Pharmacodynamics (Agonists: Mechanisms of Drug Actions)
Pharmacodynamics (Agonists: Mechanisms of Drug Actions)
Pharmacodynamics (Agonists: Mechanisms of Drug Actions)
Agonists
Partial Agonist
It is when some drugs combine with receptors and activate
them, but are incapable of elicit a maximal response, no matter
how high their concentration maybe
Buprenorphine (morphine receptors)
Oxprenolol (-adrenoreceptors)
Slow processes
Non-receptor mechanisms
Note: These agents are low potency and specificity and hardly
qualify as '' drugs'' even though some of them are useful as
medicines.
Key points
Most drugs are potent and specific; they combine with receptors
for endogenous mediators or with high affinity sites on enzymes or
other proteins, e.g. ion-transport mechanisms.
PHARMACOKINETICS
it is the study of drug absorption, distribution, metabolism and
excretion (ADME) what the body does to the drug
Basic concepts introducing three clinical dosing situations:
Constant-rate intravenous infusion
Bolus-dose injection
Repeated dosing
Clearance is the best measure of the efficiency with which a drug
is eliminated from the body whether by renal excretion, metabolism
or a combination of both familiar in Physiology
for therapeutic drugs, knowing the clearance in an individual
patient enable physicians to adjust the maintenance dose to
achieve a desired target steady-state concentration. It is useful in
clinical practice when therapy is guided by plasma drug
concentrations though such situation are limited
Key points
Diadvantages
1 pain- distention with large volumes is painful
and injected should be no greater than 5ml
2 Sciatic nerve palsy following injection into the
buttock- this is avoided by the injection into the
upper outer gluteral quadrant;
3 sterile abscesses at the injection site (e.g.
paraldehyde)
4 Elevated serum creatinine phosphokinase due
to enzyme release from muscle can cause
diagnostic confusion
5 severe adverse reactions may be protracted
because there is no way of stopping absorption of
the drug
6 for some drugs, IM is less effective than oral
route
7 haematoma formation
Subcutaneous injection
similar to IM besides that cutaneous blood flow is lower
than in muscle so absorption is slower
IV
This has the following advantages:
1 rapid action (morphine for analgesia and
furosemide in pulmonary oedema)
2 Presystemic metabolism is avoided (Glyceryl
trinitrate infusion in patients with unstable angina)
3 Intravenous injection is used for drugs that are too
painful or toxic to be given intramuscularly.
4 Cytotoxic drugs must not be allowed to leak from the
vein or considerable local damage and pain will
result as many of them are severe vesicants (e.g.
vincristine, doxorubicin);
5 Intravenous infusion is easily controlled,enabling
precise titration for drugs such as sodium
nitroprusside and epoprostenol.
6
The main drawbacks of intravenous administration:
Key Points
Oral generally safe and convenient
Buccal/sublingual circumvents presystemic
metabolism
Rectal useful in patients who are vomiting
Transdermal limited utility, avoids presystemic
metabolism
Lungs volatile anaesthetics
Nasal useful absorption of some peptides (e.g.
DDAVP; see Chapter 42)
Intramuscular useful in some urgent situations (e.g.
behavioural emergencies)
Subcutaneous useful for insulin and heparin in
particular
Intravenous useful in emergencies for most rapid and
predictable action, but too rapid administration is
potentially very dangerous, as a high concentration
reaches the heart as a bolus
Intrathecal specialized use by anaesthetists
DRUGS METABOLISM
Glomerular excretion
Glomerular filtrate contains concentrations of low-molecular-
weight solutes similar to plasma. In contrast, molecules with a
molecular weight of 66 000 (including plasma proteins and
drugprotein complexes) do not pass through the glomerulus.
Accordingly, only free drug passes into the filtrate. Renal
impairment predictably reduces the elimination of drugs that
depend on glomerular filtration for their clearance (e.g. digoxin).
Drugs that are highly bound to albumin or -1 acid glycoprotein
in plasma are not efficiently filtered.
Key points
The kidney cannot excrete non-polar substances efficiently,
since these diffuse back into blood as the urine is concentrated.
Consequently, the kidney excretes polar drugs and/or the polar
metabolites of non-polar compounds.
Renal impairment reduces the elimination of drugs that
depend on glomerular filtration, so the dose of drugs, such as
digoxin, must be reduced, or the dose interval (e.g. between
doses of aminoglycoside) must be increased, to avoid toxicity.
There are specific secretory mechanisms for organic acids
and organic bases in the proximal tubules which lead to the
efficient clearance of weak acids, such as penicillin, and weak
bases, such as cimetidine. Competition for these carriers can
cause drug interactions, although less commonly than induction
or inhibition of cytochrome P450.
Passive reabsorption limits the efficiency with which the
kidney eliminates drugs. Weak acids are best eliminated in an
alkaline urine (which favours the charged form, A), whereas
weak bases are best eliminated in an acid urine (which favours
the charged form, BH).
The urine may be deliberately alkalinized by infusing
sodium bicarbonate intravenously in the management of
overdose with weak acids such as aspirin (see Chapter 54, to
increase tubular elimination of salicylate.
Lithium ions are actively reabsorbed in the proximal tubule
by the same system that normally reabsorbs sodium, so salt
depletion (which causes increased proximal tubular sodium ion
reabsorption) causes lithium toxicity unless the dose of lithium
is reduced.
Liver Disease
Liver remain main site of drug metabolism.
Pharmacokinetic factors affected:
Absorption
portal hypertension, hypoalbuminaemia mucosal oedema.
distribution
Reduced plasma albumin reduces plasma protein binding.
Also influenced by bilirubin and other endogenous
substances that accumulate in liver disease and may
displace drugs from binding sites
metabolism
CYP450-mediated phase I drug metabolism reduced pts w/h
sever liver disease
Chronic liver diease, serum albumin most useful
prothrombin time moderate correlation with drug
clearance by liver
Clearance of indocyanine green, antipyrine and
lidocaine disappointing
prescription: drug eliminated by other routes should be
considered.
Thyroid Disease
Thyroid dysfunction affects drug disposition partly as a
result of effects on drug metabolism and partly via
changes in renal elimination.
Digoxin
Myxoedematous patients are extremely sensitive to
digoxin. On the other hand, unusually high doses are
required in thyrotoxicosis.
Hyperthyroid patients have lower plasma digoxin
concentrations and hypothyroid patients have higher
plasma concentrations than euthyroid patients on the
same dose.
GFR is increased in thyrotoxicosis and decreased in
myxoedema.
These changes in renal function influence
elimination, and the reduced plasma levels of
digoxin correlate closely with the increased
creatinine clearance in thyrotoxicosis.
Other factors including enhanced biliary
clearance, digoxin malabsorption due to intestinal
hurry and increased hepatic metabolism, have all
been postu- lated as factors contributing to the
insensitivity of thyrotoxic patients to cardiac
glycosides.
Anticoagulants
produce an exaggerated prolongation of
prothrombin time in hyperthyroid patients
This is due to increased metabolic beeakdown of
vitamin K-dependent clotting factors
Glucocorticoids
metabolised by hepatic mixed-function oxidases
(CYP3A4) which are influenced by thyroid status
Hyperthyroidism increased in cortisol production
and reduced life. The converse being true in
myxoedema
Thyroxine
normal life is reduced 3-4 days by hypothyroidism
and prolonged to nine to ten days by
hypothyroidism. This is of considerable clinical
importance when deciding on an appropriate
interval at which to increase the dose of thyroxine
in patients treated for myxoedema, especially if they
have coincident ischaemic heart disease which
would be exacerbated if an excessive steady-state
thyroxine level were achieved.
Antithyroid drugs
The life of propylthiouracil and methimazole is
pro- longed in hypothyroidism and shortened in
hyperthyroidism. These values return to normal on
attainment of the euthyroid state, probably because
of altered hepatic metabolism.
Opiates
Patients with hypothyroidism are exceptionally
sensitive to opioid analgesics, which cause
profound respiratory depression in this setting. This
is probably due to reduced metabolism and
increased sensitivity.
Key Points
Disease profoundly influences the response to many drugs by
altering pharmacokinetics and/or pharmacodynamics.
Gastro-intestinal disease:
. (a) diseases that alter gastric emptying influence the
response to oral drugs (e.g. migraine reduces gastric emptying,
limiting the effectiveness of analgesics);
. (b) ileum/pancreas relatively minor effects.
Heart failure:
. (a) absorption of drugs (e.g. furosemide) is reduced
as a result of splanchnic hypoperfusion;
. (b) elimination of drugs that are removed very
efficiently by the liver (e.g. lidocaine) is reduced as a result of
reduced hepatic blood flow, predisposing to toxicity;
. (c) tissue hypoperfusion increases the risk of lactic
acidosis with metformin (cor pulmonale especially predisposes
to this because of hypoxia).
Renal disease:(a) chronic renal failure as well as reduced
excretion,
drug absorption, distribution and metabolism may also be
altered. Estimates of creatinine clearance or GFR based on
serum creatinine concentration/ weight/age/sex/ ethnicity
provide a useful index of the need for maintenance dose
adjustment in chronic renal failure;
(b) nephrotic syndrome leads to altered drug distribution
because of altered binding to albumin and altered therapeutic
range of concentrations for drugs that are extensively bound to
albumin (e.g. some anticonvulsants). Albumin in tubular fluid
binds diuretics and causes diuretic resistance. Glomerular
filtration rate is preserved in nephrotic syndrome by
compensatory increased prostaglandin synthesis, so NSAIDs
(see Chapter 26) can precipitate renal failure.
Liver disease as well as effects on drug metabolism,
absorption and distribution may also be altered because of
portal systemic shunting, hypoalbuminaemia and ascites. There
is no widely measured biochemical marker (analogous to serum
creatinine in chronic renal failure) to guide dose adjustment in
liver disease, and a cautious dose titration approach should be
used.
Thyroid disease:(a) hypothyroidism increases sensitivity to
digoxin and
opioids;(b) hyperthyroidism increases sensitivity to warfarin and
reduces sensitivity to digoxin.
THERAPEUTIC DRUG MONITORING
Role of drug monitoring in therapeutics
Measurements of drug con- centrations in plasma are most
useful when:
1. There is a direct relationship between plasma concentration
and pharmacological or toxic effect, i.e. a therapeutic range has
been established. (Drugs that work via active metabolites, and
drugs with irreversible actions, are unsuited to this approach.
Tolerance also restricts the usefulness of plasma
concentrations.)
2. Effect cannot readily be assessed quantitatively by clinical
observation.
3. Inter-individual variability in plasma drug concentrations from
the same dose is large (e.g. phenytoin).
4. There is a low therapeutic index (e.g. if the ratio of toxic
concentration/effective concentration is <2).
5. Several drugs are being given concurrently and serious
interactions are anticipated.
6. Replacement treatment (for example, of thyroxine) is to be
optimized.
7. Apparent resistance to the action of a drug needs an
explanation, when non-compliance is suspected.
Another indication, distinct from therapeutic drug monitor- ing,
for measuring drug concentrations in plasma is in clinical
toxicology. Such measurements can guide management when
specific intervention is contemplated in treating a poisoned
patient (e.g. with paracetamol or aspirin).
Key points
Determining the plasma concentrations of drugs in order to
adjust therapy is referred to as therapeutic drug monitoring. It has
distinct but limited applications.
Therapeutic drug monitoring permits dose individualization
and is useful when there is a clear relationship between plasma
concentration and pharmacodynamic effects.
The timing of blood samples in relation to dosing is crucial.
For aminoglycosides, samples are obtained for measurement of
peak and trough concentrations. To guide chronic therapy (e.g.
with anticonvulsants), sufficient time must elapse after starting
treatment or changing dose for the steady state to have been
achieved, before sampling.
Drugs which may usefully be monitored in this way include
digoxin, lithium, aminoglycosides, several anticonvulsants,
methotrexate, theophylline, several anti-dysrhythmic drugs
(including amiodarone) and ciclosporin.
Individualization of dosage using therapeutic drug monitoring
permits the effectiveness of these drugs to be maximized, while
minimizing their potential toxicity.
DRUGS IN PREGNANCY
Drugs in Pregnancy.mmap
DRUGS IN INFANTS AND CHILDREN
Drugs in Infants & Children.mmap
DRUGS IN THE ELDERLY
Drugs in the Elderly.mmap
ADVERSE DRUG REACTIONS
Type A
PREDICTABLE
80% of adverse Drug effects
usually consequence of the drugs primary pharmacological
effect (e.g. bleeding from warfarin)
Or low therapeutic therapeutic index (e.g. nausea from digoxin)
CAUSES: inappropriate dosage especially when drug
elimination is impaired.
Term Side-Effects is often apply to minor type A reactions
Type B
IDIOSYNCRATIC UNPREDICTABLE
Not dose-related
Severe with a considerable mortality
Poorely if at all understood
Often has genetic or immunological basis
Occur infrequently (1:10001:10000 treated subjects being
typical).
Other Types
Other types of drug reaction (much rarer):
type C reaction continuous reactions due to long-
term use: analgesic nephropathy;
type D reaction delayed reactions of
carcinogenesis or teratogenesis;
type E reaction drug withdrawal reactions (e.g.
benzodiazepines).
Complex
ideal: identify drug reactions with a high degree of sensitivity +
specificity + rapid response from health-care professional
mandatory continued surveillance for new drugs
Introduction of a variety of early detection systems Adverse
reaction
Phase I/II/III TRIALS
Important tolerability and dose-responsee relationship of new
therapeutic agents
Insensitive at detecting: This is illustrated by the failure to
detect the serious toxicity of several drugs (e.g. benoxaprofen,
cerivastatin, felbamate, dexfenfluramine and fenfluramine,
rofecoxib, temofloxacin, troglitazone) before marketing.
Phase III: valuable in establishing whether common events
such as headache, constipation, lethargy or male sexual
dysfunction are truly drug related
The Medical Research Council Mild Hypertension Study
unexpectedly identified impotence as more commonly associated
with thiazide diuretics than with placebo or -adrenoceptor
antagonist therapy.
Intensive monitoring
Potential to follow-up
Investigate (allows room for lack of clinical important
association)
Only for early common and early reactions to drugs used in
hospitals since patients are not in hospital long enough to be
detected.
Monitoring from national Statistics
Information available:
o death certificates,
o hospital discharge diagnosis and similar records detecting
a change in disease trends and relate this to drug therapy
Methods for hospital discharge = difficult because information is
provisional and incomplete, may be revised during follow up.
Inexpensive
Shortcomings: large # of patients must suffer before change is
detectable