digestion so there is more blood available for muscles by decreasing peristalsis, constriction of smooth muscles in sphincters ot reduce movement of food
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sympathetic system effect on liver
breaks down adipose tissue to release free fatty acids that act as energy stores, promotes glycogenolysis and gluconeogenesis (both produce glucose
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sympathetic system effect on bladder
relaxes smooth muscle of the bladder wall reduced possibility of voiding
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sympathetic system effect on men's genitals
constricts prostate smooth muscle making it more difficult to urinate
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sympathetic system effect on muscles and eyes
* Increases circulation to muscles
* Releases energy stores
* Dilates pupils
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what are catchecholamines synthesised from?
the amino acid phenylalanine
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site of synthesis and storage of noradrenaline
Terminal branches of the sympathetic postganglionic fibres have swellings that form synaptic contact with the effector organ
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release of noradrenaline stimulated by
Arrival of nerve impulses cause noradrenaline to be released from granules in the presynaptic terminal into the synaptic cleft
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action of noradrenaline is terminated by
- Diffusion from the site of action
- Reuptake back into the presynaptic nerve ending where it is inactivated by the enzyme monoamine oxidase (MAO) in mitochondria
- Metabolism locally by the enzyme catechol-O-methyl-transferase (COMT)
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4 types of adrenoreceptors (postsynaptic cell surface receptors for catecholamines )
* alpha1-adrenoreceptor causing vasoconstriction of blood vessels
* alpha2-adrenoreceptor (in presynaptic membranes where noradrenaline release form presynaptic terminals inhibits it’s own release by feedback inhibition
* beta1-adrenoreceptors (mainly in heart) increases force and rate of contraction
* beta2-adrenoreceptors (lung) bronchial smooth muscle relaxation in bronchi and (blood vessels) vasodilation
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alpha 1 agonists
noradrenaline, adrenaline, phenylephrine, ephedrine
| for treatment of: Cardiovascular collapse & Nasal congestion
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alpha 2 agonist
clonidine
| for the treatment of: hypertension
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adverse effects of alpha 1 agonists
hypertension, tachycardia, angina
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alpha 1 antagonist
prazosin, doxazosin, tamsulosin
Indicated for the treatment of:
- Hypertension, benign prostatic hypertrophy
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adverse effects of alpha 1 antagonists
Adverse effects: hypertension, dizziness, nasal congestion
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nonselective beta 1 and beta 2 agonist
adrenaline (emergency situations), isoprenaline
| treatment of: anaphylaxis, cardiac arrest
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heart beta 1 receptors
dobutamine
| treatment of: severe heart failure
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non selective beta 1 and beta 2 antagonists
propanolol
| treatment of: tremor
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cardoselctive beta 1 antagonist
atenolol
| treatment of: hypertension, angina pectoris, heart failure
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adverse effects of beta 1 and 2 antagonists
- B1: brachycardia, heart failure
| - B2: bronchospasm, cold peripheries, lethargy
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why can adrenoreceptor drugs have effects at other receptor subtypes at high enough concentration?
not totally selective
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alpha1 receptor stimulated
phospholipase C is activated and there is an increase in IP3 and DAG
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alpha2 receptor stimulated
decreased activity of adenyl cyclase + lower concentrations of cAMP and Ca2+
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beta1 receptor stimulated
increased activity of adenyl cyclase + higher concentrations of cAMP and Ca2+
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beta2 receptor stimulated
increased activity of adenyl cyclase + lower concentrations of cAMP and K+
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effect of parasympathetic system on heart
decreased rate + force of contraction + conduction velocity
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effect of parasympathetic system on lungs
bronchial muscle contraction, increased gland secretions (mucus)
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effect of parasympathetic system on GI tract
increased motility, relaxation of sphincters, glycogen synthesis is stimulated
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effect of parasympathetic system on pupil and arteries
- Constricts pupil
- Increasing lacrimal gland secretions (production of tears)
- Dilation of arteries
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effect of parasympathetic system on bladder
- Relaxation of bladder sphincter
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why are quaternary ammonium compounds less likely to cross lipid barriers
more soluble in water
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why can small tertiary amines cross lipid barriers?
low molecular weight
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why can large tertiary amines cross lipid barriers?
lipophilicity
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muscarine
direct acting acetylcholine receptor agonist, binds to the same protein receptors and activates them in the same way that acetylcholine does.
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where are muscarinic Ach receptors located?
parasympathetic nervous system and the CNS
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5 subtypes of muscarinic receptors
* M1 receptors- neural (slow EPSP- excitatory postsynaptic potentials- in ganglia)
* M2 receptors- cardiac, decrease in heart rate and force of contraction
* M3 receptors- glandular secretion, contraction of visceral smooth muscle, vascular relaxation
* M4- CNS
* M5
142
how are muscarinic acetylcholine receptors activated?
acetylcholine is released from postganglionic nerve endings where it activates muscarinic acetylcholine receptors on effect tissues
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functions of muscarinic receptors
* Activate phospholipase C leading to production of IP3 (releasing Ca2+) and diacyl glycerol (DAG)- M1, M2, M3
* Inhibit adenylate cyclase causing a decrease in the levels of cAMP- M2, M4
* Open (activate) K+ channels, important for parasympathetic effect on heart- M2
* Inhibit Ca2+ channels- M2
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Parasympathomimetic/ Cholinomimetic
drugs that mimic effects of parasympathetic nerve simulation, particularly by activation of responses mediated by muscarinic cholinergic receptors
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direct acting agonists on muscarinic receptors
* Have mainly muscarine effects at end effectors
* Similar structure to acetylcholine
* Most synthetic direct acting compounds do not have CNS effects but plant alkaloids muscarine and pilocarpine can enter CNS
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choline esters- direct acting muscarinic agonists
* Acetylcholine- too unstable in plasma to be an effective drug, has both muscarinic and nicotinic effects
* Bethanechol- not hydrolysed by cholinesterase, very weak as nicotinic agonist, primarily a muscarinic agonist
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natural plant compounds- direct acting muscarinic agonists
neither are selective for types of muscarinic receptors, muscarine, pilocarpine
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indirect acting agonists on muscarinic receptors
* Potentiate transmission at all cholinergic junctions therefore have muscarinic, ganglionic and skeletal muscle effects
* Have CNS effects if permeable to blood-brain barrier
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reversible inhibitors of Ach-esterase that increase concentration of Ach that prolongs lifetime in the synapse
- Physostigmine- tertiary plant alkoid
| - Neostigmine- synthetic quaternary compound
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irreversible inhibitors of Ach-esterase that increase concentration of Ach that prolongs lifetime in the synapse
Organophosphates
a. Insecticide
b. Ecothiopate
c. Military nerve gases
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organophosphates
extremely lipophilic so they can cross are barriers including blood-brain
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main uses of muscarinic receptor agonists
glaucoma, intestinal & urinary atony and Alzheimer’s disease
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drugs used for treatment of Alzheimers
donepezil (mild cholinesterase), rivastigmine (delay in decline of cognitive functions due to AD)
154
drugs used for treatment of atony
bethanechol (direct acting), neostigmine (indirect acting)
Act by increasing peristalsis in intestines and micturition in bladder (contraction of muscles) by acting on muscarinic receptors there
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drugs used for treatment of glaucoma
pilocarpine (direct acting) administered as eye drops, physostigmine, ecothiopate (indirect acting so both longer lasting)
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muscarinic antagonists
- Usually competitive antagonists of muscarinic receptors
| - Have little effect on ganglion and skeletal muscle nicotinic receptors
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examples of muscarinic antagonists
Atropine and hyoscine (tertiary amines)- atropine is the prototypical muscarinic antagonist and hyoscine is more lipophilic absorbed through gut and can cross through CNS
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antimuscarinic for asthma
ipratropium
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therapeutic uses of atropine
asthma
preanesthetic medication
opthamological uses
poisoning by muscarinic agonists
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therapeutic use for benztropine
(atropine derivative)
| Parkinson's disease
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Ach release blockers
eg. botulinium toxin, acts as protease enzyme on proteins that assist the docking of vesicles containing the neurotransmitter to the pre-synaptic membrane (stops contraction), prevention of Ach release can cause muscle paralysis and death or used to relax muscle spasm
162
nicotinic Ach blockers
non depolarising blockers competitively antagonise Ach receptors to prevent depolarisation in post synaptic membrane (sarcolemma), based on curare (natural compound) and are reversed by anticholinesterases, can be used as anaesthetic, depolarising blockers agonise the receptor and continue to bind to keep ion channel shut
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anticholinesterases
prevent enzymatic breakdown of Ach so prolong presence and effects in NMJ, used to diagnose myasthenia gravis, reverse anaesthesia and increase cholinergic activity, irreversible anticholinesterases are dangerous paralysis & cholinergic crisis
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muscle relaxants
relieve spasticity by acting in CNS, PNS or both to clock signal for contraction (multiple sclerosis, cerebral palsy), dantrolene orevents calcium release from the SR to block contraction but lack of muscle use can worsen disability
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suxamethonium
hydrolysed by acetylcholinesterase slowly, actions can’t be reversed
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dantrolene
peripherally acting muscle relaxant, prevents muscle contraction, used for severe spasticity of voluntary muscle and malignant hyperthemia
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St John's Wort
herbal remedy for depression, may cause serotonin syndrome when taken with other depression medication overexcitability, reduces effects of warfarin and other drugs by inducing their metabolism
