Guide to Clinical Pharmacology



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The Hitchhiker’s Guide to Clinical Pharmacology


Pharmacodynamics: How Drugs Work



Jeffrey K Aronson



Contents

1. The types of pharmacological actions of drugs

1.1. Drug action via a direct effect on a receptor

1.2. Short-term and long-term effects of drugs at receptors

1.3. Soluble receptors

1.4. Drug action via indirect alteration of the effect of an endogenous agonist

1.5. Drug action via inhibition of transport processes

1.6. Drug action via enzyme inhibition

1.7. Drug action via direct enzymatic activity or activation of enzymes

1.8. Drug action via other miscellaneous effects

1.9. Multiplicity of pharmacological effects

2. Stereoisomerism and drug action

2.1. Pharmacokinetic differences between stereoisomers

2.2. Pharmacodynamic differences between stereoisomers

2.3. Interactions between stereoisomers

2.4. Drug interactions and stereoisomers

2.5. The clinical relevance of stereoisomerism

3. Graded responses to drugs: the dose-response curve in drug therapy


Pharmacokinetics is about how drugs move around the body, being absorbed, distributed to their sites of action, and being eliminated. Pharmacodynamics is about all those matters that are concerned with the pharmacological actions of drugs when they get to their sites of action, whether they be determinants of beneficial or adverse effects.
1. The types of pharmacological actions of drugs

The different ways in which drugs produce their pharmacological effects are classified in Table 1. Several of the examples I shall illustrate cross the boundaries of this classification. For example, cardiac glycosides can be considered as ligands that act by binding to their receptor (the Na/K-ATPase), as inhibitors of an enzyme (the Na/K-ATPase), or as inhibitors of a transport process (the Na/K pump). This reflects the complexities of pharmacology.


Table 1. The types of pharmacological actions of drugs

1. Drug action via a receptor

(a) Agonists

(b) Antagonists

(c) Partial agonists

(d) Inverse agonists

2. Drug action via indirect alteration of the effect of an endogenous agonist

(a) Physiological antagonism

(b) Increase in endogenous release

(c) Inhibition of endogenous re-uptake

(d) Inhibition of endogenous metabolism

(e) Prevention of endogenous release

3. Drug action via the inhibition of transport processes

4. Drug action via enzyme inhibition

5. Drug action via enzymatic action or activation of enzyme activity

6. Drug action via other miscellaneous effects

(a) Chelating agents

(b) Osmotic diuretics

(c) Volatile general anaesthetics

(d) Replacement drugs




1.1. Drug action via a direct effect on a receptor

Receptors are specific proteins, situated either in cell membranes or, in some cases, in the cellular cytoplasm. For each type of receptor, there is a specific group of drugs or endogenous substances (known as ligands) that are capable of binding to the receptor, producing a pharmacological effect. Most receptors are located on the cell surface. However, some drugs act on intracellular receptors; these include corticosteroids, which act on cytoplasmic steroid receptors, and the thiazolidinediones (such as pioglitazone), which activate peroxisome proliferator-activated receptor gamma (PPARy ), a nuclear receptor involved in the expression of genes involved in lipid metabolism and insulin sensitivity. The important receptor systems and their ligands are listed in Table 2.

There are four types of ligand that act by binding to a cell surface receptor, agonists, antagonists, partial agonists, and inverse agonists (Figure 1).
(a) Agonists

Ligand s that bind to a receptor and produce an appropriate response are called agonists. For example, the catecholamine adrenaline is an agonist at β-adrenoceptors. When it binds to β-adrenoceptors in the heart, it increases the heart rate.



Table 2. Examples of important receptors, their agonists and antagonists

Receptor type

Subtype

Site(s) in the body

Agonists

Antagonists

Adrenoceptors

α/β




Adrenaline

Noradrenaline



Labetalol

α12







Phentolamine

Phenoxybenzamine



α1

Pupillary dilator muscle

Vascular smooth muscle



Dopamine (high doses) Phenylephrine

Doxazosin

Indoramin

Prazosin


α2

CNS

Presynaptic nerve terminals



Clonidine


Yohimbine

β12




Dopamine

Isoprenaline



Propranolol

Oxprenolol



β1

CNS

Heart



Dobutamine

Dopamine (moderate doses)



Atenolol

Metoprolol

Propranolol


β2

Pancreatic islets

Smooth muscle

(bronchiolar, vascular, uterine)


Fenoterol

Rimiterol

Salbutamol

Terbutaline






Angiotensin

AT1

Cardiovascular

Angiotensin

Eprosartan

Irbesartan

Losartan

Valsartan



Cholinoceptors

Muscarinic

Tissues innervated by parasympathetic nerves

Acetylcholine and analogues (e.g. carbachol, bethanecol)

Atropine and analogues

Disopyramide

Orphenadrine

Pirenzepine (M1 selective)

Quinidine

Tricyclic antidepressants

Trihexyphenidyl





Nicotinic

Neuromuscular junction

Postganglionic cells in ganglia



Acetylcholine and some analogues (e.g. carbachol)

Aminoglycoside antibiotics

Ganglion-blocking drugs

Neuromuscular-blocking drugs

Quinidine



Dopamine

receptors



Various

CNS

Renal vasculature




Apomorphine

Bromocriptine

Dopamine (low doses


Butyrophenones (e.g. haloperidol)

Domperidone (D2)

Metoclopramide

Phenothiazines (e.g. chlorpromazine)

Thioxanthenes (e.g. flupentixol)


GABA

receptors



GABAA-

BDZ complex



CNS

GABA

Benzodiazepines



Bicuculine

GABAB

CNS (presynaptic)

GABA

Baclofen

Histamine

receptors



H1

Smooth muscle (bronchiolar, vascular, gastrointestinal)

Histamine

Antihistamines

(e.g. promethazine, cetirizine)



H2

Stomach

Histamine

Cimetidine

Ranitidine

Famotidine

Nizatidine



5-Hydroxy-tryptamine receptors

Various

CNS

Vascular smooth muscle

Gastrointestinal tract


5HT

Methysergide (5HT)

Sumatriptan (5HT1D)

Ketanserin (5HT2)

Ondansetron (5HT3)



Leukotriene receptors

CysLT1

Bronchial and vascular smooth muscle

Leukotrienes

Montelukast

Zafirlukast



Opioid

receptors



μ, δ, and κ

Biliary tract

CNS


Gastrointestinal tract

Genitourinary tract

Pupillary muscle

Vascular smooth muscle



Endorphins and enkephalins

Morphine and analogues (μ agonists)

Non-opioid narcotics (μ agonists, e.g. pentazocine)


Buprenorphine (κ) (partial agonist)

Methylnaltrexone (δ)

Nalbuphine (μ, δ, and κ)

Nalmefene (μ and κ)

Nalorphine (μ)

Naloxone (δ and κ)

Naltrexone (μ, δ, and κ)


Vasopressin receptors

V1A, V1b , and V2




Vasopressin (ADH)

Conivaptan (V1A and V2)

Nelivaptan (V1b)



Tolvaptan (V2)




Figure 1. Theoretical dose-response curves for different types of actions of drugs at receptors
(b) Antagonists

Ligands that prevent an agonist from binding to a receptor and thus prevent its effects are called antagonists. Antagonists do not themselves have any pharmacological actions mediated by receptors. For example, propranolol, a β-adrenoceptor antagonist, binds to β-adrenoceptors in the heart and prevents catecholamine-induced tachycardia (for example in response to exercise). However, in the absence of an agonist propranolol has no effect via adrenoceptors.


The complexity of some drugs is illustrated by the several actions of beta-adrenoceptor antagonists (beta-blockers), as shown in Table 3.
Table 3. Differences in the actions of some beta-adrenoceptor antagonists



Drug

Cardio-selectivity (i.e. β1 > β2)

Partial agonist activity

Membrane-stabilizing activity


Peripheral vasodilatation

Atenolol

+







Bisoprolol

+++





+

Carvedilol





++

++

Labetalol





±

++

Metoprolol

+



±

+

Oxprenolol



+

+



Practolol

++

+





Propranolol





++

±

Sotalol









Timolol



±

±

+

+ the drug has the indicated property

– the drug does not have the indicated property

± it is not clear whether the drug does or does not have the indicated property
(c) Partial agonists

A full agonist is one that is capable of producing a maximal response, when it binds to a sufficient number of receptors. In contrast, a partial agonist cannot produce the maximal response of which the tissue is capable, even when it binds to the same number of receptors as a full agonist binds to when it produces a complete response. Since the effects of a ligand are generally produced by concentrations of the ligand that are well below those that would bind to all the receptors necessary to produce a complete response, this means that above a certain level of binding, a partial agonist may bind to receptors without producing any further increase in effect. However, in so doing, it may prevent the action of other agonists, and may thus appear to be acting as an antagonist. It is this mixture of actions that is called partial agonism. For example, oxprenolol, which is a β-adrenoceptor antagonist, is also a partial agonist. Thus, it may have less of an effect in slowing the heart rate than adrenoceptor antagonists that do not have partial agonist action (i.e. full antagonists); this partial agonism of β-blockers is sometimes called “intrinsic sympathomimetic activity” (ISA).

In the case of β-adrenoceptor antagonists, the amount of β-blockade produced by a given dose of the β-blocker will vary according to how much endogenous sympathetic nervous system activity there is: the more activity, the more β-blockade will result from the action of a partial agonist. This is clearly seen in the actions of the β-adrenoceptor agonist/antagonist xamoterol. Xamoterol acts as a β-adrenoceptor agonist in patients with mild heart failure, improving cardiac contraction. However, it acts as a β-blocker in patients with even moderate heart failure, worsening it. For this reason it has not proved useful in clinical practice.

Most receptors have subtypes, for which certain ligands have some degree of selectivity. For example, there are two main sub­types of β-adrenoceptors, called β1 and β2, both of which can respond to adrenaline. Some β-adrenoceptor antagonists act at both β1 and β2 subtypes, while some are selective for one or other subtype. For example, propranolol is an antagonist at both β1 and β2 receptors, while atenolol is relatively selective for β1 receptors. Note that selectivity of this kind is only relative; while a drug such as atenolol acts primarily on β1 receptors, at high enough concentrations it can also have effects on β2 receptors.


(d) Inverse agonists

An inverse agonist is a compound that binds to a receptor and produces a pharmacological response that is opposite to that of the corresponding agonist. An agonist increases the activity mediated by a receptor, an inverse agonist reduces it. In the presence of the agonist the inverse agonist acts as an antagonist. An ordinary antagonist can inhibit the actions of both agonists and inverse agonists.


1.2 Short-term and long-term effects of drugs at receptors

Drugs and endogenous substances have two types of pharmacological effects: short-term and long-term effects.


(a) Short-term effects

Many drugs are used for their short-term effects. For example, dopamine is used as a renal arteriolar vasodilator, diamorphine to relieve pain in the treatment of myocardial ischaemia, and nebulized salbutamol to reverse bronchoconstriction in the treatment of acute severe asthma. The receptors that are involved in the action of a range of receptors are listed in Table 4.


Table 4. Transduction systems for a range of receptors

Receptor

Transduction

5-hydroxytryptamine

(all except 5HT3)



Gi/o (5HT1A/1B/1D/1E/1F/5A); Gq/11 (5HT1C/2A/2B/1E/1F) ; Gq/11 (5HT4/6)

5HT3

Ionotropic (cationic Cys-loop)

Acetylcholine (muscarinic)

Gq/11 (M1/3/5); Gi/o (M2/4)

Acetylcholine (nicotinic)

Ionotropic (cationic Cys-loop)

Adenosine

Gi/o (A1/3); Gs (A2A/2B)

Adrenoceptors (α1)

Gq/11

Adrenoceptors (α2)

Gi/o

Adrenoceptors (β)

Gs

Angiotensin

Gq/11 (AT1); catalytic (tyrosine, serine, and threonine phosphatases; AT2)

Bradykinin

Gq/11

Calcitonin

Gs and Gq

Cannabinoid

Gi/o

Chemokines

Gi/o

Cholecystokinin

Gq/11 and Gs (CCK1); Gs (CCK2)

Corticosteroid (glucocorticoid and mineralocorticoid)

Nuclear

Corticotropin-releasing factor

Gs

Dopamine

Gi/o (D2/3/4); Gs, and Golf (D1)

Endothelin

Gq/11 and Gs (ETA); Gq/11 and Gi/o (ETB)

Estrogen

Nuclear; Gs (GPE)

GABAA

Ionotropic (anionic Cys-loop)

GABAB

Gi/o

Glucagon

Gs

Glutamate

Gq/11 (mGlu1/5); Gi/o (mGlu2/3/4/6/7/8);

ionotropic (subtypes AMPA, kainite, NMDA)



Glycine

Ionotropic (anionic Cys-loop)

Gonadotropin-releasing hormone

Gq/11

Histamine

Gq/11 (H1); Gs (H2); Gi/o (H3/4)

Insulin

Catalytic (tyrosine kinase)

Melatonin

Gi/o

Motilin

Gq/11

Natriuretic peptides

Catalytic (guanylyl cyclase)

Opioid

Gi/o

Oxytocin

Gq/11 and Gi/o

Parathyroid hormone

Gs and Gq/11

Peroxisome proliferator activated

Nuclear

Prolactin

Catalytic (tyrosine kinase)

Prostanoid

Gs (DP1, IP); Gi/o (DP2); Gq/11 (FP, TP)

Testosterone

Nuclear

Thyroid hormone

Nuclear

Toll-like

Catalytic (protein kinases)

Tumour necrosis factor

Catalytic (various)

Vasopressin

Gq/11 (V1A/1B); Gs (V2)

Vitamin D

Nuclear


i. Metabotropic receptors

Many agonist drugs acting on cell surface receptors known as G protein-coupled receptors (GPCRs; also called metabotropic receptors), and exert their effects through so-called second messenger systems. When a ligand binds to a GPCR a conformational change occurs, which allows the receptor to act as a guanine nucleotide exchange factor (GEF). It then activates an associated G protein by exchanging its bound GDP for a GTP. The α subunit of the G protein, together with the bound GTP, then dissociates from the β and γ subunits and has effects of intracellular signaling proteins or target functional proteins directly depending on the α subunit type. GS and Gi/o proteins activate adenylate cyclase and the production of cAMP; Gq11 activates phospholipase C. The second messengers involved are shown in Figure 2 and the subtypes of G protein through which different receptors act are listed in Table 4.







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